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P L E R A I N N R A T O U A L J www.perinataljournal.com The Official Publication of Perinatal Medicine Foundation, Turkish Perinatology Society and Turkish Society of Ultrasound in Obstetrics and Gynecology

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Volume 28 | Issue 1 | April 2020

Editor-in-Chief Advisory Board Cihat fien, Abdallah Adra, Beirut, Lebanon Mohammed Momtaz, Cairo, Egypt Perinatal Medicine Center, Arif Akflit, Eskiflehir, Turkey Giovanni Monni, Cagliari, Italy Taksim, Istanbul; Saadet Arsan, Ankara, Turkey Lütfü Öndero¤lu, Ankara, Turkey Ahmet Baschat, Baltimore, MD, USA Soner R. Öner, Izmir, Turkey Memorial Bahçelievler Hospital, Christoph Berg, Bonn, Germany Okan Özkaya, Isparta, Turkey Istanbul, Turkey Julene Carvalho, London, UK Halil Gürsoy Pala, ‹zmir, Turkey Rabih Chaoui, Berlin, Germany Alexander Papitashvilli, Tbilisi, Georgia Editors Frank Chervenak, New York, NY, USA Oiu Yan Pei, Shanghai, PRC Murat Yayla Filiz Çayan, Mersin, Turkey ‹brahim Polat, Istanbul, Turkey Nur Daniflmend, Istanbul, Turkey Clinics of Obstetrics & Ritsuko Pooh, Osaka, Japan Jan Deprest, Leuven, Belgium Ruben Quintero, Miami, FL, USA Joachim Dudenhausen, Berlin, Germany Gynecology, Ac›badem Nebojsa Radunovic, Belgrade, Serbia Alaa Ebrashy, Cairo, Egypt International Hospital, Guiseppe Rizzo, Rome, Italy Hakan Erenel, Istanbul, Turkey Istanbul, Turkey Stephen Robson, Newcastle, UK Sertaç Esin, Adana, Turkey Roberto Romero, Detroit, MI, USA Elif Gül Yapar Eyi, Ankara, Turkey Olufl Api Levent Salt›k, Istanbul, Turkey Ali Gedikbafl›, Istanbul, Turkey Perinatology Clinic, Haluk Sayman, Istanbul, Turkey Ulrich Gembruch, Bonn, Germany Mekin Sezik, Isparta, Turkey Istanbul American Hospital, Anne Greenough, London, UK Jiri Sonek, Dayton, OH, USA Istanbul, Turkey Gökhan Göynümer, Istanbul, Turkey Arif Güngören, Hatay, Turkey Milan Stanojevic, Zagreb, Croatia Melih A. Güven, Istanbul, Turkey Florin Stomatian, Cluj, Romania Joseph Haddad, Tours, France Turgay fiener, Eskiflehir, Turkey Oliver Kagan, Tübingen, Germany Alper Tanr›verdi, Ayd›n, Turkey Burçin Kavak, Elaz›¤, Turkey Ebru Tar›m, Adana, Turkey U¤ur Keskin, Ankara, Turkey Basky Thilaganathan, London, UK Asma Khalil, London, UK Ilan Timor-Tritsch, New York, NY, USA Esin Koç, Ankara, Turkey Liliana Voto, Buenos Aires, Argentina Simcha Yagel, Jerusalem, Israel Perinatal Journal is currently Özge Korkmaz, ‹stanbul, Turkey Selahattin Kumru, Antalya, Turkey Ahmet Yal›nkaya, Diyarbak›r, Turkey indexed in the following abstracting As›m Kurjak, Zagreb, Croatia Jun Yoshimatsu, Osaka, Japan and indexing services: TÜB‹TAK Nilgün Kültürsay, Izmir, Turkey Emre Zafer, Ayd›n, Turkey ULAKB‹M TR Index Health Sciences Narendra Malhotra, Agra, India Yaron Zalel, Tel Aviv, Israel Database, EBSCOhost, EBSCO Alexandra Matias, Porto, Portugal Ivica Zalud, Honolulu, HI, USA (Academic Search Complete), Names are in alphabetical order. For the institutional details of the Advisory Board Members please see Editorial and Google Scholar. Board link which is available under the Information tab on the home page (www.perinataljournal.com).

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Volume 28 | Issue 1 | April 2020 iii T A L J O A U N R I N R A E L P Contents

P L E R A Volume 28, Issue 1, April 2020 I N N R A U T A L J O www.perinataljournal.com

Original Article The determination of health practices and the sexual quality of life during the prenatal period 1 Prenatal dönemde sa¤l›k uygulamalar› ve cinsel yaflam kalitesinin belirlenmesi Nazife Bak›r, P›nar Irmak Vural, Cuma Demir Evaluation of fetal stress in preeclamptic patients 7 Preeklamptik hastalarda fetal stresin de¤erlendirilmesi Esra Can, Olufl Api The role of serum fasting plasma glucose in gestational diabetes screening 11 Gestasyonel diyabet taramas›nda serum açl›k plazma glukozunun yeri ‹lknur Çöl Madenda¤, Mefkure Eraslan fiahin, Yusuf Madenda¤ The association between obesity and hematologic inflammatory markers in the first trimester pregnancies 17 ‹lk trimester gebeliklerde obezite ve hematolojik inflamasyon belirteçleri aras›ndaki iliflki Feyza Nur ‹ncesu Çintesun The investigation of the correlation between diastasis recti and the second stage of labor 23 Diyastazis rekti ile do¤umun ikinci evresi aras›ndaki iliflkinin araflt›r›lmas› Ersin Çintesun, Meltem Aydo¤du, Çetin Çelik The assessment of the perinatal outcomes of the patients who underwent quad screening test 28 Dörtlü test yap›lan hastalar›n perinatal sonuçlar›n›n de¤erlendirilmesi Mehmet Mete K›rlang›ç, Gökhan Açmaz, Erdem fiahin, Yusuf Madenda¤, Fatma Özdemir, ‹ptisam ‹pek Müderris Preterm birth and periodontitis: a dilemma of current obstetrics 36 Preterm do¤um ve periodontit: Mevcut do¤um biliminde bir ikilem Didem Ekiz, fieyda Erflahan, Ali Ekiz, Nurcan Altafl, Burak Özköse, Zeynep Özköse Coombs test positivity in cord blood: early detection of risky newborns and the assessment of their follow-up results 42 Kord kan›nda Coombs testi pozitifli¤i: Riskli yenido¤anlar›n erken saptanmas› ve izlem sonuçlar›n›n de¤erlendirilmesi Ali Ulafl Tu¤cu, Faika Ceylan Çiftçi, Esra Aktepe Keskin

Case Report Isolated levocardia with situs inversus without cardiac abnormality in fetus: prenatal diagnosis and management 48 Kardiyak anomalisi olmayan fetüste situs inversuslu izole levokardi: Prenatal tan› ve yönetim Mucize Eriç Özdemir, Oya Demirci A rare complication developing after delivery: septic pelvic thromboembophlebitis 52 Do¤um sonras› geliﬂen ender bir komplikasyon: Septik pelvik tromboemboflebit Ersin Çintesun, Denizhan Bayramo¤lu, Emine Uysal, Çetin Çelik

iv Perinatal Journal A L J O A T U N R I N R A E L P Original Article

The determination of health practices and the sexual quality of life during the prenatal period

Nazife Bak›r1 İD , P›nar Irmak Vural2 İD , Cuma Demir1 İD 1Health School, Burdur Mehmet Akif Ersoy University, Burdur, Turkey 2Department of Nursing, Faculty of Health Sciences, ‹stanbul Medipol University, Istanbul, Turkey

Abstract Özet: Prenatal dönemde sa¤l›k uygulamalar› ve cinsel yaflam kalitesinin belirlenmesi Objective: The aim of this study is to determine health practices Amaç: Bu çal›flman›n amac› prenatal dönemdeki kad›nlar›n sa¤l›k and sexual quality of life of women during the prenatal period. uygulamalar› ve cinsel yaflam kalitesinin belirlenmesidir. Methods: The study was conducted with 312 pregnant women with- Yöntem: Haziran–Eylül 2019 aras›nda Akdeniz bölgesindeki bir out threatened preterm labor who admitted to the clinic of obstetrics devlet hastanesinde kad›n hastal›klar› ve do¤um poliklini¤ine bafl- and gynecology in a state hospital in the Mediterranean region vuran, erken do¤um tehdidi bulunmayan 312 gebe kad›nla yürü- between June and September 2019. The data were collected by the tüldü. Veri toplamada Tan›t›c› Özellikler Formu, Gebelikte Sa¤- Descriptive Features Form, the Health Practices in Pregnancy l›k Uygulamalar› Ölçe¤i ve Cinsel Yaflam Kalitesi Ölçe¤i–Kad›n Questionnaire and the Sexual Quality of Life–Female Questionnaire. Formu uyguland›. Results: It was found in the study that 93.6% of the pregnant women Bulgular: Araflt›rmada gebelerin %93.6’s›n›n evli oldu¤u, were married, 69.2% of them had planned pregnancy and 54.7% of %69.2’sinin gebeli¤inin planl› oldu¤u ve %54.7’sinin 4 defadan them underwent prenatal care for more than 4 times. The mean fazla do¤um öncesi bak›m ald›¤› saptand›. Gebelikte Sa¤l›k Uygu- scores of the Health Practices in Pregnancy Questionnaire and the lamalar› Ölçe¤i puan ortalamas› 87.55±5.49, Cinsel Yaflam Kalitesi Sexual Quality of Life–Female Questionnaire were 87.55±5.49 and Ölçe¤i–Kad›n Formu puan ortalamas› 63.88±5.95 idi. Genç yaflta 63.88±5.95, respectively. It was observed that the health practices of olan ve 4’ün üzerinde do¤um öncesi bak›m alan gebelerin sa¤l›k uy- the pregnant women who were younger and underwent prenatal care gulamalar›n›n daha iyi oldu¤u görüldü. Ayr›ca 2. ve 3. trimesterde- for more than 4 times were better. Also, it was found that the pregnant ki gebelerin, 1. trimesterdekilere göre daha yüksek puan ald›¤› sap- women in the 2nd and 3rd trimesters had higher scores than those in tand›. the 1st trimester. Sonuç: Çal›flmada gebelerin sa¤l›k uygulamalar› düflük, cinsel ya- Conclusion: The health practice levels of the pregnant women are flam kalitesi ise orta düzeydedir. low while the levels of sexual quality of life are moderate in the study. Keywords: Prenatal period, health practices, sexual life, nurse. Anahtar sözcükler: Prenatal dönem, sa¤l›k uygulamalar›, cinsel yaflam, hemflire.

Introduction natal and postnatal periods from the normal.[1] Pregnancy is a period in which women undergo many Approximately 3/4 of the maternal deaths is caused by [1,2] physiological changes and prioritized care should be the preventable gestational reasons. In this case, most provided. A great part of the reasons deteriorating the of these deaths can be prevented with a good prenatal maternal health is associated the with deviation of peri- care. Women should be informed about both the bodi-

Correspondence: Nazife Bak›r, MD. Health School, Burdur Mehmet Akif Ersoy University, Burdur, Turkey. e-mail: [email protected] / Received: December 13, 2019; Accepted: February 13, 2020 Please cite this article as: Bak›r N, Irmak Vural P, Demir C. The determination of health practices and the sexual quality of life during the prenatal period. Perinatal Journal 2020;28(1):1–6. doi:10.2399/prn.20.0281001

ORCID ID: N. Bak›r 0000-0003-1324-0647; P. Irmak Vural 0000-0002-8070-2840, C. Demir 0000-0003-3361-8547 Bak›r N, Irmak Vural P, Demir C

ly changes during pregnancy and prenatal tests and course is not harmful for fetus. It should be explained to examinations, and they should adopt health practices the couples that sexuality is not limited with the sexual during prenatal care. Nurses provide training and con- intercourse, but they may also express their intimacy to sultancy to pregnant women and their spouses and help each other by caressing, hugging, and kissing.[1] them to have a healthy baby by providing accurate and This study was planned to determine the health complete information to couples about the health prac- practices and sexual quality of life of women during pre- [1] tices that may affect pregnancy and labor. Prenatal natal period. health practices can be defined as the activities affecting gestational outcome and involving the health of preg- Methods nant woman, fetus and newborn. These practices include non-smoking, undergoing dental care, balanced The study type diet and proper weight gain, not consuming alcohol and This is a descriptive and cross-sectional study. illegal substances, having training about pregnancy and Study population and sample labor, regular exercising, and avoiding risky sexual behaviors or exposure to other infection agents.[3] The study population comprised of all pregnant women without threatened preterm labor who admit- During prenatal period, sexual desires and sexual ted to the outpatient clinic of obstetrics and gynecolo- intercourse frequency vary depending on the gestation- gy in a state hospital in the Mediterranean region. The al period. Nausea, vomiting, fatigue, sleeping orienta- study sample comprised of 312 pregnant women with- tion, bodily changes, breast pain, tenderness and fre- out threatened preterm labor who admitted to the out- quent urination usually lead to the reduced sex drive in patient clinic of obstetrics and gynecology between the first trimester. The complaints start to decrease in June and September 2019 and accepted to participate the second trimester, and pelvic congestion increases. in the study. The pregnant women who accepted to The sexual desires increase in mother who adapts to participate in the study were included in the research pregnancy. The growing fetus and physical complaints by the improbable randomized sampling method. in the last trimester may cause sex drive to reduce. As the labor date approaches, the fear of having pain during Data collection labor, infection fear and the perceptions about experi- In order to collect the data of the pregnant women, the encing abnormal conditions during sexual intercourse [1] descriptive features form, “The Health Practices in may have an impact on the sexual life of the couples. Pregnancy Questionnaire” and “The Sexual Quality of The reasons such as the sex perception of the couples, Life–Female Questionnaire” were used. The pregnant cultural norms, lack of information, the idea of parent- women who were literate and had no problem with hood, negative thoughts about sex and the thought that Turkish language were included in the study while the baby may get hurt can have a negative impact on the sex- [4] pregnant women with the threatened preterm labor ual life during pregnancy. Unlike the myths, fetus does were excluded. not suffer from the sexual intercourse if the hygienic conditions are good and there are no conditions such as Descriptive Features Form placenta previa or premature rupture of membranes. The form created by the researchers includes 15 ques- Mucoid plaque which provides protection against infections collecting the socio-demographic and obstetric tions and amniotic sac which acts like an air bag prevents characteristics of the pregnant women. fetal trauma. In addition, the increased blood flow during sexual intercourse and elevation in the hormones The Health Practices in Pregnancy Questionnaire during and after the orgasm affect fetal health positive- (HPPQ) ly.[5,6] Nurses should inform couples during the prenatal It was developed by Lindgren[3] in 2005, and its follow-ups on their concerns about sex and encourage Turkish validity and reliability analysis was done by them to discuss it. They should encourage women to Er[7] in 2006. Turkish validity and reliability form of share their concerns with their spouses by initiating a the questionnaire has 33 items. The items between 1 safe communication, and tell them that sexual inter- and 16 comprise of responses in the 5-point Likert

2 Perinatal Journal The determination of health practices and the sexual quality of life during the prenatal period

type varying between “never, rarely, occasionally, fre- level of income. It was found that 69.2% of the cases quently, always”. For the questions between items 17 were planned pregnancies, half of the pregnant women and 33, appropriate answers scored between 1 and 5 were in the 2nd trimester and 54.7% of them underwent were provided. The total score is calculated by the sum prenatal care for more than 4 times (Table 1). of all items. The score range of the questionnaire is The mean scores of HPPQ and SQOL–F are given 33–165. Higher scores indicate that health practices in the Table 2, which are 87.55±5.49 and 63.88±5.95, are good. Cronbach’s alpha coefficient was found 0.74 respectively. in the validity analysis of the questionnaire.[7] In our study, Cronbach’s alpha coefficient was 0.71. Table 1. The distribution of the pregnant women according to the descriptive features. The Sexual Quality of Life–Female Questionnaire

(SQOL–F) Descriptive features (N=312) n % [8] It was developed by Symonds et al. in 2005 for the eval- Age 18–24 70 22.4 uation of sexual quality of life. Turkish validity and reli- 25–31 66 21.2 ability analysis of the questionnaire was done by Tu¤ut 32–38 157 50.3 39 and above 19 6.1 and Gölbaﬂ› in 2010. It was reported that the reliability Education level Primary education and below 172 55.1 coefficient of the total item score of SQOL–F was Secondary education 106 34.0 r=0.32–0.67, and Cronbach’s alpha coefficient was 0.83. University and above 34 10.9 Tu¤ut and Gölbaﬂ›[9] used a scoring system between 1 Place of residence City 55 17.6 and 6 in their study. In this scoring system, the minimum County 164 52.6 Village 93 29.8 score is 18 and the highest score is 108. In order to con- Marital status Married 292 93.6 vert the questionnaire score into 100, the following for- Single 20 6.4 mula is used: (raw score obtained in the questionnaire – Income level High 68 21.8 18) × 100/90. As the score obtained in the questionnaire Moderate 176 56.4 Low 68 21.8 increases, the sexual quality of life increases as well. In Pregnancy type Planned pregnancy 216 69.2 our study, Cronbach’s alpha coefficient was 0.77. Unplanned pregnancy 96 30.8 Month of gestation 1, 2, 3 months 48 15.4 Statistical analysis 4, 5, 6 months 156 50.0 The data of the study were analyzed by SPSS 20.0 (SPSS 7, 8, 9 months 108 34.6 Inc., Chicago, IL, USA) and percentage, frequency, Number of pregnancy 1 105 33.7 2 101 32.4 one-way ANOVA and independent groups t-test were 3 82 26.3 used. The significance level was considered p<0.05. 4 and more 24 7.7 Number of children None 105 33.7 The ethics aspect of the study 1–2 183 58.7 3–4 24 7.6 The ethical approval of the study was obtained from the Number of Less than 4 times 84 27.0 Non-Invasive Clinical Researches Ethics Committee of prenatal care 4 times 57 18.3 ‹stanbul Medipol University (Ethics Committee approval More than 4 times 171 54.7 no. 10840098-604.01.01-E.19312). The study was con- The history of sexually Yes 18 5.8 ducted in accordance with the Declaration of Helsinki, transmitted disease No 294 94.2 and written and verbal consents of the cases were received.

Table 2. The mean scores of the Health Practices in Pregnancy Questi- Results onnaire (HPPQ) and the Sexual Quality of Life–Female Questi- In our study, we found that 50.3% of the cases were onnaire (SQOL–F). between 32 and 38 years old, the educational level of Questionnaires Minimum Maximum Mean SD 55.1% of them were primary school or below, and 52.6% of them were living in the county. Of the pregnant HPPQ 74.00 116.00 87.55 5.49 women, 93.6% were married, and 56.4% had a moderate SQOL–F 43.33 80.00 63.88 5.95

Volume 28 | Issue 1 | April 2020 3 Bak›r N, Irmak Vural P, Demir C

Table 3. The comparison of the scores of the Health Practices in Pregnancy Questionnaire and the Sexual Quality of Life–Female Questionnaire according to the descriptive features of the pregnant women.

HPPQ SQOL–F Descriptive features (N=312) n Mean±SD Mean±SD

Age* 18–24 a 70 90.20±7.01 63.96±5.51 25–31 b 66 87.74±5.03 62.86±6.64 32–38 c 157 88.14±5.29 64.11±6.02 39 and above d 19 88.00±5.28 65.20±4.09 Test statistics 2.703 1.044 p-value 0.046 0.373 Significant difference a>b,c,d Education level* Primary education and below 172 87.11±5.10 63.35±5.60 Secondary education 106 88.14±6.20 64.31±6.57 University and above 34 87.91±4.93 65.22±5.50 Test statistics 1.122 1.841 p-value 0.295 0.190 Place of residence* City 55 87.21±5.56 64.30±5.57 County 164 87.81±5.12 63.81±5.75 Village 93 87.27±6.02 63.76±6.55 Test statistics 0.406 0.165 p-value 0.667 0.848 Marital status† Married 292 87.55±5.42 75.46±5.47 Single 20 87.45±6.53 76.00±3.44 Test statistics 2.701 4.071 p-value 0.932 0.665 Income level* High 68 88.01±5.56 64.44±5.84 Moderate 176 88.68±5.92 63.68±5.97 Low 68 88.55±5.54 63.83±6.08 Test statistics 0.336 0.397 p-value 0.715 0.363 Pregnancy type† Planned pregnancy 216 87.54±5.59 75.33±5.42 Unplanned pregnancy 96 87.56±5.28 75.86±5.22 Test statistics 0.022 1.659 p-value 0.981 0.420 Month of gestation* 1, 2, 3 months a 48 88.22±5.53 73.68±4.89 4, 5, 6 months b 156 87.22±5.50 75.97±5.34 7, 8, 9 months c 108 87.72±5.47 75.61±5.46 Test statistics 0.693 3.426 p-value 0.501 0.034 Significant difference b,c>a Number of pregnancy* 1 105 88.51±5.87 63.70±5.92 2 101 86.52±5.07 63.55±6.21 3 82 87.43±5.46 64.21±6.16 4 and more 24 88.04±5.08 64.95±4.17 Test statistics 2.358 0.475 p-value 0.072 0.700 Number of children* None 105 88.51±5.87 63.70±5.92 1–2 183 86.93±5.25 63.84±6.18 3–4 24 88.04±5.08 64.95±4.17 Test statistics 2.900 0.436 p-value 0.057 0.647 Number of prenatal care* Less than 4 times a 84 88.81±5.03 77.03±5.89 4 times b 57 88.52±4.08 76.24±5.94 More than 4 times c 171 91.54±6.20 76.00±5.53 Test statistics 10.298 1.685 p-value 0.000 0.153 Significant difference c>a,b The history of sexually Evet 18 87.88±3.34 77.55±3.88 transmitted disease† Hay›r 294 88.55±5.87 75.37±5.42 Test statistics 5.045 1.988 p-value 0.637 0.093

*One-way ANOVA, †Independent groups t-test. HPPQ: The Health Practices in Pregnancy Questionnaire; SQOL–F: The Sexual Quality of Life–Female Questionnaire.

4 Perinatal Journal The determination of health practices and the sexual quality of life during the prenatal period

In the Table 3, HPPQ and SQOL–F scores were found that the mean SQOL–F score of the pregnant compared according to the descriptive features of the women was 81.59±15.95. We found that the mean pregnant women. Accordingly, mean HPPQ scores of SQOL–F scores reported in the study of K›r›kkale and the pregnant women in the age group of 18–24 are high- two other international studies were higher than the er than the other age groups in a statistically significant mean score of our study.[9,15] Considering that the maxi- way. Also, mean HPPQ scores of the pregnant women mum score one can get in SQOL–F is 100, the score of who underwent prenatal care for more than 4 times are the sexual quality of life of the pregnant women includ- higher than the other groups in a statistically significant ed in our study is 63.88±5.95, which is a moderate level. way. Mean SQOL–F scores of the pregnant women who Hormonal, anatomical and physiological changes are in the 2nd and 3rd trimesters are higher than those may appear as the factors affecting the sexual quality of in the 1st trimester which is statistically significant. life in pregnancy negatively. In accordance with these factors, sexual responses may change compared to the [14] Discussion pregnancy period. Kodaz found in their study that the pregnant women had problems in their sexual lives due In our study, the mean score of the Health Practices in to the physical discomforts and physical changes in half Pregnancy Questionnaire (HPPQ) was 87.55±5.49. The of the cases, nausea and vomiting in nearly half of the mean HPPQ score was 114.43±17.90 in the study of Sis [10] cases, galactorrhea and tenderness in one third of the Çelik and Aksoy, 111.76±18.53 in the study of Özcan [11] cases, religious or cultural thoughts in one seventh of the and K›z›lkaya Beji, and 112.64±13.87 in the study of Çap›k et al.[12] The lowest score that a respondent can get cases and negative reactions of the spouses of the preg- is 33 while the highest score is 165 in HPPQ. nant women, and the frequency of sexual intercourse decreased during pregnancy and therefore their sexual Accordingly, the level of health practices of the pregnant [16] women is low in our study. quality of life was affected negatively. Similarly, Galazka et al. reported that the frequency of sexual We found in our study that the mean HPPQ scores intercourse and sexual activities decreased during preg- of the pregnant women in the age group of 18–24 were nancy the lack of sexual drive increased, and that primi- higher than the other age groups. Similarly, Özcan and [11] parous pregnant women experienced changes in sexual K›z›lkaya Beji found in their study that the mean arousal, vaginal lubrication and orgasm especially in the HPPQ scores of the pregnant women in the age group third trimester.[17] Another study reported sexual desire of 15–24 were higher than those of the pregnant women disorder in 88.9% of the pregnant women, sexual arous- with advanced ages. In the study of Sis Çelik and [10] al disorder in 86.9% of them, vaginal dryness in 42.8% Aksoy, the authors found that the mean HPPQ scores of them, orgasm disorder in 69.6% of them and sexual of the pregnant women in the age group of 25–34 were [18] higher than those in the other age groups. They believed satisfaction disorder in 48% of them. In our study, we that young age group obtained information by looking found that the mean SQOL–F scores of the pregnant up information about health practices in pregnancy. women who were in the 1st trimester were significantly lower than the mean SQOL–F scores of the pregnant Medical checks are the necessary practices from the women who were in the 2nd and 3rd trimesters. beginning of pregnancy up to the labor for mother and newborn health. The indication of the sufficiency of prenatal care is the number of prenatal visits.[11,13] In our Conclusion study, the mean HPPQ scores of the pregnant women In our study, the level of health practices in pregnancy is who underwent prenatal care for more than 4 times low and the level of sexual quality of life is moderate. were higher than the mean scores of those who under- Also, the health practices of the pregnant women who are went prenatal care for 4 times or less. Sis Çelik and young and underwent prenatal care for more than 4 times [10] Aksoy found in their study that the mean HPPQ are better. In terms the sexual quality of life, the scores of scores of the pregnant women who underwent prenatal the pregnant women in the 2nd and 3rd trimesters are care for more than 4 times were significantly higher. higher than the scores of those in the 1st trimester. In our study, the mean SQOL–F score of the pregnant women was 63.88±5.95. In their study, K›r›kkale[14] Conflicts of Interest: No conflicts declared.

Volume 28 | Issue 1 | April 2020 5 Bak›r N, Irmak Vural P, Demir C

References 10. Sis Çelik A, Aksoy DY. Gebelerin öz bak›m gücü ile sa¤l›k uygulamalar› düzeylerinin ve etkileyen faktörlerin belirlen- 1. K›z›lkaya Beji N, Diflsiz M. Gebelik ve hemflirelik yaklafl›m›. mesi. Gümüflhane Üniversitesi Sa¤l›k Bilimleri Dergisi 2019;8: In: K›z›lkaya Beji N, editor. Kad›n sa¤l›¤› ve hastal›klar›. 2nd 111–9. ed. ‹stanbul: Nobel T›p Kitabevleri; 2016. p. 250–97. 11. Özcan H, K›z›lkaya Beji N. Health practices of pregnant 2. Türkiye Ulusal Anne Ölümleri Çal›flmas›. 2005 [Internet] women in Gumushane City Center. Perinatal Journal 2015;23: Eriflim: http://www.hips.hacettepe.edu.tr/uaop_ankara/ozet_ 13–9. rapor.pdf 12. Çap›k A, Sakar T, Ejder Apay S. Gebelikte sa¤l›k uygulamala- 3. Lindgren K. Testing the health practices in pregnancy ques- r› ile duygusal zeka aras›ndaki iliflki. Uluslararas› Hakemli tionnaire-II. J Obstet Gynecol Neonatal Nurs 2005;34:465– Hemflirelik Araflt›rmalar› Dergisi 2016;6:75–88. 72. 13. Turan T, Ceylan S, Teyikçi S. Annelerin düzenli prenetal ba- 4. Gürkan ÖC. Gebelik döneminde cinsellik nas›l etkileniyor? k›m alma durumlar› ve etkileyen faktörler. F›rat Sa¤l›k Hiz- Androloji Bülteni 2007;28:80–5. metleri Dergisi 2008;3:157–73. 5. Quilliam S. Sex during pregnancy: yes, yes, yes! J Fam Plann 14. K›r›kkaleli Z. Gebelerin cinsel yaflam kalitesi ve etkileyen fak- Reprod Health Care 2010;36:97–8. törler. MSc thesis, Yak›n Do¤u Üniversitesi Sa¤l›k Bilimleri Enstitüsü, Lefkofla, KKTC, 2015. 6. Gibbs RS, Karlan BY, Haney AF, Nygaard I. Danforth’s 15. Maasoumi R, Lamyian M, Montazeri A, Azin SA, Aguilar- obstetrik ve jinekoloji (Ayhan A, Trsl.) 10th ed. Ankara: Günefl Vafaie ME, Hajizadeh E. The sexual quality of life-female T›p Kitabevleri; 2010. p. 1–758. (SQOL-F) questionnaire: translation and psychometric prop- 7. Er S. Gebelikte sa¤l›k uygulamalar› ölçe¤i Türkçe formunun erties of the Iranian version. Reprod Health 2013;10:1–6. geçerlik ve güvenirlik çal›flmas›. MSc thesis, Ege Üniversitesi 16. Kodaz ND. Gebelikte cinsel yaflam kalitesi ve iliflkili faktörler. Sa¤l›k Bilimleri Enstitüsü, ‹zmir, 2006. MSc thesis, Selçuk Üniversitesi Sa¤l›k Bilimleri Enstitüsü, 8. Symonds T, Boolell M, Quirk F. Development of question- Konya, 2013. naire on sexual quality of life in women. J Sex Marital Ther 17. Galazka I, Drosdzol-Cop A, Naworska B, Czajkowska M, 2005;31:385–97. Skrzypulec-Plinta V. Changes in the sexual function during 9. Tu¤ut N, Gölbafl› Z. Cinsel yaflam kalitesi ölçe¤i – Kad›n pregnancy. J Sex Med 2015;12:445–54. Türkçe versiyonunun geçerlik ve güvenirlik çal›flmas›. Cum- 18. Tosun Gülero¤lu F, Gördeles Befler N. Evaluation of sexual huriyet T›p Dergisi 2010;32:172–80. functions of the pregnant women. J Sex Med 2014;11:146–53.

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6 Perinatal Journal A L J O A T U N R I N R A E L P Original Article

Evaluation of fetal stress in preeclamptic patients

Esra Can1 İD , Oluﬂ Api2 İD 1Department of Gynecology and Obstetrics, Kanuni Sultan Süleyman Training and Research Hospital, Istanbul, Turkey 2Department of Gynecology and Obstetrics, American Hospital, Istanbul, Turkey

Abstract Özet: Preeklamptik hastalarda fetal stresin de¤erlendirilmesi Objective: Previous studies have established the association between Amaç: Daha önceki çal›flmalar, stres belirteçleri olarak bilinen art- preeclampsia (PE)-induced stress on fetus and elevated 17-hydrox- m›fl 17-hidroksiprogesteron seviyeleri (17-OHP) ile fetüsteki pre- yprogesterone levels (17-OHP) of which known as a stress markers. eklampsiye (PE) ba¤l› stres aras›ndaki iliflkiyi ortaya koymufltur. The aim of our study was to evaluate the relationship between these Çal›flmam›z›n amac›, kordon kan›yla analiz edilen bu belirteçler ile markers that were analyzed via cord blood with the severity of PE. preeklampsi fliddeti aras›ndaki iliflkiyi de¤erlendirmekti. Methods: Consecutive PE women who were admitted to Dr. Lütfi Yöntem: A¤ustos 2009 ile Aral›k 2009 tarihleri aras›nda Dr. Lüt- K›rdar Training and Research Hospital Obstetrics and Gynecology fi K›rdar E¤itim ve Araflt›rma Hastanesi Kad›n Hastal›klar› ve Do- Clinics from August 2009 to December 2009 were recruited. ¤um Klini¤ine baflvuran ard›fl›k preeklampsi olgular› çal›flmaya da- Uncomplicated pregnant women admitted at the same period con- hil edildi. Ayn› dönemde baflvuran komplikasyonsuz gebeler ise sisted the control group. Umbilical blood samples were collected kontrol grubunu oluflturdu. Do¤umun hemen ard›ndan umbilikal from umbilical artery immediately after birth and 17-OHP analyzed. arterden umbilikal kan örnekleri al›nd› ve 17-OHP analiz edildi. Results: The study group consisted of 40 mild PE (n=12) and severe Bulgular: Çal›flma grubu 40 hafif PE (n=12) ve fliddetli PE (n=28) ol- PE patients (n=28) and the control group consisted of 35 patients. gular›ndan, kontrol grubu ise 35 hastadan oluflmaktayd›. Maternal Maternal age and body mass index were similar between the study yafl ve vücut kitle indeksi de¤erleri çal›flma gruplar› aras›nda benzer- groups, but the fetuses in the severe PE group had a smaller mean di, ancak fliddetli PE grubundaki fetüsler daha küçük ortalama ges- gestational age and mean birth weight (p=0.001). Umbilical cord 17- tasyonel yafla ve ortalama do¤um a¤›rl›¤›na sahipti (p=0.001). Umbi- OHP levels were statistically significantly lower in the severe PE likal kordon 17-OHP seviyeleri kontrol grubuna k›yasla fliddetli PE patients than the controls [Control group=12.5±4.6 (n=35); mild hastalar›nda istatistiksel olarak anlaml› flekilde daha düflüktü [Kontrol PE=10.3±6 (n=12, p=0.24), severe PE=9.6±5.2 (n=28, p=0.019)]. grubu=12.5±4.6 (n=35); hafif PE=10.3±6 (n=12, p=0.24), fliddetli Although the patients with mild PE had lower 17-OHP levels, they PE=9.6±5.2 (n=28, p=0.019)]. Hafif PE hastalar›nda 17-OHP seviye- were not statistically significant (p=0.827). leri daha düflük olsa da istatistiksel olarak anlaml› de¤ildi (p=0.827). Conclusion: In our study, it is found that there is no association Sonuç: Çal›flmam›zda, PE fliddeti ile kordon kan› 17-OHP seviye- between PE severity and the cord blood levels of 17-OHP. The effect leri aras›nda hiçbir iliflki bulmad›k. Feto-maternal komplikasyonlar› of early intervention that prevent feto-maternal complications may önleyen erken müdahale etkisi, daha önceki çal›flmalarda preek- lead to normal or low levels of these markers of which was found lamptik hastalar›n kordon kan›nda artt›¤› tespit edilen bu belirteçle- increased in cord blood of preeclamptic patients in previous studies. rin normal veya düflük seviyelere sahip olmas›n› sa¤layabilir. Keywords: Preeclampsia, umbilical cord, chronic fetal stress, stress Anahtar sözcükler: Preeklampsi, umbilikal kordon, kronik fetal markers. stres, stres belirteçleri.

Introduction mother is commonly associated with increased endovas- Preeclampsia is associated with placental oxidative stress, cular dysfunction, cardiovascular mortality and morbidi- which in turn is associated with maternal and indirect ty, and as the severity increases, it affects the broad spec- fetal damage at different levels.[1–4] The effect on the trum to the extent of common organ damage.[5–8] The

Correspondence: Esra Can, MD. Department of Gynecology and Obstetrics, Kanuni Sultan Süleyman Training and Research Hospital, Istanbul, Turkey. e-mail: [email protected] / Received: December 23, 2019; Accepted: February 17, 2020 Please cite this article as: Can E, Api O. Evaluation of fetal stress in preeclamptic patients. Perinatal Journal 2020;28(1):7–10. doi:10.2399/prn.20.0281002

ORCID ID: E. Can 0000-0001-7851-4026; O. Api 0000-0003-1700-8589 Can E, Api O

main effect on the fetus is inadequate nutrition, a conse- Practice Guide was assessed on the basis of the Korotkoff quence of uteroplacental vascular insufficiency, resulting 1st auscultation sound, and the diastolic blood pressure in growth restriction. These low weight babies not only was assessed on the basis of the Korotkoff 5th ausculta- have acute problems, but also lead to long-term negative tion sound. [9,10] consequences, such as future cardiovascular risks. The After resting for 10 minutes, the pregnant women early recognition of fetal stress caused by preeclampsia who had high blood pressure were taken to rest and and therefore the prevention of perinatal mortality and blood pressure was measured again after 6 hours and the morbidity has been the main goal of many clinical trials. pregnant women with blood pressure of 140/90 mmHg For all these reasons, markers have been found to be able or more were accepted as hypertensive and in the spot to detect preeclampsia-related fetal lethargy severity or to urine analysis, 1+ and over-determined pregnancies were be able to recognize beforehand without severe damage. included in the study with the diagnosis of preeclampsia. Despite the many studies conducted so far, markers with high sensitivity and specificity, which can still predict the All severe preeclamptic pregnancies received eclamp- development of the disease, have not been identified. sia prophylaxis treatment with magnesium sulphate [12] The earliest studies that could lead to fetal distress according to the Parkland protocol. The criteria spec- have been tried to make early diagnosis by using ified in the ACOG 2002 Clinical Practice Guideline machine-based methods such as ultrasonography and were used to determine mild and severe preeclampsia cardiotocography, from the physical examination that can cases. Similarly, for the control group, healthy pregnan- measure the rudimentary indication of fetal growth, such cies were applied during the same gestational week. as the measurement of the uterine fundus and the abdom- The exclusion criteria are defined as follows: inal circumference of each antenatal visit. Besides, many • Chronic hypertension, diabetes mellitus, antiphos- studies have used stress hormones and some biochemical pholipid antibody syndrome, liver or kidney dis- markers released to uteroplacental hypoperfusion. The ease, previous thromboembolic syndrome and most common of these biochemical markers is hormone- thrombophilia, multiple pregnancy, based, and 17-hydroxyprogesterone (17-OHP) levels, • Fetal congenital malformation, chromosome which is the pioneer of the cortisol pathway, are thought anomalies, intrauterine infection [11] to be used as an intrauterine stress indicator. • Patients with a known disease that affects the In this study, we aimed to determine whether the platelet count and liver enzymes. effect of preeclampsia on umbilical cord blood of fetuses A detailed history of all cases included in the study born from preeclamptic mothers is correlated with 17- was taken and obstetric information was recorded. OHP levels, which were previously reported as fetal When patients were admitted to the hospital, full stress marker, and to investigate whether there is a rela- blood count, biochemical analysis, stool urine test were tionship between the levels of these marker and severity performed. Umbilical blood samples were taken from of preeclampsia. the umbilical artery immediately after the umbilical artery was clamped during delivery. The samples were Methods centrifuged at 2500×g for 10 minutes. Serum and plas- The study protocol was approved by the local ethics comma samples were separated and frozen and then stored mittee and informed consent was obtained from each at -80 °C. The samples were studied at Dr. Lütfi participating patient. Pregnancies complicated by K›rdar Kartal Training and Research Hospital preeclampsia are defined as having at least two separate Biochemistry Laboratory. Dissemination preparation measurements of systolic blood pressure ≥140/90 mmHg was prepared from the cord blood and the preparations and diastolic blood pressure ≥90 mmHg and presence of were evaluated in Hematology Lab. 17-OH proges- proteinuria (>300 mg / 24 h or ++ over the spot urine terone was studied with Enzyme-linked immunosor- assay). The systolic pressure measured at the sitting posi- bent assay performed manually and EL×50 was meas- tion following a 10 minute or more rest period as ured with a washing device using an EL×800 described in the blood pressure ACOG 2002 Clinical microplate reader.

8 Perinatal Journal Evaluation of fetal stress in preeclamptic patients

Statistical analysis Table 1. Demographic characteristics of patients in study and control groups. For the statistical evaluation of the data, the numerical data obtained from the events were coded and trans- Control Mild PE Severe PE ferred to the computer program. Descriptive and analyt- (n=35) (n=12) (n=28) p-value ical statistics were performed using The Statistical Age (year) 27.1±6.2 29.8±5.7 26.8±5.3 0.206 Package for Social Sciences (SPSS) 16.0 (SPSS Inc., Gestastional age (month) 38.5±1.8 37.8±1.4 37.7±3.7 0.2 Chicago, IL, USA). Birth weight (g) 3243±551 2805±458 2215±833 0.001

2 The normal distribution of the parameters of the Mother BMI (kg/cm ) 28.3±3 29±3.4 30.1±3.9 0.08 groups was assessed by the Kolmogorov-Smirnov test. BMI: body mass index; PE: preeclampsia. All values are expressed as mean ± standard deviation (SD). The significance of the difference between the numerical variables in the three groups was assessed by the Kruskal-Wallis test. In the case of a significant differ- Discussion ence between the groups in the Kruskal-Wallis test, the In our study, it is found that there is no association Mann-Whitney U test was applied in the bilateral com- between PE severity and the cord blood 17-OHP levels. parisons between the groups in order to test where the In contrast to other studies, there was no statistically sig- difference originated. A statistical significance level of nificant difference between control group and p<0.05 was accepted as the threshold value. preeclampsia group in terms of 17-OHP values used as chronic stress indicator. Moreover, our study, as Results opposed to other studies, showed lower 17-OHP levels when compared to the control group with severe During the study period, all preeclamptic pregnant preeclampsia. Preeclampsia is a complex disease affect- women (n=40) and noncomplicated pregnant women ing 3–4% of all pregnancies and causing maternal mor- (n=35) were taken to our clinic. The study group was tality to more than per year in general. Screening tests divided into 2 subgroups as mild preeclamptic group (commonly used, which are simple, non-invasive, fast (n=12) and severe preeclamptic group (n=28). results, cheap, high sensitivity and predictive value) are A total of 75 patients were included in the study ideal for predicting such a high risk clinical condition, group; 35 (46.6%) of these patients were control group, ideal for minimizing mortality and morbidity. The phys- 12 (16%) were mild PE group and 28 (37.3%) were iological role of 17-OHP, one of the stress markers we severe PE group. Table 1 shows the comparison of use in our study and is a precursor molecule in the path- maternal age, gestational age at birth, maternal birth way of cortisol synthesis, has been clearly shown. weight and maternal BMI (body mass index) values in the Cortisol releasing hormone, cortisol and dehy- study and control group. droepiandrosterone sulfate levels were found to be sig- When the study and control groups were examined, nificantly higher in the cord blood of infants of no statistically significant difference was observed preeclamptic mothers examined in the literature than in between those groups in terms of mean maternal age, healthy infants.[13,14] BMI and gestational age. Birth weights were significant- Umbilical cord blood 17-OHP levels were investi- ly different between the groups (p=0.001 for both gated in our study and unlike the expectation, no signif- groups). The mean birth weights of babies born from icant difference was found in the preeclamptic group. severe preeclamptic pregnancies were significantly lower On the contrary, the numerically lowest values were than the other groups. found in the heavily eclamptic group. In a study of Ersch The mean 17-OHP levels of the umbilical cord are given in Table 2. Umbilical cord 17-OHP levels were Table 2. Umbilical cord 17-OHP levels. found to be lower in mild preeclampsia than controls, but this difference was significantly lower in severe PE Variable Control (n=35) Mild PE (n=12) Severe PE (n=28) compared to controls, while the difference did not reach 17-OHP (pg/ml) 12.59±4.65 10.3±6.05 9.6±5.24* statistical significance. *p<0.05 severe PE vs control. 17-OHP: 17 hidroxyprogesterone; PE: preeclampsia.

Volume 28 | Issue 1 | April 2020 9 Can E, Api O

et al., in premature infants due to preeclampsia and sia. American College of Obstetricians and Gynecologists. Int J amniotic fluid infection, there was no change in fetal pH, Gynaecol Obstet 2002;77:67–75. Apgar score and baseline as an indicator of acute stress. 3. Redman CW, Sargent IL. Latest advances in understanding However, 17-OHP levels and birth weight which are preeclampsia. Science 2005;308:1592–4. used as chronic stress markers were markedly elevated. 4. Roberts JM, Redman CW. Preeclampsia: more than pregnan- In the upper zone of the reference range for 17-OHP, cy-induced hypertension. Lancet 1993;341:1447–51. [11] preeclamptic mothers’ infants were included. It is 5. Barker DJ. Fetal origins of cardiovascular disease. Ann Med interpreted that 17-OHP may be used as a chronic stress 1999;31 Suppl 1:3–6. indicator because it is thought that cortisol level may be 6. Roberts JM, Pearson GD, Cutler JA, Lindheimer MD; affected by many factors which are an acute marker. The National Heart Lung and Blood Institute. Summary of the uncertainty of the reference range of the 17-OHP level NHLBI Working Group on Research on Hypertension clearly indicates the changes in fetal immature weight During Pregnancy. Hypertens Pregnancy 2003;22:109–27. and low birth weight at 17-OHP level is unknown. The 7. Consensus Report: National High Blood Pressure Education authors also argued that the 17-OHP level could be used Program Working Group Report on high blood pressure in as a chronic stressor, and that pregnant woman who had pregnancy. Am J Obstet Gynecol 1990;163:1689–1712. an amniotic fluid infection, an acute stress, could be used 8. Levine RJ, Ewell MG, Hauth JC, Curet LB, Catalano PM, as a comparative group. Our study was a comparison of Morris CD, et al.. Should the definition of preeclampsia 17-OHP levels with preeclampsia severity and it is a include a rise in diastolic blood pressure of 15 mm Hg to a level comparison of two chronic stress groups (severe and 90 mm Hg in association with proteinuria? Am J Obstet mild PE) with the control group rather than acute and Gynecol 2000;183:787–92. chronic stress. Our work cannot be identified as a stres- 9. Carr H, Cnattingius S, Granath F, Ludvigsson JF, Edstedt sor, because it is unclear how 17-OHP levels detected by Bonamy AK. Preterm birth and risk of heart failure up to early fetal cord blood are affected by maternal and placental adulthood. J Am Coll Cardiol 2017;69:2634–42. and fetal cortisol levels and how the feto-maternal adap- 10. Kuhle S, Maguire B, Ata N, MacInnis N, Dodds L. Birth tation process will respond. weight for gestational age, anthropometric measures, and cardiovascular disease markers in children. J Pediatr 2017;182:99– Conclusion 106. There was no correlation between cord blood 17-OHP 11. Ersch J, Beinder E, Stallmach T, Bucher HU, Torresani T. 17-Hydroxyprogesterone in premature infants as a marker of levels and preeclampsia severity. However, it can be intrauterine stress. J Perinat Med 2008;36:157–60. assumed that early intervention applied to preeclamptic pregnancies may have removed the chronic stress 12. Luger R, Arnold J. Pregnancy, hypertension. 2017 May 3. that may arise in the fetus. StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2017 Jun 3. Conflicts of Interest: No conflicts declared. 13. Giles WB, McLean M, Davies JJ, Smith R. Abnormal umbilical artery Doppler waveforms and cord blood corticotropin- References releasing hormone. Obstet Gynecol 1996;87:107–11. 1. Duley L. Pre-eclampsia and the hypertensive disorders of 14. Goland RS, Tropper PJ, Warren WB, Stark RI, Jozak SM, pregnancy. Br Med Bull 2003;67:161–76. Conwell IM. Concentrations of corticotrophin-releasing hor- 2. ACOG Committee on Obstetric Practice. ACOG practice bul- mone in the umbilical-cord blood of pregnancies complicated letin. Diagnosis and management of preeclampsia and eclamp- by pre-eclampsia. Reprod Fertil Dev 1995;7:1227–30.

10 Perinatal Journal A L J O A T U N R I N R A E L P Original Article

The role of serum fasting plasma glucose in gestational diabetes screening

‹lknur Çöl Madenda¤1 İD , Mefkure Eraslan ﬁahin1 İD , Yusuf Madenda¤2 İD 1Clinics of Gynecology and Obstetrics, Kayseri City Hospital, Kayseri, Turkey 2Department of Gynecology and Obstetrics, Faculty of Medicine, Erciyes University, Kayseri, Turkey

Abstract Özet: Gestasyonel diyabet taramas›nda serum açl›k plazma glukozunun yeri Objective: We aimed to investigate the performance of fasting Amaç: Oral glukoz tolerans testi (OGTT) yapt›rmayan veya yap- plasma glucose (FPG) level, checked between 24 and 28 weeks of t›r›lamayan gebeliklerde açl›k plazma glukozu (APG) düzeyinin gestation, for the diagnosis of gestational diabetes mellitus (GDM) olas› gestasyonel diyabet (GDM) olgular›n›n saptanmas›nda yar- in order to find out whether FPG level would help to identify d›mc› olup olamayaca¤› sorusunu cevaplamak için 24–28. gebelik potential GDM cases or not in pregnancies which do or do not haftalar›nda bak›lan APG düzeyinin GDM tan›s› için nas›l bir per- undergo oral glucose tolerance test (OGTT). formans sergiledi¤ini araflt›rmay› amaçlad›k. Methods: This study was performed retrospectively in a tertiary cen- Yöntem: Bu çal›flma tersiyer bir merkezde, retrospektif olarak ter by accessing the records of 2950 patients who underwent 75-g 24–28. gebelik haftalar› aras›nda 75 g OGTT yapt›ran toplam 2950 OGTT in between 24 and 28 weeks of gestation. GDM diagnosis hastan›n kay›tlar›na ulafl›larak gerçeklefltirildi. Tek basamakl› tarama was established according to the one-step screening test results. In test sonuçlar›na göre GDM tan›s› konuldu. GDM tan›s› konulan the patients diagnosed with GDM, the most successful threshold hastalarda APG için istatistiksel olarak hesaplanm›fl, tan› için en ba- value for the diagnosis calculated statistically was determined for flar›l› eflik de¤er hesapland›. APG için özgüllük ve duyarl›l›k de¤erle- FPG. The specificity and sensitivity values were calculated for FPG. ri hesapland›. Results: After applying the exclusion criteria, 1736 of 2043 preg- Bulgular: D›fllama kriterleri sonras› kalan 2043 gebenin 1736’s› nant women were normal and 307 (15%) of them were diagnosed normal iken 307’sine (%15) GDM teflhisi konuldu. Sa¤l›kl› gebeler with GDM. The mean age was higher in the pregnant women with ile GDM’li gebeler aras›nda demografik özelliklere göre yap›lan GDM than the healthy pregnant women when they were compared karfl›laflt›rmada, GDM’li gebelerde ortalama yafl sa¤l›kl› gebelerden according to the demographic characteristics (28.6±4.3 vs. 26.2±4.1, yüksek idi (28.6±4.3’e karfl› 26.2±4.1, p<0.001). Vücut kitle indeksi p<0.001). Body mass index was also higher in the pregnant women de yine GDM’li gebelerde sa¤l›kl› gebelerden daha yüksek idi with GDM compared to the health pregnant women (26±2.1 vs. (26±2.1’e karfl› 24±3.1 kg/m2, p<0.001). Di¤er özellikler her iki 24±3.1 kg/m2, p<0.001). Other characteristics were similar in both grup için benzerdi. APG performans› için ROC analizi yap›ld› ve groups. ROC analysis was performed for FPG and the most signifi- sonras›nda en anlaml› eflik de¤eri 88 mg/dL olarak tespit edildi cant threshold value was found 88 mg/dL (p<0.001, area under curve (p<0.001, e¤ri alt›nda kalan alan 0.876, %95 güven aral›¤› 0.850– 0.876, 95% confidence interval 0.850–0.903). 0.903). Conclusion: When FPG is >88 mg/dl in pregnant women who do Sonuç: OGTT yapt›rmak istemeyen gebelerde, APG>88 mg/dl ol- not want to undergo OGTT, they should be informed in detail mas› durumunda olas› GDM için gebe hem OGTT hem de GDM about both OGTT and GDM and its potential complications. Thus, ve olas› komplikasyonlar› hakk›nda detayl› olarak bilgilendirilmeli- the number of GDM cases without diagnosis and its potential com- dir. Böylece tan›s› olmayan GDM olgular› ve olas› komplikasyonla- plications would decrease. r› azalacakt›r. Keywords: Fasting glucose, gestational diabetes, glucose tolerance, Anahtar sözcükler: Açl›k glukozu, gestasyonel diyabet, glukoz tole- pregnancy, screening. rans›, gebelik, tarama.

Correspondence: ‹lknur Çöl Madenda¤, MD. Clinics of Gynecology and Obstetrics, Kayseri City Hospital, Kayseri, Turkey. e-mail: [email protected] / Received: December 13, 2019; Accepted: February 17, 2020 Please cite this article as: Çöl Madenda¤ ‹, Eraslan ﬁahin M, Madenda¤ Y. The role of serum fasting plasma glucose in gestational diabetes screening. Perinatal Journal 2020;28(1):11–16. doi:10.2399/prn.20.0281003

ORCID ID: ‹. Çöl Madenda¤ 0000-0001-6700-2236; M. Eraslan ﬁahin 0000-0001-6484-9132, Y. Madenda¤ 0000-0002-7622-2991 Çöl Madenda¤ ‹, Eraslan ﬁahin M, Madenda¤ Y

Introduction Ethics Committee of the Faculty of Medicine, Erciyes University was obtained for the study. Since the ethnic Gestational diabetes mellitus (GDM) which is the most origins in our country have a high risk for diabetes mel- common endocrinological disorder seen during preg- litus, all pregnant women admitting to our clinic are rec- nancy is defined as the carbohydrate intolerance found ommended 75-g OGTT in accordance with the recom- during second or third trimester and where it is not mendation of the Practice Guidelines of Turkish known clearly if pregnant woman is Type I or Type II [1] Perinatology Society and the tests are carried out for diabetes or not. It is associated with prenatal and peri- [6] those who accept it. The pregnant women with local natal complications such as hyperglycemia, preeclamp- ethnic origin (Caucasian race) in between 24 and 28 sia, macrosomia, preterm labor, polyhydramnios, trau- weeks of gestation and 18–35 years old who admitted to matic labor, and elevated risk for cesarean section devel- our hospital for routine pregnancy follow-up were oped during pregnancy. Glucose regulation usually included in the study. The patients with fasting plasma becomes normal in a short time after delivery, but the glucose above 126 mg/dl and had previously diagnosed risk of developing Type II diabetes mellitus increases in with diagnosis, those with an endocrine disease (Cushing [1] these women and their children in the long term. disease, Addison’s disease, hypopituitarism, acromegalia Advanced maternal age, belonging to a certain ethnic etc.) which may affect blood glucose level, or the preg- group (Hispanic, African, Asian), multiparity, obesity, nant women with the history of medication use (cortisol, GDM in previous pregnancy, giving birth to baby over progesterone) which are known that they may affect 4000 g and familial history of diabetes are among the blood glucose level were excluded from the study (n=280 major risk factors.[2] pregnant women). Also, the patients and immigrants Gestational diabetes screening has still been debated from different races were excluded (n=595). The weeks today. There are many recommendations for the screen- of gestation were determined according to the last men- ing. These recommendations are serum fasting glucose strual period. The weeks of gestation for women whose level, postprandial glucose level, HbA1C and glucose last menstrual period are not known were determined tolerance tests. Fasting serum glucose threshold value according to the ultrasonographic measurements con- accepted for gestational diabetes diagnosis varies accord- ducted in the first trimester. ing to the races.[3,4] It is also controversial that perform- The patients who were screened by one-step 75-g ing glucose tolerance test to which pregnant women OGTT accepted by IADPSG (International Association according to the fasting blood glucose levels would be of the Diabetes and Pregnancy Study Groups) and ADA more significant. Sometimes, tolerance tests cannot be (American Diabetes Association) were included in the tolerated or are rejected by patients. The number of study. In order to establish diagnosis in one-step screen- patients who does not want to undergo the test increasing test, fasting plasma glucose is measured following es day by day particularly due to the speculations in the 12-hour overnight fasting. Then, patient drinks 75 g social media or the thought that it may harm fetus.[5] In glucose and venous blood samples are collected at 1st ≥ our study, we aimed to investigate the performance of and 2nd hours. 92 mg/dl for fasting plasma glucose, ≥ ≥ fasting plasma glucose level, checked between 24 and 28 180 mg/dl for 1st hour plasma glucose and 153 mg/dl weeks of gestation, for the diagnosis of gestational dia- for 2nd hour plasma glucose are accepted as threshold values.[7] GDM diagnosis was established when one or betes mellitus in pregnancies which do or do not under- more of these values were higher. The most successful go oral glucose tolerance test (OGTT). threshold value for the diagnosis was determined by statistically calculating specificity and sensitivity values for Methods fasting plasma glucose (FPG). In this study, 2 simulation The study was designed retrospectively in the Kayseri screening tests were created. First one was designed to City Hospital by using the hospital data bank. The study be screening test with single FPG threshold value and was carried out by accessing the laboratory results and the second one to be GDM screening test with two FPG hospital records of 2950 patients who underwent GDM threshold values. screening by 75-g OGTT in our clinic between July The data were processed and compared by PASW 2018 and July 2019. The approval of Clinical Researches statistics software version 18 (SPSS Inc.; Chicago, IL,

12 Perinatal Journal The role of serum fasting plasma glucose in gestational diabetes screening

USA). The descriptive statistics were prepared. The val- ance test was 118 (5.7% in all pregnant women, 38.4% ues were presented as mean ± standard deviation, n(%) in the pregnant women with HDM). Of the pregnant and median (min–max). The diagnosis performance of women with GDM, single value positivity was observed FPG value for GDM was analyzed on the basis of ROC in 63% (193), 2-value positivity in 25.9% (79), and 3- (receiver operating characteristic) curve. The sensitivity, value positivity in 10.8% (33). specificity, positive and negative likelihood ratios, preva- The most significant threshold value was found 88 lence, and positive and negative predictive values were mg/dL in the ROC analysis for FPG performance determined. (p<0.001, area under curve 0.876, 95% confidence interval 0.850–0.903). The parameters such as sensitiv- Results ity and specificity were calculated according to the new Of 2950 pregnant women included in the study, 595 threshold value and showed in Table 2. Accordingly, were excluded due to different ethnic origin, 32 due to when the best threshold value for FPG was accepted 88 being unable to complete the test, and 280 due to exclu- mg/dL, the false positivity was 6.6%, the specificity sion criteria. While 1736 of remaining 2043 pregnant was 93.4% and the sensitivity was 69.7%. Another sim- women were normal, 307 (15%) of them were diagnosed ulation in this study was to create a screening test with with GDM (according to IADPSG criteria). The demo- two threshold values according to the FPG level. graphic characteristics were compared between the Three groups were established for that purpose.[4] The healthy pregnant women and the pregnant women with first group consisted of 984 (48.2%) pregnant women GDM, and they were presented in the Table 1. with FPG level <79 mg/dL and there were 38 (12.3%) According to this comparison, mean age was higher in patients with GDM in this group. The second group the pregnant women with GDM than the healthy preg- consisted of 868 (42.5%) pregnant women with FPG nant women (28.6±4.3 vs. 26.2±4.1, p<0.001). The body level between 79 and 91 mg/dL and there were 78 mass index was also higher in the pregnant women with (25.4%) patients with GDM in this group. The third GDM than the healthy pregnant women (26±2.1 vs. group had a total of 191 (9.3%) pregnant women with 2 24±3.1 kg/m , p<0.001). Other characteristics were sim- FPG level 92 mg/dL and higher, and they all had ilar for both groups (Table 1). GDM (191/307, 62.2%). According to this new strate- There were 191 patients with fasting blood glucose gy, if we would establish the cases with APG level 92 92 mg/dL and higher (9.3% in all pregnant women, mg/dL and higher with the diagnosis of GDM direct- 62.2% in the pregnant women with GDM). There were ly and perform glucose tolerance test to those between 179 patients with blood glucose 180 mg/dL and higher 91 and 79 mg/dL, 88% of the patients with GDM at the 1st hour of oral glucose tolerance test (8.7% in all could be diagnosed by conducting OGTT in 42% of pregnant women, 58.3% in the pregnant women with the population. Approximately 58% of our population GDM). The number of the patients with blood glucose would not need OGTT. According to this screening level 153 mg/dL and higher at the 2nd hour of the toler- test with two threshold values, specificity was found

Table 1. Comparison of the demographic characteristics between the groups.

Healthy pregnant Pregnant women women (1736) with GDM (307) p-value

Age 26.1±4.1 28.6±4.3 <0.001 BMI 24±3 26±2.1 <0.001 Week of gestation at screening 26.2±1.2 25.9±1.3 0.675 Gravida 2 (1–5) 2 (1–6) 0.234 Parity 1 (0–31 (0–3)0.454

BMI: body mass index; GDM: gestational diabetes mellitus. The values were presented as mean ± standard deviation or median (min–max). p<0.05 was considered statistically significant.

Volume 28 | Issue 1 | April 2020 13 Çöl Madenda¤ ‹, Eraslan ﬁahin M, Madenda¤ Y

Table 2. The performance when the serum fasting glucose threshold value is calculated 88 mg/dL.

Statistics Results 95% CI

Sensitivity 69.71% 64.23–74.8% Specificity 93.43% 92.16–94.55% Positive likelihood ratio 10.62 8.76–12.87 Negative likelihood ratio 0.32 0.27–0.38 Prevalence 15.03% 13.5–16.65% Positive predictive value 65.24% 60.77–69.46% Negative predictive value 94.58% 93.64–95.39% Accuracy 9.87% 88.48–91.14%

ROC analysis was conducted for the performance of serum fasting glucose level, and then 88 mg/dL was considered to be the most significant threshold value (p<0.001, area under curve 0.876, 95% confidence interval 0.850–0.903). For the disease diagnosis, the results of 75-g oral glucose tolerance test, which is the reference test, was used.

100% and sensitivity 87.6%. The calculations of other we designed the study population to be between 18 and threshold values are given in Table 3. 35 years old. Unlike similar studies, we excluded different ethnic origins from our study, and included only Discussion local individuals. Also, we included pregnant women whose body mass index was between 20 and 30 kg/m2 in In our study, we investigated the diagnosis convenience our study in order to increase the reliability of our study. for GDM which is one of the most common medical issues encountered during pregnancy and may lead to The first strategy we considered as a hypothesis in our many poor health outcomes by affecting both mother study was to conduct screening by using a single thresh- and baby in short- and long-term. GDM screening and old value which has the highest performance for GDM diagnosis are still controversial. In our study, we investi- diagnosis, and the FPG level with the highest validity was gated the diagnosis performance of FPG levels between 88 mg/dL. When assuming that this value is considered 24 and 28 weeks of gestation. There are few studies in as threshold value in the screening, we will be able to the literature investigating the diagnosis performance of establish GDM diagnosis to our population with an FPG. We developed the methods of our study and acceptable specificity rate of 93.4% and sensitivity rate of improved the power of the study by taking the limita- 69.7%, and the need for conducting tolerance test will be tions in these studies into consideration (advanced eliminated for a great part (83%) of the pregnant women. maternal age, different ethnic groups, risky pregnancies However, a significant part (30%) of the pregnant and obese pregnant women in the study groups). Firstly, women with GDM would be missed in this assumption.

Table 3. The performance of serum fasting glucose at different threshold values.

92 88 79 75 72 70

Number of pregnant women 191/2043 328/2043 1059/2043 1475/2043 1721/2043 1846/2043 above threshold (9.3%) (16.1%) (51.8%) (72.2%) (84.2%) (90.4%) Number of pregnant women 1852/2043 1715/2043 984/2043 568/2043 322/2043 197/2043 that do not require OGTT (90.7%) (83.9%) (48.2%) (27.8%) (15.8%) (9.6%) Number of GDM cases missed 116/307 93/307 38/307 21/307 12/307 4/307 by the test (37.7%) (30.2%) (12.3%) (6.8%) (3.9%) (1.3%) Sensitivity 191/307 214/307 269/307 286/307 295/307 303/307 (62.2%) (69.7%) (87.6%) (93.2%) (96.1%) (98.7%) Specificity 1736/1736 1622/1736 946/1736 547/1736 310/1736 193/1736 (100%) (93.4%) (54.5%) (31.5%) (17.9%) (11.1%)

GDM: gestational diabetes mellitus; OGTT: oral glucose tolerance test. The values were presented as n(%). The descriptive statistics were done.

14 Perinatal Journal The role of serum fasting plasma glucose in gestational diabetes screening

Another strategy is to separate pregnant women to 3 ficity is 84% and the sensitivity is 88%; but if the thresh- groups between 24 and 28 weeks of gestation according old value is considered to be 130 mg/dL according to to their FPG levels.[4,8–10] In accordance with the reports of NDDG (National Diabetes Data Group) criteria, the similar studies, pregnant women with FPG level 92 specificity is 88% and the sensitivity is 66%.[11] It can be mg/dL and higher are already diagnosed with GDM said that a better performance than 50-g glucose screen- according to the reference test and glucose tolerance test ing test is obtained in two-threshold screening strategy is not required. The pregnant women with FPG levels with 100% specificity and 87.6% sensitivity. below 79 mg/dL which are almost half of the population This study has a few weak points. Conducting the (48.2%) do not undergo tolerance test. The purpose here study retrospectively, in a single center and with low is to determine risk group, and recommend glucose tol- number of pregnant women are among them. The num- erance test to those with FPG level between 79 and 92 ber of pregnant women included in the study decreased mg/dL. When we evaluate the results of our study with due to the exclusion criteria. However, the exclusion cri- this scenario, glucose tolerance test is not required in a teria increase the strength of the study. Another signifi- great part (58%) of all pregnant women and 88% of the cant aspect of the study is that we conducted it with the patients will be diagnosed who are established with GDM data of our country. diagnosis according to the reference test by conducting OGTT in 44% of them. In this way, the sensitivity was 88% and the specificity was 100% in this strategy. We Conclusion found that a similar study in the literature reported con- According to the results of our study, a GDM screening sistent results with our study. Zhu et al. reported the sen- test using FPG threshold value 88 mg/dL alone missed sitivity 87% in their study performed with 24,854 30% of real GDM cases, and exhibited a poor perform- patients in China in 2013.[9] In a similar study which has ance with 93.4% specificity and 69.7% sensitivity. 100% specificity but different sensitivity compared to our Another GDM screening test designed in the study had study, Agarwal et al. used this strategy on 10,283 patients two threshold values. This screening test designed by in 2010 and reached a sensitivity of 95.4%.[10] In a similar using 92 and 79 mg/dL FPG values missed 12% of the study conducted with 2298 cases, Ryser Rüetschi et al. cases, and exhibited a good performance with 100% reported the sensitivity rate 78.5%.[4] When this strategy specificity and 87.6% sensitivity. In the cases who could was compared with the data of HAPO (Hyperglycemia not undergo or did not want to undergo OGTT, reeval- and Adverse Pregnancy Outcome) study, it was reported uating the cases with FPG values would provide an that 57% of the patients would not need OGTT with a opportunity to inform the cases in detail about potential sensitivity of 84.1%.[8] While these different results are gestational diabetes and to perform diagnosis test. Thus, reported as the study limitations, secondary factors such the number of non-diagnosed GDM cases and potential as different ethnic groups, pregnancies at advanced ages, complications would decrease. risky pregnancies and obesity may lead to different rates of prevalence, sensitivity and specificity. Conflicts of Interest: No conflicts declared. A good screening test is expected to be cheap and References easy to perform in a short time without requiring detailed preparations, and its validity (total of sensitivity 1. American Diabetes Association. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2018. and specificity), the method used in other words, should Diabetes Care 2018;41:S13–27. be real, solid and have a high rate of identifying patients. 2. Hod M, Kapur A, Sacks DA, Hadar E, Agarwal M, Di Renzo The ideal one is the high sensitivity with 95% specifici- GC, et al. The International Federation of Gynecology and ty, which means 5% false positivity rate. If we consider Obstetrics (FIGO) initiative on gestational diabetes mellitus: a 88 mg/dL as the threshold FPG value, the rates accept- pragmatic guide for diagnosis, management, and care. Int J ed in many screening tests can be achieved with 93.4% Gynaecol Obst 2015;131 Suppl 3:S173–211. specificity and 69.7% sensitivity. It is similar in 50-g glu- 3. Sacks DA, Hadden DR, Maresh M, Deerochanawong C, Dyer [11] AR, Metzger BE, et al.; HAPO Study Cooperative Research cose screening test. When 140 mg/dL is accepted as Group. Frequency of gestational diabetes mellitus at collabo- the threshold value according to ADA criteria, the speci- rating centers based on IADPSG consensus panel-recom-

Volume 28 | Issue 1 | April 2020 15 Çöl Madenda¤ ‹, Eraslan ﬁahin M, Madenda¤ Y

mended criteria: the Hyperglycemia and Adverse Pregnancy mendations on the diagnosis and classification of hyper- Outcome (HAPO) study. Diabetes Care 2012;35:526–8. glycemia in pregnancy. Diabetes Care 2010;33:676–82. 4. Ryser Rüetschi J, Jornayvaz FR, Rivest R, Huhn EA, Irion O, 8. Agarwal MM, Weigl B, Hod M. Gestational diabetes screen- Boulvain M. Fasting glycaemia to simplify screening for gesta- ing: the low-cost algorithm. Int J Gynaecol Obstet 2011;115 tional diabetes. BJOG 2016;123:2219–22. Suppl 1:S30–3. 5. Baﬂbu¤ A, Sönmez CI, Kaya AE, Y›ld›r›m E. An important 9. Zhu WW, Fan L, Yang HX, Kong LY, Su SP, Wang Z, et al. problem in gestational diabetes scan: why do pregnant women Fasting plasma glucose at 24–28 weeks to screen for gestation- refuse to have oral glucose tolerance test? [Article in Turkish] al diabetes mellitus: new evidence from China. Diabetes Care Konuralp T›p Dergisi 2018;10:144–8. 2013;36:2038–40. 6. ﬁen C, Yayla M, Api O, Yapar Eyi EG, Ülkümen BA. Diabetes 10. Agarwal MM, Dhatt GS, Shah SM. Gestational diabetes mel- in pregnancy: diagnosis and treatment. Practice Guidelines of litus: simplifying the International Association of Diabetes Turkish Perinatology Society. Perinatal Journal 2016;24:110– And Pregnancy diagnostic algorithm using fasting plasma glu- 27. cose. Diabetes Care 2010;33:2018–20. 7. International Association of Diabetes and Pregnancy Study 11. Donovan L, Hartling L, Muise M, Guthrie A, Vandermeer B, Groups Consensus Panel; Metzger BE, Gabbe SG, Persson B, Dryden DM. Screening tests for gestational diabetes: a sys- Buchanan TA, Catalano PA, Damm P, et al. International tematic review for the US Preventive Services Task Force. association of diabetes and pregnancy study groups recom- Ann Intern Med 2013;159:115–22.

16 Perinatal Journal A L J O A T U N R I N R A E L P Original Article

The association between obesity and hematologic inflammatory markers in the first trimester pregnancies

Feyza Nur ‹ncesu Çintesun İD Department of Gynecology and Obstetrics, Konya Training and Research Hospital, University of Health Sciences, Konya, Turkey

Abstract Özet: ‹lk trimester gebeliklerde obezite ve hematolojik inflamasyon belirteçleri aras›ndaki iliflki Objective: Obesity is the defined as the abnormal or excessive accu- Amaç: Obezite, sa¤l›¤a zarar veren anormal ya da afl›r› ya¤ birikimi mulation of the fat which is harmful for the health, and its prevalence olarak tan›mlanmakta olup s›kl›¤› giderek artmaktad›r. Obezitenin has been increasing. Many studies have shown that obesity alone tek bafl›na inflamasyona sebep olup olumsuz gebelik sonuçlar›na se- leads to inflammation and causes poor gestational outcomes. In our bep oldu¤u birçok çal›flmada gösterilmifltir. Bu çal›flmam›zda basit study, we aimed to investigate the association between basic hemato- hematolojik belirteçler ile ilk trimester gebeliklerde obezite durumu- logic markers and obesity in the first trimester pregnancies. nun araflt›r›lmas› amaçlanm›flt›r. Methods: A total of 321 pregnant women who admitted to the clinic of Yöntem: Üçüncü basamak bir devlet hastanesinin kad›n hastal›klar› gynecology and obstetrics in a tertiary state hospital were included in the ve do¤um poliklini¤ine baflvuran 321 gebe çal›flmaya dâhil edildi. study. The patients were separated into three groups, which were nor- Hastalar normal kilolu (VK‹: 18–24.9 kg/m2), fazla kilolu (VK‹: mal weight (BMI: 18–24.9 kg/m2), overweight (BMI: 25–29.9 kg/m2), 25–29.9 kg/m2) ve obez (VK‹>30 kg/m2) olarak gruplandr›ld›. Hasta- and obese (BMI>30 kg/m2). Of the patients, the demographic data (age, lar›n demografik verilerine (yafl, gravida, parite) ve rutin olarak gebe gravida, and parity) and the parameters of hemoglobin, hematocrit, takibinde ilk trimesterde bak›lan, tam kan say›m›nda ölçülen hemog- white blood cell, neutrophil, lymphocyte, platelet (PLT), eosinophil, lobin, hematokrit, beyaz küre, nötrofil, lenfosit, trombosit, eozinofil, basophil, mean platelet volume (MPV), platelet distribution width bazofil, ortalama trombosit hacmi (MPV), trombosit da¤›l›m geniflli- (PDW), neutrophil/lymphocyte ratio (NLR), red blood cell distribution ¤i (PDW), nötrofil-lenfosit oran› (NLR), eritrosit da¤›l›m geniflli¤i width (RDW), plateletcrit (PCT) and platelet/lymphocyte ratio (PLR) (RDW), plateletkrit (PCT) ve trombosit-lenfosit oran› (PLR) para- measured in the complete blood count which was checked in the first metrelerine bak›ld›. Bu üç grup inflamasyon belirteçleri aç›s›ndan trimester routinely during the pregnancy follow-up were analyzed. The karfl›laflt›r›ld›. three groups were compared in terms of inflammatory markers. Bulgular: Hastalar 108 normal kilolu (Grup 1), 109 fazla kilolu Results: The patients were evaluated in three groups: 108 patients with (Grup 2) ve 104 obez (Grup 3) olmak üzere 3 grupta incelendi. normal weight (Group 1), 109 overweight patients (Group 2) and 104 Gruplar aras›nda demografik veriler incelendi¤inde; yafl, parite ve obese patients (Group 3). No significant difference was found in terms of gravida aç›s›ndan anlaml› fark gözlenmedi (p>0.05). Hematolojik be- age, parity and gravida when the demographic data were analyzed among lirteçlere bak›ld›¤›nda beyaz küre, nötrofil, lenfosit, PLT, PCT de- the groups (p>0.05). When the groups were compared in terms of hema- ¤erleri d›fl›nda di¤er belirteçler gruplar aras›nda benzer bulundu. Be- tologic markers, similar values were found in the markers other than yaz küre, nötrofil, lenfosit, PLT, PCT de¤erleri aras›ndaki farkl›l›k white blood cell, neutrophil, lymphocyte, PLT and PCT values. The normal kilolu ile obez hastalar aras›nda olup, bu belirteçlerin de¤er- difference among white blood cell, neutrophil, lymphocyte, PLT and leri fazla kilolu / obez hasta grubunda normal gruba göre daha yük- PCT values were between the patients with normal weight and obese sek bulundu (p<0.05). patients, and the values of these markers were found higher in over- Sonuç: Obez hastalarda inflamasyonla iliflkisi gösterilmifl beyaz kü- weight / normal weight patient groups than the normal group (p<0.05). re, nötrofil, lenfosit, PLT, PCT de¤erleri daha yüksek olarak bulun- Conclusion: The values of white blood cell, neutrophil, lympho- mufltur. cyte, PLT and PCT which were shown to be associated with inflammation were higher in the obese patients. Keywords: Obesity, platelet, inflammation, hemoglobin. Anahtar sözcükler: Obezite, trombosit, inflamasyon, hemoglobin.

Correspondence: Feyza Nur ‹ncesu Çintesun, MD. Department of Gynecology and Obstetrics, Konya Training and Research Hospital, University of Health Sciences, Konya, Turkey. e-mail: [email protected] / Received: December 2, 2019; Accepted: March 11, 2020 Please cite this article as: ‹ncesu Çintesun FN. The association between obesity and hematologic inflammatory markers in the first trimester pregnancies. Perinatal Journal 2020;28(1):17–22. doi:10.2399/prn.20.0281005

ORCID ID: F. N. ‹ncesu Çintesun 0000 0003 2131 962X ‹ncesu Çintesun FN

Introduction phocyte ratio), RDW (red blood cell distribution width) and PCT (plateletcrit) have prognostic and predictive Obesity is the defined as the abnormal or excessive accu- features in various diseases such as coronary artery dis- mulation of the fat which is harmful for the health. Since [1] ease, autoimmune diseases, inflammatory diseases, and 1975, its rate increased three times all over the world. gynecological and gastrointestinal cancers.[7,8] It was According to the data of the World Health Organization found that the levels of these markers increased in the (WHO) in 2016, 40% of adult women and 39% of adult inflammatory processes of pregnancy such as gestation- men are overweight while 15% of adult women and 11% [9–11] al diabetes, acute appendicitis, preeclampsia, etc. In of adult men are obese.[2] According to the data of Public this study, we aimed to investigate the change of inflam- Health Agency of Turkey in 2010, 20.5% of men, 41% matory markers according to BMI values in the first of women and 30.3% of the society are obese.[3] trimester pregnancies. Clinically most appropriate marker for the classification of obesity is body mass index (BMI). BMI is found by dividing weight in kilograms by height in meters squared Methods 2 (kg/m ). WHO classified obesity in 6 groups according A total of 321 pregnant women during first trimester to BMI values: Underweight BMI<18.5 kg/m2, normal who admitted to the Clinic of Gynecology and weight BMI: 18–24.9 kg/m2, overweight BMI: 25–29.9 Obstetrics of a tertiary state hospital between January kg/m2, obese class 1 BMI: 30–34.9 kg/m2, obese class 2 2019 and June 2019 were included in the study. The BMI: 35–39.9 kg/m2, and obese class 3 BMI>40 kg/m2.[1] approval of the local ethics committee was obtained for Obesity a significant public health problem with many this study. The patient data were accessed retrospec- potential risks in the long term; cardiovascular disease, tively from the hospital records. diabetes, osteoarthritis and cancer (breast, endometrium, The patients were classified as normal weight (BMI: ovary, liver, colon, prostate etc.) are among these risks. 18–24.9 kg/m2), overweight (BMI: 25–29.9 kg/m2) and Maternal obesity is important in terms of the complica- obese (BMI>30 kg/m2). Of the patients, the demograph- tions before, during and after pregnancy. Subfertility ic data such as age, gravida and parity, and the levels of during preconceptional period, spontaneous abortion, hemoglobin, hematocrit, white blood cell, neutrophil, gestational hypertension, preeclampsia, gestational dia- lymphocyte, platelet, eosinophil, basophil, MPV, betes, surmaturity, macrosomia, dystocia and intrauter- platelet distribution width (PDW), NLR, RDW, PCT ine death during antenatal period, and increased risks of and PLR measured in the complete blood count which hemorrhage, infection and thromboembolism during was checked in the routine pregnancy follow-up were [4] postnatal period are associated with maternal obesity. It analyzed. is known that fat tissue is associated with inflammation The patients on medications for those except preges- and infection.[5] It is considered that obesity leads to tational diabetes, folic acid and infection which may inflammation and therefore causes poor obstetric out- cause chronic and acute inflammation were excluded comes (preeclampsia, gestational diabetes) and neonatal from the study. complications.[6] It is known that fat tissues in non-pregnant obese women call macrophage and initiate inflam- Statistical analysis matory process, and that they secrete high levels of The data were analyzed by using Statistical Package proinflammatory cytokines such as tumor necrosis factor Social Sciences (SPSS), version 22.0 (SPSS Inc., Chicago, α (TNF- ), IL 6, monocyte chemoattractant protein 1 IL, USA). The descriptive statistics were presented as β β [5] (MCP 1), and transforming growth factor (TGF- ). standard deviations and mean values for numerical vari- The levels of high sensitivity C-reactive protein ables. In order to determine the normal distribution of the (HsCRP), leptin and MCP-1 were correlated with the variables, Histogram and Kolmogorov-Smirnov test were [6] increase of BMI in obese pregnant women. used. Where applicable, Mann-Whitney U test and Complete blood count is a cheap and simple labora- Student’s t-test were used for the comparisons of two tory examination used routinely in pregnancy. When groups. For multiple group comparisons, one-way hematologic parameters are evaluated, it is known that ANOVA and Kruskal-Wallis H test were used. In the val- NLR (neutrophil/lymphocyte ratio), PLR (platelet/lym- ues with significant multiple group results, Tukey test was

18 Perinatal Journal The association between obesity and hematologic inflammatory markers in the first trimester pregnancies

Table 1. The comparison of demographic data and hematologic markers between the patients with normal weight, and overweight and obese patients.

Patients with normal weight Overweight patients Obese patients (n=108) (n=109) (n=104) p-value

Age 26.5 (18–40) 29 (18–40) 26 (18–40) 0.178 Gravida 4 (1–7) 4 (1–7) 4 (1–7) 0.583 Parity 3 (0–6) 3 (0–6) 3 (0–6) 0.558 Hgb 12.7 (10.1–15.1) 13.0 (10.2–15.0) 12.6 (10.1–14.7) 0.286 Htc 37.4±2.94 37.9±2.8 38.0±2.9 0.200 WBC 8.4±2.2* 8.6±2.3 c 9.4±2.0*,† 0.001 Neutrophil 5.4 (2.3–10.6)*,† 5.3 (2.5–13.2) 6.34 (2.8–10.2)*,† <0.001 Lymphocyte 2.0 (0.05–5.01)*,† 2.0 (0.97–5.6) 2.3 (1.1–5.9)*,† 0.023 PLT 263 (134–464)*,† 266 (155–529) 295 (122-462)*,† <0.001 PCT 0.28 (0.17–0.45)*,† 0.28 (0.15–0.51) 0.31 (0.15–0.51)*,† <0.001 PDW 12.4 (8.8–19.4) 12.7 (8.1–24.9) 12.7 (9.6–46.4) 0.170 MPV 10.6 (8.6–42.5) 10.7 (6.6–81) 10.6 (6.6–12.4) 0.886 RDW 40.7 (32.3–62.2) 39.8 (13.1-63.2) 40.5 (33.9–48.5) 0.119 NLR 2.6 (0.9–18.4) 2.6 (0.009–5.57) 2.7 (0.8–7.7) 0.775 PLR 133 (58.2–6880) 130 (<0.001–282) 134 (45–238) 0.630

Hgb: hemoglobin; Htc: hematocrit; MPV: mean platelet volume; NLR: neutrophil/lymphocyte ratio; PCT: plateletcrit; PDW: platelet distribution width; PLR: platelet/lymphocyte ratio; PLT: platelet; RDW-SD: red blood cell distribution width; WBC: white blood cell. *Between the patients with normal weight and obese patients; †Between the overweight patients and obese patients. Median value (min–max) has been given for those underwent Kruskal-Wallis test. Mean (±SD) value has been given for those underwent one-way ANOVA test. used for those with homogeneous variance and Mann- the groups. White blood cell, neutrophil, lymphocyte, Whitney U test when non-parametric test was used. The PLT and PCT levels were higher overweight/obese value of p<0.05 was considered statistically significant. patient groups than the normal group (p<0.05).

Results Table 2. The comparison of demographic data and hematologic markers between the patients with normal weight and The results of demographic and hematologic compar- overweight/obese patients.. isons according to BMI values are summarized in Table 1. The patients were evaluated in three groups, which Patients with Overweight and normal weight obese patients were normal weight with 108 patients (Group 1), over- (n=108) (n=213) p-value weight with 109 patients (Group 2) and obese with 104 Age 26.5 (18–40) 27 (18–40) 0.376 patients (Group 3). When the demographic data were Gravida 4 (1–7) 4 (1–7) 0.805 evaluated among the groups, no significant difference Parity 3 (0–6) 3 (0–6) 0.677 was observed in terms of age, parity and gravida Hgb 12.7 (10.1–15.1) 12.8 (10.1–15) 0.096 (p>0.05). In terms of hematological markers, all markers Htc 37.4±2.94 37.9±2.8 0.097 except white blood cell, neutrophil, lymphocyte, PLT WBC 8.4±2.2 9.0±2.2 0.017 Neutrophil 5.4 (2.3–10.6) 5.8 (2.5–13.2) 0.013 and PCT levels were similar among the groups. The dif- Lymphocyte 2.0 (0.05–5.01) 2.2 (0.9–5.9) 0.042 ference among white blood cell, neutrophil, lympho- PLT 263 (134–464) 285 (122–529) 0.013 cyte, PLT and PCT values were between the patients PCT 0.28 (0.17–0.45) 0.30 (0.15–0.51) 0.010 with normal weight and obese patients. PDW 12.4 (8.8–19.4) 12.7 (8.1–46.4) 0.060 MPV 10.6 (8.6–42.5) 10.7 (6.6–81) 0.704 The patients were also compared by separating them RDW 40.7 (32.3–62.2) 40.2 (13.1–63.2) 0.108 into two groups as the patients with normal weight and NLR 2.6 (0.9–18.4) 2.7 (0.009–7.7) 0.580 overweight/obese patients. The results of this comparison PLR 133 (58.2–6880) 132 (<0.001–282) 0.886 are shown in Table 2. The demographic data were simi- Hgb: hemoglobin; Htc: hematocrit; MPV: mean platelet volume; NLR: neutrophil/lym- lar between two groups (p>0.05). For the hematological phocyte ratio; PCT: plateletcrit; PDW: platelet distribution width; PLR: platelet/lymphocyte ratio; PLT: platelet; RDW-SD: red blood cell distribution width; WBC: white blood markers, all markers except white blood cell, neutrophil, cell. Median value (min–max) has been given for those underwent Mann-Whitney U lymphocyte, PLT and PCT levels were similar among test. Mean (±SD) value has been given for those underwent Student’s t-test.

Volume 28 | Issue 1 | April 2020 19 ‹ncesu Çintesun FN

Discussion MPV indicates mean platelet volume, and it ranges [10] Due to the rapid increase of obesity rates in the world, between 7.4 and 10.4 fl. Elevated MPV levels are cor- WHO has considered obesity as one of the most serious related with the increased hemostasis and coagulation global health problems of the 21st century. The obesity systems. This is explained with higher activity with the [23,27] prevalence in pregnancy has been reported between increase of platelet levels. Elevated MPV levels are [28] 1.8% and 25.3%.[4,12] The Centers for Disease Control also associated with diabetes and its complications. and Prevention (CDC) reported that the obesity preva- Bozkurt et al. reported elevated MPV levels in the preg- lence among the pregnant women completely reflects nant women with gestational diabetes who are at the 3rd [29] the obesity among women in fertility ages, 25% of the trimester. In our study, we did not find any difference women at fertility ages in the USA were overweight and among the BMI groups in the first trimester in terms of 25% of them were obese, and that maternal obesity is a MPV levels. major risk factor for maternal and perinatal mortality.[13] PCT shows the volume of platelets by percentage in × The obesity has many adverse impacts on pregnancy. the blood, and it is calculated with the formula PLT In Lashen et al. showed in their study that spontaneous MPV / 10,000 and it is much more significant parame- [30] abortion risk increases 1.2 times and recurring abortion ter than PLT and MPV. Its normal level in the blood [31] risk increases 3.5 times in the first trimester of the preg- is 0.22–0.24%. Many studies investigated PCT level nant women whose BMI was over 30 kg/m2.[14] There are for many diseases associated with pregnancy. For exam- [32] also studies reporting that the obesity increases the inci- ple, it was high in hyperemesis gravidarum, low in [33] dences of gestational diabetes, preeclampsia and macroso- preeclamptic patients, and there was no difference in [34] mia,[15,16] and that it increases the rates of shoulder dysto- molar pregnancies. In our study, we found that PCT cia during delivery and cesarean section.[17] Pregestational level was significantly higher in obese group than the maternal obesity is accounted for the most common rea- normal weight group and in the obese/underweight son of unexplained intrauterine fetal deaths.[18] groups than normal weight group. Chronic inflammatory conditions such as obesity PDW is a marker indicating the variations in the causes elevated white blood cell (WBC) levels by platelet volume. Its level varies according to the size and increasing granulocyte production. It is known that the activation of platelets. Its normal reference range in the [30] impaired glucose metabolism of WBC is associated with blood is between 8.3% and 56.6%. It is known that insulin resistance and type 2 diabetes.[19] It was reported PDW decreases during pregnancy compared to the that elevated WBC caused gestational diabetes during pregestational period. Some studies reported that it has early pregnancy.[20] In our study, we found that WBC, a positive correlation with preeclampsia severity and [33,35] neutrophil and lymphocyte levels which are directly ectopic pregnancy, while there is a negative correla- [22] associated with inflammation were significantly high in tion with ablatio placentae. In our study, we did not the obese group. This supports our hypothesis. find any increase in PDW level by elevated BMI value. There are evidences showing that platelets do not NLR and PLR levels are the systemic inflammatory only play a role in the coagulation mechanisms in the indices associated with platelet. There is a study show- [36] body, but also are associated with the development of ing that NLR is associated with metabolic syndrome. immune response, allergic reactions and inflamma- It is known that high NLR and PLR are associated with [9,37] tion.[21] While the number of platelets decreases in order gestational diabetes and preterm labor. We did not to provide hemostasis in the gestational thrombocytope- find any difference between the groups in terms of NLR nia, its functions and predispositions to aggression and PLR values in our study. increase.[22] However, there are controversial opinions in RDW shows the variation in the red blood cell vol- terms of PDW, PCT and MPV levels in the blood dur- ume called anisocytosis, and its reference value is ing pregnancy. While some studies claim that there are 11.5–15.5%.[10] While it is considered that high RDW differences between the trimesters,[23,24] there are also levels indicate inflammation and oxidative stress, the studies asserting that there is no difference between mechanism is still unclear.[38] There are studies asserting pregestational and post-gestational periods.[25,26] that it is associated with the impairment of iron metab-

20 Perinatal Journal The association between obesity and hematologic inflammatory markers in the first trimester pregnancies

olism and the suppression of erythropoietin.[39] Many 5. Greenberg AS, Obin MS. Obesity and the role of adipose tis- studies in the literature investigated the association of sue in inflammation and metabolism. Am J Clin Nutr 2006;83: S461–5. RDW level with the diseases in pregnant women. While there is no association with hyperemesis,[40] its associa- 6. Madan JC, Davis JM, Craig WY, Collins M, Allan W, Quinn [8,11] R, et al. Maternal obesity and markers of inflammation in tion with preeclampsia is controversial, and it is not pregnancy. Cytokine 2009;47:61–4. associated with gestational diabetes.[41] In our study, 7. Vilchez G, Lagos M, Kumar K, Argoti P. Is mean platelet vol- RDW level was similar among the groups. ume a better biomarker in pre-eclampsia? J Obstet Gynaecol The limitations of our study are being retrospective, Res 2017;43:982–90. single-centered, limited number of patients, and not 8. Yücel B, Ustun B. Neutrophil to lymphocyte ratio, platelet to checking other inflammatory markers except hemato- lymphocyte ratio, mean platelet volume, red cell distribution logic markers. In addition, we did not investigate gesta- width and plateletcrit in preeclampsia. Pregnancy Hypertens 2017;7:29–32. tional and neonatal outcomes of inflammatory markers. 9. Yilmaz H, Celik HT, Namuslu M, Inan O, Onaran Y, There are no studies in the literature investigating the Karakurt F, et al. Benefits of the neutrophil-to-lymphocyte association between obesity during pregnancy and ratio for the prediction of gestational diabetes mellitus in preg- inflammatory markers. Further clinical researches which nant women. Exp Clin Endocrinol Diabetes 2014;122:39–43. are planned prospectively, randomized controlled and 10. Sahbaz A, Cicekler H, Aynioglu O, Isik H, Ozmen U. investigating the obstetric outcomes of maternal obesity Comparison of the predictive value of plateletcrit with various and inflammation values are needed. other blood parameters in gestational diabetes development. J Obstet Gynaecol 2016;36:589–93. 11. Çintesun E, Çintesun FN, Ezveci H, Akyürek F, Çelik C. Conclusion Systemic inflammatory response markers in preeclampsia. J Hematologic inflammatory markers are simple and Lab Physicians 2018;10:316–9. cheap markers which can be detected in the hemogram 12. Sirimi N, Goulis DG. Obesity in pregnancy. Hormones (Athens) 2010;9:299–306. count easily. The association between inflammation and obesity during pregnancy has been proven, and it 13. Shaikh H, Robinson S, Teoh TG. Management of maternal obesity prior to and during pregnancy. Semin Fetal Neonatal is considered that it is associated with the potential Med 2010;15:77–82. poor outcomes during pregnancy. We found that white 14. Lashen H, Fear K, Sturdee DW. Obesity is associated with blood cell, neutrophil, lymphocyte, platelet and PCT increased first trimester and recurrent miscarriage: matched levels are associated with high BMI values during preg- case-control study. Hum Reprod 2004;19:1644–6. nancy. Further studies are needed to confirm the asso- 15. Davies GA, Maxwell C, McLeod L, Gagnon R, Basso M, Bos ciation between these markers and poor obstetric and H, et al.; Society of Obstetricians and Gynaecologists of neonatal outcomes. Canada. SOGC clinical practice guidelines: obesity in pregnancy. No. 239, February 2010. Int J Gyneacol Obstet 2010;110: 167–73. Conflicts of Interest: No conflicts declared. 16. Robinson HE, O'Connell CM, Joseph KS, McLeod NL. References Maternal outcomes in pregnancies complicated by obesity. Obstet Gynecol 2005;106:1357–64. 1. Tjepkema M. Adult obesity in Canada: measured height and 17. Sheiner E, Levy A, Menes TS, Silverberg D, Katz M, Mazor weight. Ottawa: Statistics Canada; 2005. M. Maternal obesity as an independent risk factor for caesare- 2. Nishtar S, Gluckman P, Armstrong T. Ending childhood obe- an delivery. Paediatr Perinat Epidemiol 2004;18:196–201. sity: a time for action. Lancet 2016;387(10021):825–7. 18. Fretts RC. Etiology and prevention of stillbirth. Am J Obstet 3. TBSA. “Türkiye Beslenme ve Sa¤l›k Araflt›rmas› 2010: Beslen- Gynecol 2005;193:1923–35. me Durumu ve Al›flkanl›klar›n›n De¤erlendirilmesi Sonuç Ra- 19. Y›lmaz ZV, Y›lmaz E, ‹çer B, Küçüközkan T. Association of poru.” Sa¤l›k Bakanl›¤› Sa¤l›k Araflt›rmalar› Genel Müdürlü- complete blood count parameters with gestational diabetes ¤ü, Hacettepe Üniversitesi Sa¤l›k Bilimleri Fakültesi Beslenme mellitus. Gynecology Obstetrics & Reproductive Medicine ve Diyetetik Bölümü, Ankara Numune E¤itim ve Araflt›rma 2017;23:65–9. Hastanesi. Ankara: Sa¤l›k Bakanl›¤› Yay›n No: 931.2014. 20. Pattanathaiyanon P, Phaloprakarn C, Tangjitgamol S. 4. Lee CY, Koren G. Maternal obesity: effects on pregnancy and Comparison of gestational diabetes mellitus rates in women the role of pre-conception counselling. J Obstet Gynaecol 2010; with increased and normal white blood cell counts in early 30:101–6. pregnancy. J Obstet Gynaecol Res 2014;40:976–82.

Volume 28 | Issue 1 | April 2020 21 ‹ncesu Çintesun FN

21. Kocabafl CN. Alerjik inflamasyonda yeni aktör trombositler. 32. Tayfur C, Burcu DC, Gulten O, Betul D, Tugberk G, Onur Türkiye Çocuk Hastal›klar› Dergisi 2016;10(2):XI–XII. O, et al. Association between platelet to lymphocyte ratio, 22. Arlier S, Adiguzel C, Yilmaz ES, Seyfettinoglu S, Helvacioglu plateletcrit and the presence and severity of hyperemesis gravi- Ç, Ekin GU, et al. The role of mean platelet volume and darum. J Obstet Gynaecol Res 2017;43:498–504. platelet distribution width in the prediction of placental abrup- 33. Karateke A, Kurt RK, Baloglu A. Relation of platelet distribution. J Obstet Gynaecol 2016;36:950–3. tion width (PDW) and platelet crit (PCT) to preeclampsia. 23. Dundar O, Yoruk P, Tutuncu L, Erikci AA, Muhcu M, Ergur Ginekol Pol 2015;86:372–5. AR, et al. Longitudinal study of platelet size changes in gesta- 34. Soylu Karap›nar O, Benk fiilfeler D, Dolapç›o¤lu K, Kurt tion and predictive power of elevated MPV in development of Keskin R, Beyaz›t A. The effect of molar pregnancies on pre-eclampsia. Prenat Diagn 2008;28:1052–6. platelet parameters. J Obstet Gynaecol 2016;36:912–5. 24. James TR, Reid HL, Mullings MA. Are published standards 35. Artunc Ulkumen B, Pala HG, Calik E, Oruc Koltan S. Can for haematological indices in pregnancy applicable across populations: an evaluation in healthy pregnant Jamaican women. mean platelet volume and platelet distrubition width be possi- BMC Pregnancy Childbirth 2008;8:8. ble markers for ectopic pregnancy and tubal rupture? (MPV and PDW in ectopic pregnancy). Pak J Med Sci 2014;30:352– 25. Holthe MR, Staff AC, Berge LN, Lyberg T. Different levels of 5. platelet activation in preeclamptic, normotensive pregnant, and nonpregnant women. Am J Obstet Gynecol 2004;190:1128–34. 36. Buyukkaya E, Karakas MF, Karakas E, Akçay AB, Tanboga IH, Kurt M, et al. Correlation of neutrophil to lymphocyte 26. Ahmed Y, van Iddekinge B, Paul C, Sullivan HF, Elder MG. ratio with the presence and severity of metabolic syndrome. Retrospective analyses of platelet numbers and volumes in Clin Appl Thromb Hemost 2014;20:159–63. normal pregnancy and in preeclampsia. Br J Obstet Gynaecol 1993;100:216–20. 37. Tamer LH, Aykanat Y, Sa¤›r FG, Olmuflçelik O, Özdemir S. 27. Kamath S, Blann A, Lip G. Platelet activation: assessment and Status of neutrophil-lymphocyte ratio and 25-hydroxyvitamin quantification. Eur Heart J 2001;22:1561–71. D in preeclampsia and preterm birth. Perinatal Journal 2017;25: 91–6. 28. Leader A, Pereg D, Lishner M. Are platelet volume indices of clinical use? A multidisciplinary review. Ann Med 2012;44: 38. Wen Y. High red blood cell distribution width is closely asso- 805–16. ciated with risk of carotid artery atherosclerosis in patients with hypertension. Exp Clin Cardiol 2010;15:37–40. 29. Bozkurt N, Yilmaz E, Biri A, Taner Z, Himmetoglu O. The mean platelet volume in gestational diabetes. J Thromb 39. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl Thrombolysis 2006;22:51–4. J Med 2005;352:1011–23. 30. Budak YU, Polat M, Huysal K. The use of platelet indices, 40. Beyazit F, Öztürk FH, Pek E, Ünsal MA. Evaluation of the plateletcrit, mean platelet volume and platelet distribution width hematologic system as a marker of subclinical inflammation in in emergency non-traumatic abdominal surgery: a systematic hyperemesis gravidarum: a case control study. Ginekol Pol review. Biochem Med (Zagreb) 2016;26(2):178–93. 2017;88:315–9. 31. Wiwanitkit V. Plateletcrit, mean platelet volume, platelet dis- 41. Erdo¤an S, Özdemir O, Do¤an HO, Sezer S, Atalay CR, tribution width: its expected values and correlation with paral- Y›lmaz FM, et al. Liver enzymes, mean platelet volume, and lel red blood cell parameters. Clin Appl Thromb Hemost 2004; red cell distribution width in gestational diabetes. Turk J Med 10:175–8. Sci 2014;44:121–5.

22 Perinatal Journal A L J O A T U N R I N R A E L P Original Article

The investigation of the correlation between diastasis recti and the second stage of labor

Ersin ÇintesunİD , Meltem Aydo¤duİD , Çetin Çelik İD Department of Gynecology and Obstetrics, Faculty of Medicine, Selçuk University, Konya, Turkey

Abstract Özet: Diyastazis rekti ile do¤umun ikinci evresi aras›ndaki iliflkinin araflt›r›lmas› Objective: In our study, we investigated whether the distance Amaç: Çal›flmada abdominal rektus kaslar› aras›ndaki mesafe ile do- between rectus abdominis muscles is correlated with the second ¤umun ikinci evresi aras›nda iliflkinin olup olmad›¤› araflt›r›lm›flt›r. stage of labor or not. Yöntem: Bu çal›flma 1 Eylül 2019 – 31 Aral›k 2019 tarihleri ara- Methods: This is a prospective study conducted on the patients who s›nda klini¤imizde spontan vajinal do¤um yapm›fl hastalar üzerin- underwent spontaneous vaginal delivery in our clinic between de yap›lm›fl prospektif bir çal›flmad›r. Gebelik esnas›nda bu ölçüm- September 1, 2019 and December 31, 2019. Since these measure- ler teknik olarak zor oldu¤undan do¤um sonras› postpartum 48 sa- ments were difficult during pregnancy, they were done after the deliv- at içerisinde ölçümler yap›lm›flt›r. Ölçümler üç anatomik bölgeden ery within postpartum 48 hours. The measurements were done on yap›lm›fl olup, yüzeyel ultrasonografi ile abdominal rektus kaslar› three anatomic areas, and the distance between rectus abdominis mus- aras›ndaki mesafe ve en kal›n rektus kas› kal›nl›¤› ölçülmüfltür. Öl- cles and the thickest rectus muscle were measured by superficial ultra- çüm yeri olarak ksifoid seviyesi, umbilikal bölgenin 2 cm üstü ve sonography. Xiphoid level, and 2 cm above and below the umbilical alt› al›nm›flt›r. Daha sonra hasta dosyas›nda bulunan partografa ba- area were selected as measurement sites. Afterwards, the partographs k›larak do¤umun ikinci evresinin kaç dakika sürdü¤ü hesaplanm›fl in the patient files were checked to calculate the duration of the second ve bu iki de¤er aras›nda iliflki hesaplanm›flt›r. Çal›flma için topla- stage of labor in minutes, and the correlation between these two val- nan hastalar›n analizleri primipar ve multipar olarak ayr› ayr› he- ues was calculated. The analyses of the patients collected for the study saplanm›flt›r. were calculated separately as primiparous and multiparous analyses. Bulgular: Primigravid 57, multigravid 63 hastan›n verileri karfl›- Results: The data of 57 primigravid patients and 63 multigravid laflt›r›lm›flt›r. Primigravidlerde gebelik haftas›, fetal a¤›rl›k ve ksi- patients were compared. In the primigravid patients, there was a statis- foid üzeri rektus kaslar› aras›ndaki mesafe ile do¤umun ikinci ev- tically significant weak correlation between the week of gestation, fetal resi aras›nda istatistiksel olarak anlaml›, zay›f derecede korelasyon weight and the distance between rectus muscles above xiphoid level and saptanm›flt›r (p<0.05 ve s›ras›yla r=0.351, 0.369, 0.336). Di¤er ul- the second stage of labor (p<0.05; r=0.351, 0.369, and 0.336, respective- trasonografik de¤iflkenler aras›nda anlaml› iliflki saptanmam›flt›r. ly). No significant correlation was found between other ultrasono- Multigravid hastalarda ise abortus say›s› ile do¤umun ikinci evresi graphic variables. There was a statistically significant weak correlation aras›nda istatistiksel olarak anlaml›, zay›f derecede korelasyon sap- between the number of abortion and the second stage of labor in multi- tanm›flt›r (p=0.002, r=0.390). Multigravid hastalarda rektus kaslar› gravid patients (p=0.002, r=0.390). No significant correlation was ve fetal veriler ile do¤umun ikinci evresi aras›nda anlaml› bir iliflki found between the rectus muscles and fetal data and the second stage tespit edilmemifltir (p>0.05). of labor in multigravid patients (p>0.05). Sonuç: Primipar hastalarda ksifoid seviyesindeki diyastazis rekti ile Conclusion: There was a significant correlation between the second do¤umun ikinci evresi aras›nda anlaml› iliflki saptanm›flt›r. ‹leriye dö- stage of labor and the diastasis recti at the xiphoid level in primi- nük diyastazis rekti ile kar›n içi bas›nc›n›n etkisini inceleyen çal›flma- parous patients. Further studies investigating the diastasis recti and lar, do¤umun ikinci evresi üzerine etkisini de daha direkt belirleme- intraabdominal pressure would help to determine the impact on the ye yard›mc› olacakt›r. second stage of labor directly. Keywords: Diastasis recti, labor, rectus abdominis. Anahtar sözcükler: Diyastazis rekti, do¤um, rektus abdominis.

Correspondence: Ersin Çintesun, MD. Department of Gynecology and Obstetrics, Faculty of Medicine, Selçuk University, Konya, Turkey. e-mail: [email protected] / Received: January 21, 2020; Accepted: March 123, 2020 Please cite this article as: Çintesun E, Aydo¤du M, Çelik Ç. The investigation of the correlation between diastasis recti and the second stage of labor. Perinatal Journal 2020;28(1):23–27. doi:10.2399/prn.20.0281006

ORCID ID: E. Çintesun 0000-0001-8507-5850; M. Aydo¤du 0000-0002-2364-6870; Ç. Çelik 0000-0001-6165-5092 Çintesun E, Aydo¤du M, Çelik Ç

Introduction Methods The labor is defined as the fetus going out of uterus This is a prospective study conducted on the patients after the regular contractions of uterus. The labor who underwent spontaneous vaginal delivery in a terti- process has been defined in four stages. The first stage ary university hospital between September 1, 2019 and begins with the uterus contractions and cervical dila- December 31, 2019. The approval of the local ethics tion and ends when the cervix is fully dilated. The sec- committee of the university was obtained before the ond stage begins when the cervical dilation is 10 cm study. The informed consents were received from the and it ends with the fetus moving through the birth patients included in the study. canal. In the second stage of labor, fetal head makes the The pregnant women who underwent vaginal internal rotation in the mid-pelvis through uterus con- delivery between 37 and 42 weeks of gestation in our tractions and pushes and reaches right below the sym- clinic were included in the study. The women who physis and after completing the internal rotation here, delivered at preterm and post-term weeks of gestation, it goes out of perineum by performing extension. The those with known muscle and connective tissue dis- second stage of labor is a significant milestone in the eases and the cases who underwent abdominal and cos- obstetric management, and its ideal duration has been metic surgery were excluded from the study. Standard still controversial today.[1] Many factors affecting the physiological pushing methods are used in our clinic as second stage of labor have been defined.[2–5] Among labor method, and the cases which were applied these factors, applying epidural anesthesia was shown to maneuvers that may shorten the second stage of labor extend the second stage of labor. The position of moth- were excluded from the study. er and presence of pushes are among the factors that Since it was technically difficult to measure the dis- shortens the second stage of labor.[2,3,5] Physiological tance between rectus muscles during pregnancy, these pushing methods have been defined by the active measurements were done within postpartum 48 hours. directed pushing methods among today’s pushing The measurements were done on three anatomic areas, methods.[6,7] Physiological pushing methods are fre- and the distance between rectus muscles and the thick- quently today.[8] est rectus muscle were measured by superficial ultra- Diastasis recti (DR) is the abnormal separation of the sonography, and these measurements were done by the right and left rectus abdominis muscles at the linea alba same physician. Xiphoid level, and 2 cm above and level. Although there is no clear definition for the abnor- below the umbilical area were selected as measurement mal inter-rectus distance in DR, some authors consider sites. Afterwards, the partographs in the patient files the distances more than 2 cm as diastasis.[9] However, it were checked to calculate the duration of the second stage of labor in minutes, and the correlation between is clinically possible that there may be overt diastasis these two values was calculated. The analyses of the cases with inter-rectus distances less than 2 cm. DR can patients collected for the study were calculated sepa- be seen during pregnancy, postmenopausal period and [4] rately as primiparous and multiparous analyses. in men. In pregnancy, particularly DR occur physio- logically and it may recover after delivery in some The data were analyzed by using Statistical Package patients while it either progresses or remains same in Social Sciences (SPSS), version 21.0 (SPSS Inc., some patients. Advanced age, multiparity, undergoing Chicago, IL, USA). Histogram, Kolmogorov-Smirnov cesarean section, weight, high birth weight and ethnici- analysis and Scatterplots analysis were used for the ty are the risk factors.[10,11] Observing herniation in the normality and linearity analyses of the data. Where inter-rectus distance through the increased intraabdom- applicable, Pearson or Spearman’s correlation analysis inal pressure in case of DR indicated that DR may the- was performed for the correlation analyses. Statistical oretically cause defect in the increase of intraabdominal significance level was considered p<0.05. pressure, and therefore it inspired us for this study. In our study, we investigated whether the distance Results between rectus muscles is correlated with the second The duration of the second stage of labor were com- stage of labor or not. pared separately in primigravid and multigravid

24 Perinatal Journal The investigation of the correlation between diastasis recti and the second stage of labor

Table 1. The correlation between diastasis recti and the second stage of labor.

Primiparity (n=57) Multiparity (n=63)

Full dilation time Full dilation time Full dilation time Full dilation time r-value p-value r-value p-value

Age -0.31 0.817 -0.010 0.938 Gravida - - 0.057 0.656 Parity - - -0.218 0.087 Living - - -0.218 0.087 Abortion - - 0.390 0.002 Week of gestation 0.351 0.007 0.155 0.226 Fetal weight 0.369 0.005 0.020* 0.879 Distance between xiphoid rectus muscles 0.336* 0.011 -0.076* 0.556 Thickness of xiphoid rectus muscles 0.013* 0.921 -0.027 0.836 Distance between xiphoid rectus muscles 2 cm above umbilicus 0.217* 0.105 0.024* 0.853 Thickness of xiphoid rectus muscles 2 cm above umbilicus 0.067 0.619 -0.023 0.856 Distance between xiphoid rectus muscles 2 cm below umbilicus 0.223 0.096 -0.097 0.451 Thickness of xiphoid rectus muscles 2 cm below umbilicus 0.032 0.814 -0.094 0.461

*Presented as Pearson correlation. Spearman’s correlation was used for the other values. patients. The data of 57 primigravid patients and 63 Diastasis recti is defined as the increase in distance multigravid patients were compared. The correlation between rectus muscles, and it develops the majority of between 2nd stage of labor and DR, and demographic the pregnant women. In the study performed by Hsia et and fetal variables are summarized in Table 1. In the al., the authors measured the distance between rectus primigravid patients, there was a statistically signifi- muscles at 36 weeks of gestation and postpartum 12th cant, positive and weak correlation between the week weeks and found that difference was 300–400%.[12] In of gestation, fetal weight and the distance between rec- another study, the authors made measurements through tus muscles above xiphoid level and the second stage of three different anatomic areas on 84 healthy primi- labor (p<0.05; r=0.351, 0.369, and 0.336, respectively). parous patients and they followed up the cases at 35 No significant correlation was found between other weeks of gestation and postpartum periods for four ultrasonographic variables (p>0.05). No correlation times in terms of DR. In this study, the researchers con- was found between the duration of the second stage of sidered 16 mm threshold value 2 cm below umbilicus for labor and the distance between rectus muscles, fetal DR, and they established all patients with DR diagnosis weight and demographic data in multiparous patients. at 35 weeks of gestation. However, the authors observed that this rate dropped to 35–39% in the ultrasonography performed on the postoperative sixth month.[13] Also, Discussion there is no full consensus on the ideal DR distance. In this study, we investigated the correlation between While some authors accept direct 2 cm threshold, some the second stage of labor and the distance between rec- studies found different threshold values for DR dis- tus muscles. We found significant correlation in our tances.[14–16] However, some studies based on symptoms study between the duration of the second stage of labor found that DR symptoms were observed below 2 cm as and fetal weight, week of gestation and the distance well.[15] DR is an anatomic variability developing during between rectus muscles at xiphoid level in primiparous the pregnancy according to the literature, and we inves- patients. There was a significant correlation between the tigated the correlation between DR distances and labor number of abortion and the second stage of labor in in our study. We did not use a cut-off value in our study multiparous patients. considering the threshold values in the literature. There

Volume 28 | Issue 1 | April 2020 25 Çintesun E, Aydo¤du M, Çelik Ç

was a moderate and statistically significant correlation xiphoid level in the primiparous patients. Moreover, between the DR distance at xiphoid level in the primi- we found a positive and weak correlation between the parous patients and the second stage of labor in primi- duration of the second stage of labor and week of ges- parous patients. However, we did not find any correla- tation and fetal weight in the primiparous patient, tion in the multiparous patients. which supports the study hypothesis. We found no In the literature, there is no study conducted on the correlation between the gaps above and below the labor outcomes of DR, and in fact, there is a limited umbilicus and the second stage of labor in the primi- number of studies on DR and pregnant women. parous and multiparous patients. Further studies inves- Sperstad et al. investigated the correlation between DR tigating the diastasis recti and intraabdominal pressure and lumbosacral pain in the pregnant women in their would help to determine the impact on the second study. They also assessed the patients 12 weeks later stage of labor more directly. after the labor. In their study, the authors found DR prevalence between 30% and 45%, and found no risk Conflicts of Interest: No conflicts declared. factor for DR except pregnancy, and could not observe References any difference between the presence and absence of DR in terms of lumbosacral pain.[13] In the study of 1. Cheng YW, Caughey AB. Defining and managing normal and Gannurson et al., the authors investigated the correla- abnormal second stage of labor. Obstet Gynecol Clin North tion between DR distance and abdominal muscle force. Am 2017;44:547–66. In this study, the authors measured muscular forces 2. Gupta JK, Sood A, Hofmeyr GJ, Vogel JP. Position in the sec- intraoperatively and found a significant and negative ond stage of labour for women without epidural anaesthesia. Cochrane Database Syst Rev 2017;5:CD002006. correlation between abdominal muscle force and DR [17] 3. Lemos A, Amorim MM, Dornelas de Andrade A, de Souza AI, distance. Benjamin et al. found no correlation between Cabral Filho JE, Correia JB. Pushing/bearing down methods DR and lumbosacral pain and incontinence in their sys- for the second stage of labour. Cochrane Database Syst Rev tematic review, but found a correlation between pelvic 2017;3:CD009124. organ prolapse, quality of life, muscular force and severe 4. Sperstad JB, Tennfjord MK, Hilde G, Ellström-Engh M, Bø [18] back pain. The inspiration for our study is the investi- K. Diastasis recti abdominis during pregnancy and 12 months gation of the impact of muscle weakness caused by dias- after childbirth: prevalence, risk factors and report of lum- tasis recti on the labor. In our study, we observed the bopelvic pain. Br J Sports Med 2016;50:1092–6. impact of DR on the second stage of labor only at the 5. Tuuli MG, Frey HA, Odibo AO, Macones GA, Cahill AG. xiphoid level in the patients with primiparity, but did not Immediate compared with delayed pushing in the second stage observe this impact on other levels in the patients with of labor: a systematic review and meta-analysis. Obstet Gynecol primiparity and multiparity. Indirect measurements 2012;120:660–8. without invasive methods can be misleading due to var- 6. Hansen SL, Clark SL, Foster JC. Active pushing versus passive ious reasons such as the presence of the impact of many fetal descent in the second stage of labor: a randomized controlled trial. Obstet Gynecol 2002;99:29–34. factors on labor and the unknown impact of DR on the intraabdominal pressure. 7. Maresh M, Choong KH, Beard RW. Delayed pushing with lumbar epidural analgesia in labour. Br J Obstet Gynaecol 1983; Investigating the correlation between DR and the 90:623–7. duration of the second stage of labor is the advantage of 8. Hanson L. Second-stage labor care: challenges in spontaneous our study as it has not been investigated yet. Not meas- bearing down. J Perinat Neonatal Nurs 2009;23:31–9. uring intraabdominal pressure, absence of data on DR 9. Akram J, Matzen SH. Rectus abdominis diastasis. J Plast Surg and intraabdominal pressure in the literature the low Hand Surg 2014;48:163–9. number of patients included in the study are the limita- 10. Candido G, Lo T, Janssen PA. Risk factors for diastasis of the tions of our study. recti abdominis. Journal of the Association of Chartered Physiotherapists in Womens’ Health 2005;97:49–54. Conclusion 11. Turan V, Colluoglu C, Turkyilmaz E, Korucuoglu U. Prevalence of diastasis recti abdominis in the population of In conclusion, we found a significant correlation young multiparous adults in Turkey. Ginekol Pol 2011;82: between the second stage of labor and diastasis recti at 817–21.

26 Perinatal Journal The investigation of the correlation between diastasis recti and the second stage of labor

12. Hsia M, Jones S. Natural resolution of rectus abdominis diastasis recti abdominis in the early postpartum period. Phys Ther tasis. Two single case studies. Aust J Physiother 2000;46:301– 2018;98:182–90. 7. 16. Akram J, Matzen SH. Rectus abdominis diastasis. J Plast Surg 13. Fernandes da Mota PG, Pascoal AG, Carita AI, Bø K. Hand Surg 2014;48:163–9. Prevalence and risk factors of diastasis recti abdominis from 17. Gunnarsson U, Stark B, Dahlstrand U, Strigård K. Correlation late pregnancy to 6 months postpartum, and relationship with between abdominal rectus diastasis width and abdominal mus- lumbo-pelvic pain. Man Ther 2015;20:200–5. cle strength. Dig Surg 2015;32;112–6. 14. Beer GM, Schuster A, Seifert B, Manestar M, Mihic-Probst D, 18. Benjamin DR, Frawley HC, Shields N, van de Water ATM, Weber SA. The normal width of the linea alba in nulliparous Taylor NF. Relationship between diastasis of the rectus abdo- women. Clin Anat 2009;22:706–11. minis muscle (DRAM) and musculoskeletal dysfunctions, pain 15. Keshwani N, Mathur S, McLean L. Relationship between and quality of life: a systematic review. Physiotherapy 2019; interrectus distance and symptom severity in women with dias- 105:24–34.

Volume 28 | Issue 1 | April 2020 27 A L J O A T U N R I N R A E L P Original Article

The assessment of the perinatal outcomes of the patients who underwent quad screening test

Mehmet Mete K›rlang›çİD , Gökhan AçmazİD , Erdem ﬁahinİD , Yusuf Madenda¤İD , Fatma ÖzdemirİD , ‹ptisam ‹pek Müderris İD Department of Gynecology and Obstetrics, Faculty of Medicine, Erciyes University, Kayseri, Turkey

Abstract Özet: Dörtlü test yap›lan hastalar›n perinatal sonuçlar›n›n de¤erlendirilmesi Objective: The aim of this study is to assess the correlation between Amaç: Bu çal›flman›n amac›, dörtlü test s›ras›nda de¤erlendirilen the poor perinatal outcomes and the serum biochemical markers such maternal serum alfa fetoprotein (AFP), insan koryonik gonadotro- as maternal serum alpha fetoprotein (AFP), human chorionic pini (hCG), unkonjuge estriol (uE3) ve inhibin-A (INH-A) serum gonadotropin (hCG), unconjugated estriol (uE3) and inhibin-A (INH- biyokimyasal belirteçleri ile olumsuz perinatal sonuçlar aras›ndaki A) checked during the quad screening test. iliflkiyi de¤erlendirmektir. Methods: In this retrospective study, the results of 485 pregnant Yöntem: Bu retrospektif çal›flmada Ocak 2018 – Ocak 2019 tarih- women who underwent quad screening test in the Outpatient Clinic leri aras›nda Erciyes Üniversitesi T›p Fakültesi Kad›n Hastal›klar› of Gynecology and Obstetrics of Faculty of Medicine at Erciyes ve Do¤um poliklini¤inde dörtlü tarama testi yapt›ran ve çal›flmaya University, Kayseri, Turkey between January 2018 and January 2019 dahil edilme kriterlerini karfl›layan 485 gebenin sonuçlar› analiz and met the inclusion criteria were analyzed. The primary result of edildi. Çal›flman›n primer sonucu olumsuz perinatal sonuçlar›n the study was established as the development of poor perinatal out- geliflmesi olarak belirlendi. Olumsuz perinatal sonuçlar gestasyo- comes. The poor perinatal outcomes were defined as gestational dia- nel diyabet (GDM), gestasyonel hipertansiyon (GHT), preek- betes (GDM), gestational hypertension (GHT), preeclampsia, lampsi, intrauterin geliflim gerili¤i (IUGR), preterm do¤um, erken intrauterine growth restriction (IUGR), preterm labor, premature membran rüptürü (EMR), oligohidroamniyoz, polihidroamniyoz, rupture of membranes (PRM), oligohydramnios, polyhydramnios, HELLP sendromu, gebeli¤in intrahepatik kolestaz› (G‹K) olarak HELLP syndrome, and intrahepatic cholestasis of pregnancy (ICP). tan›mland›. Results: A total of 485 pregnant women, who met the inclusion crite- Bulgular: Çal›flmaya, dahil edilme kriterlerini karfl›layan 485 gebe ria, were included in the study. A significant correlation was found çal›flmaya dahil edildi. AFP’nin MoM≥2 olmas› ile GHT, EMR, between AFP MoM≥2 and GHT, PRM, preterm labor, and the devel- preterm do¤um, IUGR geliflimi aras›nda anlaml› iliflki bulundu opment of IUGR (p=0.017, p=0.033, p=0.037, and p=0.038, respec- (s›ras›yla p=0.017, p=0.033, p=0.037, p=0.038). GHT riskinde 5.1 tively). It was seen that the risk increased 5.1 times for GHT, 3.2 times kat, preterm do¤um riskinde 3.2 kat, IUGR geliflme riskinde 3.8 for preterm labor, and 3.8 times for the development of IUGR. There kat art›fl oldu¤u görüldü. hCG’nin MoM≥2 olmas› ile GHT gelifl- was a significant correlation between hCG MoM≥2 and the risk of me riski aras›nda anlaml› iliflki bulundu (p=0.024); bu de¤erin üs- GHT development (p=0.024); however, the risk of GHT develop- tünde GHT geliflme riskinde 3.8 kat art›fl oldu¤u tespit edildi. ment increased for 3.8 times above this value. A significant correlation INH-A’n›n MoM≥2 olmas› ile GHT, HELLP sendromu geliflimi was found between INH-A being MoM≥2 and the development of aç›s›ndan anlaml› iliflki saptand› (s›ras›yla p=0.009, p=0.005). Bu GHT and HELLP syndrome (p=0.009 and p=0.005, respectively). In gebelerde HELLP sendromu geliflme riskinde 31 kat, GHT ris- these pregnant women, the risk increased 31 times for the develop- kinde 9.4 kat art›fl tespit edildi. uE3 MoM de¤eri ≤0.5 olanlarda ment of HELLP syndrome, and 9.4 times for GHT. In the cases with preeklampsi ve HELLP sendromu gelifliminde anlaml› iliflki oldu- uE3 MoM≤0.5, there was a significant correlation for the development ¤u görüldü (s›ras›yla p=0.033, p=0.049). Ek olarak GDM, G‹K, of preeclampsia and HELLP syndrome (p=0.033 and p=0.049, respec- polihidroamniyoz ve oligohidroamniyoz ile AFP MoM, beta-hCG tively). On the other hand, there was no significant correlation MoM, uE3 MoM ve INH-A MoM de¤erleri aras›nda anlaml› ko- between GDM, ICP, polyhydramnios, and oligohydramnios and AFP relasyon saptanmad›. MoM, beta-hCG MoM, uE3 MoM and INH-A MoM values. Sonuç: Çal›flmam›zda AFP, hCG, uE3, INH-A seviyelerindeki Conclusion: In our study, we found correlation between poor perina- de¤iflim ile kötü perinatal sonuçlar aras›nda iliflki bulundu¤u gö- tal outcomes and the changes in AFP, hCG, uE3 and INH-A levels. rülmüfltür. Keywords: AFP, quad screening test, hCG, inhibin-A, perinatal Anahtar sözcükler: AFP, dörtlü test, hCG, inhibin-A, perinatal so- outcome, uE3. nuç, uE3.

Correspondence: Yusuf Madenda¤, MD. Department of Gynecology and Obstetrics, Faculty of Medicine, Erciyes University, Kayseri, Turkey. e-mail: [email protected] / Received: February, 29 2020; Accepted: April 8, 2020 Please cite this article as: K›rlang›ç MM, Açmaz G, ﬁahin E, Madenda¤ Y, Özdemir F, Müderris ‹‹. The assessment of the perinatal outcomes of the patients who underwent quad screening test. Perinatal Journal 2020;28(1):28–35. doi:10.2399/prn.20.0281007

ORCID ID: M. M. K›rlang›ç 0000-0002-9750-1594; G. Açmaz 0000-0002-4215-3676; E. ﬁahin 0000-0001-9492-6223; Y. Madenda¤ 0000-0002-7622-2991; F. Özdemir 0000-0003-1626-3609; ‹. ‹. Müderris 0000-0002-9288-889X The assessment of the perinatal outcomes of the patients who underwent quad screening test

Introduction antenatal follow-ups and labors in our clinic and whose labor data could be accesses were included in the study. The purpose of prenatal diagnosis today is to detect genetic diseases and congenital anomalies of fetus before Of the patients, the demographic characteristics, age, birth. The genetic tests performed for the diagnosis gravida, parity, early pregnancy loss, number of living include cytogenetic tests and molecular tests which eval- child, gestational age at which quad screening test was uate mutation analyses at DNA level. Thanks to the pre- performed, body weight, AFP, hCG, uE3, INH-A MoM natal diagnosis, it is possible to establish intrauterine levels, week of gestation, labor type, reason for cesarean diagnosis in pregnancies with risk, and it also enables to section if any, birth weight, 1-minute and 5-minute Apgar scores, and blood gas values measured through initiate treatment disease, if any, before labor and to cord blood at birth were accessed from the records. The manage treatment after labor by taking necessary pregestational ages were calculated on the basis of the last cautions. The serum biochemical markers such as mater- menstrual dates of the patients, and ultrasound results nal serum alpha fetoprotein (AFP), human chorionic were used to calculate the gestational ages for those gonadotropin (hCG), unconjugated estriol (uE3) and whose last menstrual dates were unknown. For the cases inhibin-A (INH-A) are used to screen for aneuploidies without early period ultrasonography results, the bipari- such as trisomy 21, trisomy 18 and trisomy 13, and con- etal diameter (BPD) during the test was based on. genital anomalies such as neural tube defects in the sec- [1–3] All maternal markers were evaluated by solid-phase ond trimester. The correlation of positive prenatal competitive immunoassay method. The blood samples screening tests with the congenital anomalies such as were collected through antecubical vein between 15 and anterior abdominal wall defects and neural tube defect 20 weeks of gestation. The blood samples were kept at has been shown clearly.[4–6] In addition, some studies the room temperature for the coagulation for 20–30 reported that these serum biochemical markers may be minutes, and then they were processed by centrifuging at correlated with poor perinatal outcomes in the fetuses [4,6,7] 3000 rpm for 5 minutes. AFP values were reported in without aneuploidy and congenital anomaly. IU/ml, hCG values in mIU/ml, uE3 values in ng/ml, and In our study, we aimed to investigate the correla- INH-A values in pg/ml. The values were adapted to the tion between poor perinatal outcomes and the second- body weights of the patients. The results were analyzed trimester serum markers, which are out of the deter- by using licensed SsdwLab 5 software (SBP SOFT, mined threshold ranges, of fetuses without aneuploidy Girona, Spain), and the MoM value predetermined and congenital anomaly. according to the weeks of gestation and risk rates for age, trisomy 21, trisomy 13, and trisomy 18 were reported. Methods For test calculation, the risk was calculated by using the age, weight, smoking habit, diabetes and previous histo- This retrospective study was carried out in accordance ry of child with anomaly, IVF pregnancy, sample collec- with the Declaration of Helsinki by the approval of the tion date and ultrasound date of the patients. Ethics Committee (2019/632) of the Department of The primary result of the study was determined as the Gynecology and Obstetrics of Faculty of Medicine, development of poor perinatal outcomes. The poor peri- Erciyes University. The results of 889 pregnant natal outcomes were defined as gestational diabetes women who underwent quad screening test in the (GDM), gestational hypertension (GHT), preeclampsia, obstetrics clinic between January 2018 and January intrauterine growth restriction (IUGR), preterm labor, 2019 were analyzed in the study. Multiple pregnancies, premature rupture of membranes (PRM), oligohydram- the pregnant women with congenital anomaly such as nios, polyhydramnios, HELLP syndrome, and intrahep- chromosomal anomaly, neural tube defect (NTD) and atic cholestasis of pregnancy (ICP). The cases with glu- anterior abdominal wall defects during the follow-up, cose level >180 at 1st hour after 50-g OGGT were con- the pregnant women who had abortion before 24 sidered GDM. The patients with glucose level >140 weeks of gestation during the follow-up and those mg/dl underwent 3-hour diagnosis test by 100-g OGTT. whose labor data could not be accessed were excluded The 100-g OGTT values being 2 or more (preprandial from the study. After the final analysis, 485 pregnant ≥95 mg/dl, 1st hour ≥180 mg/dl, 2nd hour ≥155 mg/dl, women who underwent their quad screening tests, 3rd hour ≥140 mg/dl) were accepted as GDM.[8] GHT

Volume 28 | Issue 1 | April 2020 29 K›rlang›ç MM et al.

was defined as two blood pressure values measured with tical analysis. Levene’s test statistics was used to check 6-hour interval being >140/90 mmHg without protein- the homogeneity of the variances. The descriptive statis- uria.[9] Preeclampsia was considered as the hypertension tics were presented as mean, standard deviation, and in a pregnant woman at the 20 weeks of gestation, who minimum and maximum values. The differences was previously normotensive (systolic blood pressure between the groups in terms of mean values were ana- ≥140 mmHg or diastolic blood pressure ≥90 mmHg for lyzed by t-test and Mann-Whitney U test for the contin- 2 times with at least 4-hour interval, and systolic blood uous variables and by Pearson’s chi-squared test for the pressure ≥160 mmHg or diastolic blood pressure ≥110 categorical variables. The values of AFP MoM, HCG mmHg for 2 times with a few minutes of interval) with MoM, ‹NH-A MoM and uE3 MoM variables causing concomitant proteinuria (≥0.3g proteinuria in 24-h urine risks in terms of other variables were compared. The or 2+ or more proteinuria in spot urine if quantitative risks were presented by odds ratios and confidence inter- measurement is not possible) or target organ dysfunction vals. All statistical analyses were conducted by TUR- (platelet count <100,000/mm3, serum creatinine >1.1 COSA Analitik software (https://turcosa.com.tr/; mg/dl or double amount of serum creatinine without any Turkosa Analitik, Kayseri, Turkey). For the statistical other renal disease, liver transaminases being at least 2 significance, p-value was determined 0.05. times more than normal concentrations, pulmonary [9] edema, cerebral symptoms). When amniotic mem- Results branes were ruptured before 37 weeks of gestation, it was A total of 485 pregnant women who met inclusion crite- considered PRM. The preterm labor was defined as the ria were included in the study after the final analysis. The fulfilment of the labor by the cervical dilation and efface- demographic characteristics of the pregnant women are ment accompanying to uterine contractions before 37 shown in Table 1. The mean values of adjusted maternal weeks of gestation. Except those which were constitu- serum AFP MoM, hCG MoM, uE3 MoM and INH-A tional and below 10th percentile according to the growth MoM are presented in Table 2. The distribution of poor curves based on the estimated fetal weight (EFW) meas- perinatal outcomes of 485 pregnant women in the study ured by the ultrasonography, the pregnancies presenting are given in Fig. 1. Of 485 pregnant women, 161 (34%) progressive deviation from the growth curve during 3- delivered by normal labor while 324 (66%) by cesarean week follow-up and having concomitant oligohydram- section. Of the pregnant women, 30 (6%) had GDM, 19 nios and pathological fetal Doppler findings were [10] (3.9%) had GHT, 46 (9.4%) had PRM, 35 (7.2%) had defined as IUGR. Oligohydramnios and polyhydram- preterm labor, 27 (5.5%) had IUGR, 19 (3.9%) had nios were defined as the amniotic fluid index being ≤5 cm [11] preeclampsia, 18 (3.7%) had polyhydramnios, 17 (3.5%) and ≥25 mm, respectively. ICP was defined as the ele- had oligohydramnios, 2 (0.4%) had cholestasis and 5 vation in liver enzyme levels or bile acid levels due to the [12] (1%) had HELLP syndrome. rash began in the third trimester of pregnancy. HELLP syndrome was diagnosed according to The correlation between poor perinatal outcomes Mississippi criteria. AST or ALT values being ≥70 IU/l, and biochemical markers, and the values for risk increase LDH ≥600 IU/l, and platelet count being 100,000– in the poor perinatal outcomes are shown in Tables 3 and 150,000 were accepted as HELLP syndrome.[13] Based on 4. There was no significant correlation between GDM, the cut-off values in the literature, the patients with AFP ICP, polyhydramnios, and oligohydramnios and AFP MoM ≥2, beta-hCG MoM ≥2, INH-A MoM ≥2 and MoM, hCG MoM, uE3 MoM and INH-A MoM values. uE3 MoM ≤0.5 were identified, and the presence of There was a significant correlation between AFP correlation between these patients and gestational MoM ≥2 and the development of GHT, PRM, preterm complications (GDM, GHT, preeclampsia, IUGR, labor and IUGR (p=0.017, p=0.033, p=0.037, and preterm labor, PRM, oligohydramnios, polyhydram- p=0.038, respectively). It was found that the risk increased nios, HELLP syndrome, ICP) was investigated. 5.1 times for GHT (OR 1.578–16.713; p=0.010), 3.2 times for preterm labor (OR 1.147–9.166; p=0.027), 3.8 Statistical analysis times for the development of IUGR (OR 1.203–12.059; Histogram and q-q plot graphics as well as Shapiro-Wilk p=0.023), and 2.9 times for PRM (OR 1.139–7.825; test were used to test the normality of data in the statis- p=0.026) when AFP MoM was ≥2.

30 Perinatal Journal The assessment of the perinatal outcomes of the patients who underwent quad screening test

Table 1. The demographic characteristics of pregnant women.

Mean SD Minimum Maximum

Age 30.08 6.409 17 46 Weight (kg) 70.37 14.792 36 160 Week of gestation 16.49 1.084 15 20 Gravida 3.04 1.54 1 10 Parity 1.50 1.17 0 7 Number of abortion 0.53 0.94 0 6 Number of living child 1.41 1.09 0 6 Week of gestation during labor 38.03 2.06 24 42 Birth weight (g) 3162 578 536 4530 1-minute Apgar 7.93 0.478 3 8 5-minute Apgar 9.95 0.433 6 10 Cord blood gas (mmHg) 7.33 0.074 6.90 7.49

SD: standard deviation.

There was a significant correlation between hCG Table 2. The adjusted maternal serum hCG, uE3, AFP and INH-A MoM values. MoM ≥2 and the risk of GHT development (p=0.024).

It was found that the risk increased for 3.8 times for the Mean SD Minimum Maximum development of GHT (OR 1.303–11.104; p=0.020) AFP MoM 1.22 0.62 0.30 7.54 when hCG MoM was ≥2. Similarly, we did not find a hCG MoM 1.12 0.74 0.14 7.71 correlation between low hCG MoM values and poor uE3 MoM 0.67 0.25 0.10 1.95 gestational outcomes in our study. INH-A MoM 0.74 0.45 0.19 3.79 There was a significant correlation between the devel- SD: standard deviation. opment of GHT and HELLP syndrome, and INH-A MoM ≥2 (p=0.009 and p=0.005, respectively). It was found that the risk increased for 31 times for the develop- Discussion ment of HELLP syndrome (OR 4.667–206.813; Maternal AFP, hCG, uE3 and ‹NH-A serum biochem- p<0.001) and 9.4 times for GHT (OR 2.331–38.215; p= ical markers are important parameters used in the 0.002). screening of aneuploidies and congenital anomalies, and A significant correlation was observed between uE3 the changes in their levels provide information about the MoM ≤0.5 and the development of preeclampsia and prognosis of pregnancy. In our study, we investigated HELLP syndrome (p=0.030 and p=0.050, respectively). the correlation between poor perinatal outcomes and

Fig. 1. The distribution of perinatal complications.

Volume 28 | Issue 1 | April 2020 31 K›rlang›ç MM et al.

Table 3. The correlation between poor perinatal outcomes and biochemical markers.

AFP MoM hCG MoM uE3 MoM INH-A MoM

<2 ≥2 <2 ≥2 >0.5 ≤0.5 <2 ≥2 MoM MoM MoM MoM MoM MoM MoM MoM Perinatal complications n (%) n (%) p n (%) n (%) p n (%) n (%) p n (%) n (%) p

GDM 29 (6.0) 1 (0.2) 0.490 28 (5.8) 2 (0.4) 0.459 16 (3.3) 14 (2.9) 0.138 29 (6.2) 0 (0.0) 0.470 GHT 15 (3.1) 4 (0.8) 0.017 14 (2.9) 5 (1.0) 0.020 12 (2.5) 7 (1.4) 0.810 16 (3.3) 3 (0.6) 0.010 Preeclampsia 18 (3.9) 1 (0.2) 0.714 17 (3.5) 2 (0.4) 0.540 8 (1.6) 11 (2.3) 0.030 17 (3.5) 1 (0.2) 0.370 IUGR 23 (4.7) 4 (0.8) 0.038 20 (4.1) 4 (0.8) 0.170 14 (4.9) 10 (6.0) 0.430 21 (4.5) 3 (0.6) 0.180 PRM 40 (8.2) 6 (1.2) 0.033 39 (8.0) 7 (1.4) 0.120 29 (9.1) 17 (3.5) 0.400 46 (9.6) 0 (0.0) 0.300 Preterm labor 30 (6.2) 5 (1.0) 0.037 31 (6.4) 4 (0.8) 0.410 24 (4.9) 11 (2.3) 0.440 35 (7.3) 0 (0.0) 0.400 Oligohydramnios 16 (3.3) 1 (0.2) 0.629 15 (3.1) 2 (0.4) 0.510 12 (2.5) 5 (1.0) 0.670 17 (3.5) 0 (0.0) 0.650 Polyhydramnios 18 (3.7) 0 (0.0) 0.350 16 (3.3) 2 (0.4) 0.511 11 (2.3) 7 (1.4) 0.671 18 (3.7) 0 (0.0) 0.629 ICP 2 (0.4) 0 (0.0) 0.892 2 (0.4) 0 (0.0) 0.820 2 (0.4) 0 (0.0) 0.430 2 (0.4) 0 (0.0) 0.950 HELLP syndrome 0 (0.0) 5 (1.0) 0.750 3 (0.6) 2 (0.4) 0.070 1 (0.2) 4 (0.8) 0.050 3 (0.6) 2 (0.4) 0.010

The values are presented as n (%). Statistically significant p-values are given in bold. GDM: gestational diabetes; GHT: gestational hypertension; ICP: intrahepatic cholestasis of pregnancy; IUGR: intrauterine growth restriction; PRM: premature rupture of membrane. second trimester serum markers being out of predeter- trimester markers can be compared with the poor mined cut-off ranges in the fetuses without aneuploidy obstetric outcomes in the advanced periods of pregnan- and congenital anomaly. The results of our study cy for the normal fetuses without aneuploidy or neural showed that the serum markers assessed in the second tube defect.[14] AFP is a oncofetal glycoprotein weighing trimester screening test can be used to detect aneuploidy 69 kDa. It is produced by secondary yolk sac beginning and congenital anomalies as well as the pregnancies with with the second month of the pregnancy and by fetal high risk. We found in our study that AFP, hCG, uE3 liver and gastrointestinal system after the third month of and INH-A levels are correlated with the poor perinatal pregnancy.[15] The conditions where AFP is >2.5 MoM outcomes. in the pregnancies without placenta anomalies such as There are studies in the literature showing that the fetal chromosomal anomalies, structural anomalies increased maternal serum AFP, hCG, INH-A and (NTD, abdominal wall defect, etc.) and chorioangioma, decreased uE3 levels which are among the second and maternal conditions such as choriocarcinoma or

Table 4. Risk increase values in poor perinatal outcomes.

AFP MoM ≥2 MoM beta-hCG MoM ≥2 MoM uE3 MoM ≤0.5 MoM INH-A MoM ≥2 MoM Perinatal complications OR (95% CI) p OR (95% CI) p OR (95% CI) p OR (95% CI) p

GDM GHT 5.136 (1.578–16.713) 0.010 3.804 (1.303–11.104) 0.020 9.437 (2.331–38.215) 0.002 Preeclampsia 0.362 (0.143–0.919) 0.030 IUGR 3.809 (1.203–12.059) 0.023 PRM 2.986 (1.139–7.825) 0.026 Preterm labor 3.242 (1.147–9.166) 0.027 Oligohydramnios Polyhydramnios Cholestasis HELLP syndrome 6.775 (1.102–41.666) 0.039 31.067 (4.667–206.813) <0.001

Statistically significant p-values are given in bold. CI: confidence interval; GDM: gestational diabetes; GHT: gestational hypertension; IUGR: intrauterine growth restriction; OR: odds ratio; PRM: premature rupture of membrane.

32 Perinatal Journal The assessment of the perinatal outcomes of the patients who underwent quad screening test

ovary pathology are considered to be increased AFP HELLP syndrome. uE3 is synthesized from 16-alpha- level. Although the reason of this increased value is not hydroxy-DHEA-S, which is a fetal precursor, by syncy- clear, the authors in a study considered that there is tiotrophoblasts in the placenta. It is converted to 16- pathology in chorionic villi or placental vascular struc- alpha-hydroxy-DHEA-S by 16-alpha hydroxylase tures.[16] In our study, we found significant correlation enzyme in the fetal liver. The product emerging after between AFP MoM level being ≥2 and the development being deconjugated by the placental sulfatase enzyme is of GHT, PRM, preterm labor and IUGR, and we found aromatized by the aromatase enzyme, and uE3 is out that the risk increased for 5.1 times for GHT, 3.2 obtained.[20] A study showed that the low level of uE3 is times for preterm labor, 3 times for IUGR development associated with fetal chromosomal anomalies, structural and 2.9 times for PRM. The results of our study are con- anomalies (anencephaly), fetal death or fetal metabolic sistent with the other studies in the literature. Crandall conditions (steroid sulfatase deficiency, congenital adre- et al. found significant correlation between AFP MoM nal hypoplasia, Smith-Lemli-Opitz syndrome).[21] In the level being ≥2 and the development of GHT, PRM, literature, Gündüz et al. showed that uE3 levels (<0.5 preterm labor and IUGR, and they reported that the MoM) are correlated with the poor perinatal out- rate of obtaining poor perinatal outcome was 19% when comes.[3] In addition, it was reported that low uE3 levels MoM level was 2.5–2.9, and up to 70% when the MoM (<0.05 MoM) are also correlated with poor perinatal [17] level was >5. Another study reported that the inci- outcomes such as GHT, IUGR and oligohydram- dence of GHT was significantly high with the increased nios.[3,5,22] In our study, we found that there is a significant [3] AFP MoM levels, and the risk increased for 4 times. correlation between uE3 level <0.05 MoM and the In our study, we found significant correlation for development of preeclampsia and HELLP syndrome. ≥ hCG MoM being 2 only with the risk of developing In our study, we found a significant correlation GHT, and found out that the risk for developing GHT between INH-A MoM being ≥2 and developing GHT ≥ increased for 3.8 times when hCG MoM was 2. and HELLP syndrome. In these pregnant women, the Similarly, Gündüz et al. reported that there was a signif- risk for developing HELLP syndrome increased for 31 ≥ icant correlation between increased beta-hCG levels ( 2 times and GHT for 9.4 times. INH-A is a glycoprotein MoM) and the development of hypertension induced by in dimeric structure, synthesized in placental tissues and the pregnancy and isolated fetal growth restriction, and gonads, and it has two sub-units which are α and β. they found that the risk increased 3 times for the hyper- INH-A levels are quite high in the cases of triploid tension induced by the pregnancy and 2 times for isolat- [3] (except Down syndrome), HELLP syndrome and when ed fetal growth restriction. In another study, Walton et one of the twins is aborted in the first trimester in twin al. reported that there was a correlation between hCG [18] pregnancies. INH-A levels are particularly low in the levels and preterm labor and stillbirth. Similarly, [23] Heionnen et al. showed in their study that there was a primary antiphospholipid antibody syndrome. In a correlation between increased hCG level and IUGR, study conducted, the authors found that INH-A level is preeclampsia, and GHT. In our study, we found a signif- higher in the women who developed gestational hyper- icant correlation between hCG level and GHT, and tension in concurrence with proteinuria during the sec- reported that elevated hCG level increased the risk of ond trimester. The authors reported that there is a sig- developing GHT for 3.8 times. Although a significant nificant correlation between INH-A MoM levels and correlation could not be found between HELLP syn- GHT and HELLP syndrome. In addition, the authors drome and hCG MoM level, the regression analysis stated that INH-A MoM level increases the risk of [24] showed that the elevation in hCG MoM level increased developing HELLP syndrome 31 times alone. the risk of developing HELLP syndrome for 6.7 times.[19] Despite the clear correlations between abnormal In the literature, no correlation was shown between low serum marker values and undesired perinatal complica- [14,20] hCG level and poor perinatal outcomes, and similar- tions, no research showed that such screening methods ly, we did not found any correlation between low hCG are sufficiently sensitive and specific enough to use as a MoM values and poor perinatal outcomes. screening test for potential poor outcomes. Also, as it is We observed a significant correlation between uE3 not clear whether these distinct correlations are associ- MoM ≤0.5 and the development of preeclampsia and ated with other factors or not, it is unknown if such

Volume 28 | Issue 1 | April 2020 33 K›rlang›ç MM et al.

screening methods can be used in clinical settings safely 5. Madenda¤ Y, Çöl Madenda¤ ‹, Dan›flman N. Birinci trimester or not. Wider studies with more patient populations did tarama testi belirteçlerinin intrauterin geliflme gerili¤i ile iliflkisi ve neonatal sonuçlar› üzerine etkisi. Jinekoloji Obstetrik not investigate the correlations through advanced ve Neonatoloji T›p Dergisi 2018;15:61–5. regression analyses by checking positive and negative 6. Summers AM, Huang T, Meier C, Wyatt PR. The implica- predictive values to see if they are associated with other tions of a false positive second-trimester serum screen for factors. However, under the light of the data, the clini- Down syndrome. Obstet Gynecol 2003;101:1301–6. cians should keep in mind that the screening tests con- 7. Spencer K. Second-trimester prenatal screening for Down ducted may predict undesired perinatal complications as syndrome and the relationship of maternal serum biochemical well as detecting chromosomal diseases. In patients markers to pregnancy complications with adverse outcome. Prenat Diagn 2000;20:652–6. whose MoM values are in risk category in terms of 8. Sahin E, Col Madendag I, Sahin ME, Madendag Y, Acmaz G, preeclampsia, initiating low dose aspirin for prophylac- Muderris II. Effect of vitamin D deficiency on the 75 g oral tic purposes may be a suitable approach although there glucose tolerance test screening and insulin resistance. is no study today proving that it is beneficial.[25] Gynecol Endocrinol 2019;35:535–8. 9. Tayyar AT, Karakus R, Sahin ME, Topbas NF, Sahin E, Karakus S, et al. Wnt signaling pathway in early- and late- Conclusion onset preeclampsia: evaluation with Dickkopf-1 and R- As a result of our study, we are of the opinion that quad Spondin-3 glycoproteins. Arch Gynecol Obstet 2019;299: test as the second trimester screening test may predict 1551–6. perinatal complications and the results of quad screen- 10. Sahin ME, Col Madendag ‹, Ak M. The effect of birth weight percentile on adverse neonatal morbidity in term uncomplicat- ing tests may be a guide in terms of gestational compli- ed pregnancies. Annals of Medical Research 2019;26:2535–9. cations. In our study, we found that AFP, hCG, uE3 11. Madendag Y, Madendag IC, Sahin E, Aydin E, Sahin ME, and INH-A levels are correlated with the poor perina- Acmaz G. How well do the popular ultrasonic techniques esti- tal outcomes. mate amniotic fluid volume and diagnose oligohydramnios, in fact? Ultrasound Q 2019;35:35–8. Pregnant women should be informed in detail about the potential gestational complications, the com- 12. Tayyar AT, Kozal› S, Yetkin Yildirim G, Karakus R, Yuksel IT, Erel O, et al. Role of ischemia-modified albumin in the plications that may develop should be explained to evaluation of oxidative stress in intrahepatic cholestasis of them, and pregnant women should be assessed in detail pregnancy. J Matern Fet Neonat Med 2019;32:3836–40. and very carefully during pregnancy. 13. Ding L, Blitz MJ, Wing DA, Epstein AJ, Gjessing HK, Wilson ML. PHLDA2 gene polymorphisms and risk of HELLP syn- Conflicts of Interest: No conflicts declared. drome and severe preeclampsia. Pregnancy Hypertension 2020; 19:190–4. References 14. Dugoff L; Society for Maternal-Fetal Medicine. First and second trimester maternal serum markers for aneuploidy and 1. Chitayat D, Langlois S, Wilson RD; Genetics Committee of adverse obstetric outcomes. Obstet Gynecol 2010;115:1052– the Society of Obstetricians and Gynaecologists of Canada; 61. Prenatal Diagnosis Committee of the Canadian College of 15. Fox H. Effect of hypoxia on trophoblast in organ culture: a Medical Geneticists. Prenatal screening for fetal aneuploidy in morphologic and autoradiographic study. Am J Obstet Gynecol singleton pregnancies. J Obstet Gynaecol Can 2011;33:736– 1970;107:1058–64. 50. 16. Cheng PJ, Chu DC, Chueh HY, See LC, Chang HC, Weng 2. Currier R, Wu N, Van Meter K, Goldman S, Lorey F, Flessel DR. Elevated maternal mid-trimester serum free beta-human M. Integrated and first trimester prenatal screening in chorionic gonadotropin levels in vegetarian pregnancies that California: program implementation and patient choice for cause increased false-positive Down syndrome screening follow-up services. Prenat Diagn 2012;32:1077–83. results. Am J Obstet Gynecol 2004;190:442–7. 3. Gündüz ÖD, Eser A, Çoban U, Tekeli S. Evaluation of the 17. Crandall BF, Robinson L, Grau P. Risks associated with an impact of triple test results on perinatal outcomes. Perinatal elevated maternal serum alpha-fetoprotein level. Am J Obstet Journal 2016;24:26–3. Gynecol 1991;165:581–6. 4. Alamillo CM, Krantz D, Evans M, Fiddler M, Pergament E. 18. Walton DL, Norem CT, Schoen EJ, Ray GT, Colby CJ. Nearly a third of abnormalities found after first-trimester Second-trimester serum chorionic gonadotropin concentra- screening are different than expected: 10-year experience from tions and complications and outcome of pregnancy. N Engl J a single center. Prenat Diagn 2013;33:251–6. Med 1999;341:2033–8.

34 Perinatal Journal The assessment of the perinatal outcomes of the patients who underwent quad screening test

19. Heinonen S, Ryynänen M, Kirkinen P, Saarikoski S. Elevated 22. Kim SY, Kim SK, Lee JS, Kim IK, Lee K. The prediction of midtrimester maternal serum hCG in chromosomally normal adverse pregnancy outcome using low unconjugated estriol in pregnancies is associated with preeclampsia and velamentous the second trimester of pregnancy without risk of Down’s syn- umbilical cord insertion. Am J Perinat 1996;13:437–41. drome. Yonsei Med J 2000;41:226–9. 20. Gagnon A, Wilson RD; Society of Obstetricians and 23. Goodwin KM, Sweeney PJ, Lambert-Messerlian GM, Canick Gynaecologists of Canada Genetics Committee. Obstetrical JA. High maternal serum inhibin A levels following the loss of complications associated with abnormal maternal serum mark- one fetus in a twin pregnancy. Prenat Diagns 2000;20:1015–7. ers analytes. J Obstet Gynaecol Can 2008;30:918–32. 24. Kim SY, Ryu HM, Yang JH, Kim MY, Ahn HK, Shin JS, et 21. Summers AM, Langlois S, Wyatt P, Douglas Wilson R; al. Maternal serum and amniotic fluid inhibin A levels in Members of the SOGC Genetics Committee; Members of the women who subsequently develop severe preeclampsia. J CCMG Committee on Prenatal Diagnosis; Members of the Korean Med Sci 2006;21:452–6. SOGC Diagnostic Imaging Committee. Prenatal screening 25. ACOG Committee Opinion No. 743. Low-dose aspirin use for fetal aneuploidy. J Obstet Gynaecol Can 2007;29:146–61. during pregnancy. Obstet Gynecol 2018;132:e44–52.

Volume 28 | Issue 1 | April 2020 35 A L J O A T U N R I N R A E L P Original Article

Preterm birth and periodontitis: a dilemma of current obstetrics

Didem Ekiz1 İD , fieyda Erflahan1 İD , Ali Ekiz2 İD , Nurcan Altafl3 İD , Burak Özköse4 İD , Zeynep Özköse2 İD 1Department of Endodontics, Faculty of Dentistry, Istanbul Medipol University, Istanbul, Turkey 2Maternal-Fetal Medicine Unit, Clinics of Obstetrics and Gynecology, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul , Turkey 3Faculty of Dentistry, Istanbul Medipol University, Istanbul, Turkey 4Clinics of Obstetrics and Gynecology, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey

Abstract Özet: Preterm do¤um ve periodontit: Mevcut do¤um biliminde bir ikilem Objective: In current obstetric literature, the influence of periodon- Amaç: Mevcut do¤um literatüründe, periodontal hastal›¤›n advers tal disease on adverse perinatal outcome is a matter of debate. In this perinatal sonuç üzerindeki etkisi tart›flmal›d›r. Bu prospektif kohort prospective cohort study, we aimed to investigate whether there is çal›flmas›nda, periodontal durum ile preterm do¤um (PD) aras›nda an association between periodontal status and preterm birth (PTB) bir iliflki olup olmad›¤›n› daha önce kullan›lmam›fl bir metodolojiy- via previously unused methodology. le araflt›rmay› amaçlad›k. Methods: In this prospective cohort study, we examined the peri- Yöntem: Bu prospektif kohort çal›flmas›nda, do¤umdan sonraki odontal status of mothers within 24 hours following birth. In total, 24 saat içinde kad›nlar›n periodontal durumunu inceledik. Puerpe- 226 puerperal women were examined and placed in two groups; a ral dönemde olan toplam 226 kad›n incelendi ve iki gruba ayr›ld›; PTB group consisting of 71 patients, and a term birth (TB) group PD grubunda 71, miad›nda do¤um (MD) grubunda ise 155 hasta consisting of 155 patients. All risk factors known to be etiologic fac- yer almaktayd›. PD için etiyolojik faktör oldu¤u bilinen tüm risk tors for PTB were excluded. The patients were classified into three faktörleri çal›flma d›fl› b›rak›ld›. Hastalar, her iki grupta oral mu- main groups in both groups based on oral examination findings: gin- ayene bulgular› temel al›narak üç ana gruba ayr›ld›: Gingivit (G), givitis (G), periodontitis (P), and healthy (H). periodontit (P) ve sa¤l›kl› (S). Results: Both groups were identical in terms of demographic fac- Bulgular: Her iki grup da demografik faktörler aç›s›ndan ayn›yd›. tors. Regarding possibly influencing factors including smoking, pas- Olas›l›kla etkisi olan sigara kullan›m›, pasif içicilik ve difl f›rçalama sive smoking and tooth brushing habits, both groups were also iden- al›flkanl›¤› gibi faktörler de her iki grupta ayn› idi. Gruplar aras›n- tical. The distribution of G, P and H among the groups were simi- daki G, P ve S da¤›l›m› benzerdi ve aradaki fark anlaml› de¤ildi lar and the difference was not significant (p=1). p-values among the (p=1). PD ve MD gruplar› aras›ndaki p de¤erleri s›ras›yla %40.8 ve PTB and TB groups were 40.8% and 40.6%, respectively, and the %40.6 idi ve fark anlaml› de¤ildi. Toplanan veriler PD grubunu difference was not significant. When collected data were reanalyzed erken ve geç PD fleklinde ikiye ay›rarak yeniden analiz edildi¤in- by splitting the PTB group into early and late PTB, the results were de, elde edilen sonuçlar benzerdi ve fark anlaml› de¤ildi. similar and the difference was not significant. Sonuç: Bu çeliflkili iliflkiye yönelik kafa kar›fl›kl›¤›n›n, PD’ye ne- Conclusion: The confusion over this conflicting association likely den olabilecek ve periodontal hastal›¤a yönelik tan› kriterleri üze- results from confounding factors, other factors that can cause PTB rinde fikir birli¤i olmayan çeliflkili di¤er faktörlerden kaynaklan- and lack of consensus over the diagnostic criteria for periodontal dis- mas› muhtemeldir. Son olarak, muhtemelen çeliflkili de¤iflkenleri ease. Finally, our prospective cohort study, which strictly excluded kesin flekilde çal›flma d›fl› tutan prospektif kohort çal›flmam›z, peri- possible confounding variables, has not confirmed any association odontit ve preterm do¤um aras›nda herhangi bir iliflkiyi do¤rula- between periodontitis and preterm birth. mamaktad›r. Keywords: Preterm birth, periodontitis, gingivitis, adverse preg- Anahtar sözcükler: Preterm do¤um, periodontit, gingivit, advers nancy outcome, risk factor. do¤um sonucu, risk faktörü.

Correspondence: fieyda Erflahan, MD. Department of Endodontics, Faculty of Dentistry, Istanbul Medipol University, Istanbul, Turkey. e-mail: [email protected] / Received: December 10, 2019; Accepted: April 8, 2020 Please cite this article as: Ekiz D, Erflahan fi, Ekiz A, Altafl N, Özköse B, Özköse Z. Preterm birth and periodontitis: a dilemma of current obstetrics. Perinatal Journal 2020;28(1):36–41. doi:10.2399/prn.20.0281008

ORCID ID: D. Ekiz 0000-0002-6407-9243; fi. Erflahan 0000-0002-0354-5108; A. Ekiz 0000-0003-1102-6436; N. Altafl 0000-0001-7439-5015; B. Özköse 0000-0002-3068-1543; Z. Özköse 0000-0001-6662-8042 Preterm birth and periodontitis: a dilemma of current obstetrics

Introduction preterm deliveries and named the preterm group, and Preterm birth (PTB), which refers to a delivery before the second group was constituted of term deliveries 37 weeks of gestation, is still a major cause of perinatal and named term group. Preterm delivery was defined morbidity and mortality. Despite advances in technol- as delivery before the completion of 37 weeks of gesta- ogy and increasing antenatal surveillance quality, the tion. incidence of preterm birth exhibits a regular rising The primary outcome measure was the presence of trend in both developing and developed countries. The periodontitis. The prevalence of periodontitis was preterm infants are at elevated risk for death, neurode- reported between 10% and 60%.[17,18] We expected the velopmental disabilities, cognitive impairment, and rate of periodontitis in preterm deliveries 40%.[19] behavioral disorders.[1] PTB is a major public health Thus, an enrollment of at least 146 patients was problem. Since a considerable amount of singleton required such that the study would have a power %80 pregnancies, approximately 11%, give birth before 37 to detect the difference with 0.05 type 1 error. weeks of gestation, the etiology of preterm birth takes Required sample size was estimated using MedCalc more attention gradually.[2] (version 13.3; MedCalc Software, Mariakerke, Belgium) Although a number of causes have been identified statistical software. for PTB, approximately 70% of cases of PTB are spon- Inclusion criteria for the preterm group were spon- [3] taneous, meaning no specific cause can be identified. taneous delivery between 24 and 37 gestational weeks Infection and/or inflammation can play a role as a without any known risk factors for PB, and the pres- causative factor in PTB pathogenesis. Previous studies ence of at least 20 teeth on oral examination. Inclusion have reported an association between infection and/or criteria for the term group were spontaneous delivery [3–6] inflammation and preterm birth. Periodontal dis- between 37 and 41 gestational weeks and the presence ease, an inflammatory disease that destroys tooth-sup- of at least 20 teeth on oral examination. The following porting connective tissue and bone, has been accused findings constituted exclusion criteria for enrollment of causing adverse perinatal outcomes. According to in the study: (1) patients who had any risk factors for current literature, although many studies –even meta- preterm delivery, such as a short cervix, previous analyses– have been published in this field, results are preterm delivery, adolescent pregnancy, premature still conflicting. Some authors have demonstrated a rupture of membrane, multiple gestations or congeni- positive association between periodontal disease and tal uterine abnormality; (2) patients who had medical PTB,[7–12] whereas others have failed to demonstrate an problems or infections during pregnancy (like urinary association.[13–16] infections); (3) presence of fetal structural anomaly; (4) Therefore, we aimed to examine the periodontal medically indicated preterm deliveries; (5) patients status of mothers both who gave birth preterm without who had labor induction. any reasons known to be etiologic factors for PTB, and Patients were consecutively enrolled in the study those who gave full-term birth (TB). between the dates mentioned above and informed consent was obtained from all participants. Before exami- Methods nation, patients were questioned on whether they are This prospective cohort study was conducted on smokers and whether they have tooth brushing habits. maternity patients at the obstetrics department of Oral evaluation was performed within 24 hours after Kanuni Sultan Suleyman Training and Research delivery. The periodontal status of patients was evalu- Hospital between December 2015 and June 2016. The ated in terms of the number of teeth and clinical peri- study was conducted with ethical approval from the odontal parameters. According to the physical exami- hospital’s Ethics Committee dated June 16, 2015 and nation results, plaque index (PI), gingival index (GI) the study number of 10902. Patients who were in the and probing pocket depth (PPD) were detected quan- postpartum period within 24 hours after birth were titatively. All examinations were performed by the recruited from the postpartum unit. Patients were allo- same researcher at six points of each tooth (mesiobuc- cated to two groups: The first group was constituted of cal, midbuccal, distobuccal, mesiolingual, midlingual,

Volume 28 | Issue 1 | April 2020 37 Ekiz D et al.

and distolingual) by using Williams’ marked probe. Results The patients were classified into three main groups in During the research period, 226 puerperal women’s both groups based on oral examination findings: First, results were analyzed after inappropriate oral examina- the gingivitis group (G) (who had no periodontal pock- tions were excluded. Thus, 71 cases of PTB and 155 ets, but had bleeding on more than 10% of gum sur- cases of TB were evaluated. The demographic charac- faces after light mechanical stimulation); second, the teristics, oral examination results, and final diagnosis of periodontitis group (P) (who had 4 mm pocket depth the cases are shown in Table 1. There were no statis- on two or more surfaces); and third, the healthy group tically significant differences between the two groups (H) (who did not meet G or P criteria or were com- in terms of age, gravidity and parity. As expected, the pletely orally healthy).[20] mean gestational age at delivery and weight of new- A total of 226 puerperal women who met all inclu- borns at delivery were significantly higher in the term sion criteria were enrolled the study. Seventy-one of group. them constituted the preterm group and the remaining Both groups contained similar ratios of smoking, pas- 155 constituted the term group. The statistical analysis sive smoking and tooth brushing. Thus, the groups were was carried out with MedCalc statistical software. Data also identical in terms of these influencing factors. When are presented as means ± SD (standard deviation). The Kolmogorov-Smirnov test assessed the normality of the the groups were compared with respect to PI, GI and distribution of continuous variables. A Chi-squared test PPD, no statistically significant difference was observed. and Fisher’s exact test were used to analyze categorical The distributions of PI, GI and PPD that constitute variables, and Student’s t-test was used for the analysis of diagnostic criteria of periodontitis are shown in box plot normally distributed continuous variables. Mann- graph format (Fig. 1). Whitney U-test was used for non-normally distributed According to the oral examination results, 38% of variables. A p-value <0.05 was deemed statistically signif- the patients classified as healthy were in the preterm icant. group and 38.7% in the term group; this difference is

Table 1. The demographic characteristics, oral examination results and final diagnosis of the cases.

Preterm group (n= 71) Term group (n=155) Mean ± SD/range Mean ± SD/range p-value

Age* 27.97±5.46 27.43±4.42 0.467 BMI* 27.34±5.13 28.01±3.77 0.324 G† 2 (1–9) 2 (1–6) 0.464 P† 2 (1–9) 2 (1–5) 0.135 A† 0 (0–3) 0 (0–3) 0.457 GA at delivery† 35.86 (3.57) 39 (1.29) <0.0001 Newborn weight† 2540±650 3350±520 <0.0001 PI (mean)* 1.50±0.92 1.57±0.90 0.587 GI (mean)* 0.96±0.76 0.95±0.78 0.929 PPD (mean)† 2.42±0.39 2.5±0.55 0.534

n (%) n (%) p-value

CS, n (%)‡ 37 (52.1) 75 (48.4) 0.668 Smoking‡ 11 (15.5) 24 (15.5) 1.000 Passive smoking‡ 40 (56.3) 75 (48.4) 0.316 Tooth brush‡ 39 (54.9) 71 (45.8) 0.251 Healthy‡ 27 (38) 60 (38.7) 1.000 Gingivitis‡ 15 (21.1) 32 (20.6) 1.000 Periodontitis‡ 29 (40.8) 63 (40.6) 1.000

*Student’s t-test; †Mann-Whitney U test; ‡Chi-square test. A: abortion; CS: cesarean section; G: gravida; GA: gestational age; GI: gingival index; P: parity; PI: plaque index; PPD: probing pocket depth.

38 Perinatal Journal Preterm birth and periodontitis: a dilemma of current obstetrics

Preterm delivery Term delivery

Fig. 1. The distributions of PI, GI and PPD that constitute diagnostic criteria of periodontitis. GI: gingival index; PI: plaque index; PPD: probing pocket depth.

not statistically significant. Finally, both periodontitis Since the aim of this study was to analyze the asso- and gingivitis ratios were similar in both groups. ciation between periodontitis and PB, we have not ana- The collected data were reanalyzed by splitting the lyzed the association between presence of periodontitis preterm group into early and late preterm. Early and birth weight. The distribution of diagnoses preterm group was defined as deliveries before complet- according to both groups are presented in Table 2. ing 34 gestational weeks (GW) and late preterm group was defined as deliveries between 34 and 37 GW. The Discussion early preterm group group included 20 patients and Maternal periodontitis has been linked to an increased mean gestational age at delivery and standard deviations risk for adverse perinatal outcomes including preterm were 30.21 weeks and 2.59 respectively. The late birth, preeclampsia, fetal growth restriction, or perinatal preterm group consisted of 51 patients and mean gesta- death. Although the associations between periodontitis tional age at delivery and standard deviations were 36.02 and adverse perinatal outcomes are still questionable, weeks and 0.83 respectively. Finally, the periodontitis some mechanisms have been put forward, such as rates were the same for all three groups. In other words, increasing inflammatory mediators in plasma or expo- the results were uniform. sure to systemic bacterial products from chronic infec-

Volume 28 | Issue 1 | April 2020 39 Ekiz D et al.

Table 2. Reanalyzed results according to early and late preterm birth.

Early preterm group Late preterm group Term group (mean±SD) (mean±SD) (mean±SD) (n=20) (n=51) (n=155) p-value

P‹* 1.66±1.01 1.44±0.88 1.57±0.90 0.626 G‹* 1.08±0.85 0.92±0.73 0.95±0.78 0.772 PPD† 2.36±0.6 2.5±0.4 2.5±0.6 0.691 Healthy‡ (n, %) 7 (35) 20 (39.2) 60 (38.7) 0.943 Gingivitis‡ (n, %) 4 (20) 11 (21.6) 32 (20.6) 0.986 Periodontitis‡ (n, %) 9 (45) 20 (39.2) 63 (40.6) 0.905

*Kruskal-Wallis test; †Median interquartile range; ‡Chi-square test. GI: gingival index; PI: plaque index; PPD: probing pocket depth.

tion.[16] As a result, many studies have been published cally rigorous studies are needed in this field. Besides, a regarding these associations. Conflicting results may number of important studies[21] and meta-analyses[22,23] arise from varying definition of periodontitis and other reported that treatment of periodontitis during pregnan- factors that can cause PTB. cy does not reduce spontaneous preterm birth. These In our prospective cohort study, 226 puerperal results make the already-debated association more ques- women`s periodontal status was examined within 24 tionable. hours after giving birth. In our study, we defined peri- One of the unique features of the present study is its odontitis as patients whose oral examinations had 4 mm methodology. According to our knowledge, there is or more pocket depth on two or more dental surfaces. not any study in the current literature which prospec- Our groups were identical in terms of demographical tively examines patients in the early postpartum period. factors. Our study results failed to demonstrate an asso- On the other hand, a limited number of early preterm ciation, and the results are in line with a large prospec- birth cases was a weakness of sub-group analysis. tive study which was published by Srinivas et al.[15] This In the present study, 1999 classification of periodon- study was a multicenter prospective study and a large tal disease was used.[24] In 2018, the classification of peri- [25] number of patients were included, but Srinivas et al.[15] odontal diseases was renewed. The new classification used a periodontal attachment loss 3 mm on three or addressed unresolved issues with the previous classifica- [24] more teeth as criteria for periodontitis diagnosis, which tion by identifying three different forms of periodon- is slightly different from our criteria. Likewise, a recent titis based on current knowledge on the diseases’ patho- study by Fogacci et al.[17] reported that maternal peri- physiology: (a) necrotizing periodontitis, (b) periodonti- odontal disease is not a risk factor associated with tis as a manifestation of systemic disease and (c) peri- preterm infants’ low birth weights. Similar results are odontitis, whereas the last form includes the previously reported in studies conducted in different ethnic groups recognized subtypes of “chronic” and “aggressive” peri- [25] such as the Spanish population,[16] and they also used 3 odontitis. Therefore, further studies evaluating PTB mm for diagnosis. However, one recent study found lit- in relation to the new classification are needed. tle correlation with serum levels of pro-inflammatory proteins in women with PTB and low birth weight.[18] Conclusion Some meta-analyses, for example Corbella et al.’s In conclusion, according to our results, we have not [19] study, make abstainer comments over this association detected any associations between spontaneous PTB because of important confounding variables. In a system- and periodontitis. Nevertheless, future large scale ran- [20] atic review by Xiong et al., researchers reviewed 25 domized controlled trials are needed to clarify the con- studies and speculated that periodontal disease may be troversial association. associated with an increased risk of adverse pregnancy outcomes, but they underlined that more methodologi- Conflicts of Interest: No conflicts declared.

40 Perinatal Journal Preterm birth and periodontitis: a dilemma of current obstetrics

References ship between periodontal disease and adverse pregnancy outcome. Br Dent J 2004;197:251–8. 1. Bhutta AT, Cleves MA, Casey PH, Cradock MM, Anand KJ. 15. Srinivas SK, Sammel MD, Stamilio DM, Clothier B, Jeffcoat Cognitive and behavioral outcomes of school-aged children MK, Parry S, et al. Periodontal disease and adverse pregnancy who were born preterm: a meta-analysis. JAMA 2002;288: outcomes: is there an association? Am J Obstet Gynecol 2009; 728–37. 200:497.e1–8. 2. Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker 16. Santa Cruz I, Herrera D, Martin C, Herrero A, Sanz M. F, Munson ML. Births: final data for 2003. Natl Vital Stat Rep Association between periodontal status and pre-term and/or 2005;54:1–116. low-birth weight in Spain: clinical and microbiological param- 3. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemi- eters. J Periodontal Res 2013;48:443–51. ology and causes of preterm birth. Lancet 2008;371:75–84. 17. Fogacci MF, Cardoso EOC, Barbirato DDS, de Carvalho DP, 4. Gibbs RS, Romero R, Hillier SL, Eschenbach DA, Sweet RL. Sansone C. No association between periodontitis and preterm A review of premature birth and subclinical infection. Am J low birth weight: a case-control study. Arch Gynecol Obstet Obstet Gynecol 1992;166:1515–28. 2018;297:71–6. 5. Gibbs RS. The relationship between infections and adverse 18. Mesa F, Pozo E, O’Valle F, Puertas A, Magan-Fernandez A, pregnancy outcomes: an overview. Ann Periodontol 2001;6: Rosel E, et al. Relationship between periodontal parameters 153–63. and plasma cytokine profiles in pregnant woman with preterm 6. Tütüncü L, Ard›ç N, Müngen E, Ergür AR, Yergök YZ. birth or low birth weight. Clin Oral Investig 2016;20:669–74. Urinary tract infection in pregnancy. Perinatal Journal 2005;13: 19. Corbella S, Taschieri S, Francetti L, De Siena F, Del Fabbro 114–21. M. Periodontal disease as a risk factor for adverse pregnancy 7. Xiong X, Buekens P, Vastardis S, Yu SM. Periodontal disease outcomes: a systematic review and meta-analysis of case-con- and pregnancy outcomes: state-of-the-science. Obstet Gynecol trol studies. Odontology 2012;100:232–40. Survey 2007;62:605–15. 20. Xiong X, Buekens P, Fraser WD, Beck J, Offenbacher S. 8. Goepfert AR, Jeffcoat MK, Andrews WW, Faye-Petersen O, Periodontal disease and adverse pregnancy outcomes: a sys- Cliver SP, Goldenberg RL, et al. Periodontal disease and tematic review. BJOG 2006;113:135–43. upper genital tract inflammation in early spontaneous preterm 21. Macones GA, Parry S, Nelson DB, Strauss JF, Ludmir J, birth. Obstet Gynecol 2004;104:777–83. Cohen AW, et al. Treatment of localized periodontal disease in pregnancy does not reduce the occurrence of preterm birth: 9. Radnai M, Gorzo I, Nagy E, Urban E, Novak T, Pal A. A pos- results from the Periodontal Infections and Prematurity Study sible association between preterm birth and early periodonti- (PIPS). Am J Obstet Gynecol 2010;202:147.e1–8. tis. A pilot study. J Clin Periodontol 2004;31:736–41. 22. Xiong X, Buekens P, Goldenberg RL, Offenbacher S, Qian X. 10. Boggess KA, Lieff S, Murtha AP, Moss K, Beck J, Offenbacher Optimal timing of periodontal disease treatment for preven- S. Maternal periodontal disease is associated with an increased tion of adverse pregnancy outcomes: before or during preg- risk for preeclampsia. Obstet Gynecol 2003;101:227–31. nancy? Am J Obstet Gynecol 2011;205:111.e1–6. 11. Jeffcoat MK, Geurs NC, Reddy MS, Cliver SP, Goldenberg 23. Polyzos NP, Polyzos IP, Mauri D, Tzioras S, Tsappi M, RL, Hauth JC. Periodontal infection and preterm birth: Cortinovis I, et al. Effect of periodontal disease treatment dur- results of a prospective study. J Am Dent Assoc 2001;132:875– ing pregnancy on preterm birth incidence: a metaanalysis of 80. randomized trials. Am J Obstet Gynecol 2009;200:225–32. 12. Vergnes JN, Sixou M. Preterm low birth weight and maternal 24. Armitage GC . Development of a classification system for periodontal status: a meta-analysis. Am J Obstet Gynecol 2007; periodontal diseases and conditions. Ann Periodontol 1999;4: 196:135.e1–7. 1–6. 13. Skuldbol T, Johansen KH, Dahlen G, Stoltze K, Holmstrup 25. Caton JG, Armitage G, Berglundh T, Chaleppe ILC, Jepsen S, P. Is pre-term labour associated with periodontitis in a Danish Kornman KS, et al. A new classification scheme for periodon- maternity ward? J Clin Periodontol 2006;33:177–83. tal and peri-implant diseases and conditions – introduction and 14. Moore S, Ide M, Coward PY, Randhawa M, Borkowska E, key changes from the 1999 classification. J Clin Periodontol Baylis R, et al. A prospective study to investigate the relation- 2018;45 Suppl 20:S1–8.

Volume 28 | Issue 1 | April 2020 41 A L J O A T U N R I N R A E L P Original Article

Coombs test positivity in cord blood: early detection of risky newborns and the assessment of their follow-up results

Ali Ulaﬂ Tu¤cu1 İD , Faika Ceylan Çiftçi2 İD , Esra Aktepe Keskin3 İD 1Neonatology Clinic, Medisis Hospital, Yenido¤an Ankara, Turkey 2Obstetrics & Gynecology Clinic, Koru Hospital, Ankara, Turkey 3Obstetrics & Gynecology Clinic, Medisis Hospital, Ankara, Turkey

Abstract Özet: Kord kan›nda Coombs testi pozitifli¤i: Riskli yenido¤anlar›n erken saptanmas› ve izlem sonuçlar›n›n de¤erlendirilmesi Objective: Direct Coombs test (DCT) is a screening process to Amaç: Direkt Coombs testi (DCT), yenido¤anlar›n k›rm›z› kürele- detect antibodies which are produced against the antigens in the rinde bulunan antijenlere karfl› oluflan ve hemolitik hastal›¤a yol açan red blood cells of newborns and cause hemolytic disease. In our antikorlar›n tespiti için yap›lan bir tarama ifllemidir. Çal›flmam›z, study, we aimed to compare the demographic data and early peri- DCT pozitifli¤i olan ve olmayan yenido¤anlar›n demografik verileri- od outcomes of the newborns with and without DCT positivity. nin ve erken dönem sonuçlar›n›n karfl›laflt›r›lmas› amaçlanm›flt›r. Methods: The data of all newborns who were born in our hospital Yöntem: Ocak 2019 ile Eylül 2019 tarihleri aras›nda hastanemizde between January 2019 and September 2019, of whose mothers gave do¤an, do¤um öncesinde annelerinden bilgilendirilmifl onam formu informed consent before the labor and whose cord blood samples al›nan ve kordon kan› çal›fl›lan tüm yenido¤anlar›n bilgileri geriye were examined were reviewed retrospectively. The data were ana- dönük olarak tarand›. Verilerin de¤erlendirilmesinde SPPS 25 lyzed by using SPPS 25 (IBM Corp. Released 2017; IBM SPSS (IBM Corp. Released 2017; IBM SPSS Statistics for Windows, Ver- Statistics for Windows, Version 25.0; IBM Corp., Armonk, NY, siyon 25.0; IBM Corp., Armonk, NY, ABD) istatistik paket progra- USA) statistics software. m› kullan›ld›. Results: A total of 302 newborns were included in the study. The Bulgular: Çal›flmaya 302 yenido¤an dahil edildi. Direkt Coombs results of Direct Coombs test were positive in 27 cases. The photother- testi sonucu, 27 olguda pozitif saptand›. Direkt Coombs testi po- apy rate of the cases with positive DCT results was 74% (20/27). It was zitifli¤i olan vakalar›n fototerapi oranlar› %74 (20/27) bulundu. found that the cases with positive DCT results underwent more pho- Direkt Coombs testi pozitif olgular›n, negatif olgulara göre istatis- totherapy, started to undergo phototherapy earlier, were hospitalized tiksel olarak anlaml› flekilde daha fazla fototerapi ald›¤›, daha erken longer and had lower serum total bilirubin levels compared to the fototerapi baflland›¤›, hastanede daha uzun süre yatt›¤› ve daha dü- cases with negative DCT results, and these differences were statistical- flük serum total bilirubin de¤erleri oldu¤u tespit edildi (s›ras›yla ly significant (p=0.003, p=0.015, p=0.038 and p=0.026, respectively). p=0.003, p=0.015, p=0.038 ve p=0.026). Conclusion: Today, there is no specific method to prevent jaundice Sonuç: Günümüzde sar›l›¤›n önlenmesi için özellikle risk faktörü particularly for the newborns with a risk factor. The only thing to do olan yenido¤anlarda kesin bir yöntem bulunmamaktad›r. Yenido- for newborns at this point is to detect if they have risk factors or not, ¤anlar için bu noktada yap›labilecek olan, risk faktörüne sahip olup and to follow up newborns with risk factors appropriately. Direct olmad›¤›n›n tespiti ve risk faktörü saptanan yenido¤anlar›n uygun Coombs test has still been playing an important role to predict flekilde izlemidir. Direkt Coombs testi, yenido¤anlarda hemolitik hemolytic anemia and potential manifestation of hyperbilirubinemia anemi ve buna ba¤l› geliflebilecek hiperbilirubinemi klinik tablosu- in association with hemolytic anemia in the newborns, and to initi- nun önceden öngörülebilmesinde ve gecikme olmadan tedavi sü- ate treatment process as soon as possible. recinin bafllanabilmesinde, halen önemli rol oynamaktad›r. Keywords: Direct Coombs test, hyperbilirubinemia, hemolytic ane- Anahtar sözcükler: Direkt Coombs testi, hiperbilirubinemi, hemo- mia. litik anemi.

Correspondence: Ali Ulaﬂ Tu¤cu, MD. Neonatology Clinic, Medisis Hospital, Yenido¤an Ankara, Turkey. e-mail: [email protected] / Received: January 25, 2020; Accepted: April 10, 2020 Please cite this article as: Tu¤cu AU, Çiftçi FC, Aktepe Keskin E. Coombs test positivity in cord blood: early detection of risky newborns and the assessment of their follow-up results. Perinatal Journal 2020;28(1):42–47. doi:10.2399/prn.20.0281009

ORCID ID: A. U. Tu¤cu 0000-0001-6942-1872; F. C. Çiftçi 0000-0001-5359-8542, E. Aktepe Keskin 0000-0001-7319-1299 Coombs test positivity in cord blood: early detection of risky newborns and the assessment of their follow-up results

Introduction itive were recorded. The antenatal and postnatal period characteristics of the newborns, whose direct antiglobu- Direct antiglobulin test, which is also known as Direct lin tests were normal, were reviewed via the hospital Coombs test (DCT), is a screening process to detect databank. The antenatal, natal and postnatal records of antibodies which are produced against the antigens in the newborns, whose direct antiglobulin tests were neg- the red blood cells (RBC) of newborns and cause ative and underwent phototherapy with the preliminary hemolytic disease. These antibodies pass to the fetus diagnosis of indirect hyperbilirubinemia, were reviewed. from the immunoglobulin G (IgG) structure in the The maternal age, gestational diabetes, maternal infec- maternal serum transplacentally, and attach to the anti- tion during pregnancy, and the presence or absence of gens on RBCs. Then, the deterioration process starts, maternal alloimmunization and fetal hydrops were which may lead to shortening the lifetime of RBCs of recorded in the both groups. The data of birth weights newborn, deterioration of RBCs, and severe anemia and [1] and sexes of newborns, week of gestation, delivery type hyperbilirubinemia. (normal spontaneous vaginal delivery [NSVD] or cesare- The reason causing DCT positivity in the newborns an section [C/S]), nourishment method (only breastfeed- is mostly the ABO incompatibility between mother and ing, only formula, both breastfeeding and formula), ane- fetus and/or newborn. In addition, Rh group incompat- mia, polycythemia, cephalohematoma and ecchymosis ibilities, incompatibilities among small and sub-groups were recorded. The presence of hemolysis was con- (anti-E, anti-C, etc.) and the presence of autoimmune firmed by peripheral smear and reticulocyte count. It was hemolytic disease in mother may also cause DCT posi- noted down that whether phototherapy was performed [2,3] tivity. In our study, we aimed to compare the demo- or not, its duration (hour) if performed, serum bilirubin graphic data and early period outcomes of the newborns level when the phototherapy was initiated, whether a sec- with and without direct antiglobulin test positivity. ond hospitalization was carried out or not due to elevated bilirubin level, whether blood transfusion was con- Methods ducted or not, and whether intravenous immunoglobulin (IVIG) treatment was done or not. ABO incompatibility The study was conducted as a retrospective review of between mother and newborn was defined as the condi- the data of all newborns who were born in Obstetrics tion where the blood type of mother was 0 while it was & Gynecology Clinic of Medisis Hospital between A, B or AB for the newborn. January 2019 and September 2019, of whose mothers gave informed consent before the labor and whose Phototherapy decision was made according to the 2004 and 2011 (revised) guidelines of the American cord blood samples were examined. The preterm new- [4] borns whose week of gestation was <36, and the term Academy of Pediatrics. Follow-up of the bilirubin lev- newborns diagnosed with sepsis, congenital malforma- els of the newborns who were decided to receive treat- tion, chromosomal anomaly and congenital heart dis- ment, discharge decision and check-up time for disease were excluded from the study. charged newborns were decided by the same physician via the hour-specific Bhutani nomogram.[5] The demo- Cord bloods were collected during labor by 5 ml graphic data and early period outcomes of the newborns sterile injector, and the obtained samples were studied with and without the direct antiglobulin test positivity by hemagglutination and antiglobulin antibody assay for were compared. SPPS 25 (IBM Corp. Released 2017; blood type and Rh determination and gel centrifugation IBM SPSS Statistics for Windows, Version 25.0; / colon agglutination method for Direct Coombs test via Armonk, NY, USA) statistics software was used to eval- ® DiaMED-ID Micro Typing System (Diamed, Morat, uate the data. The variables were presented as Switzerland) in the blood bank. Direct antiglobulin mean±standard deviation, percentage and frequency. results were classified as negative, +1, +2, +3 and +4. The variables were evaluated after checking the normal- The blood bank data of the patients who gave ity and variance homogeneity preconditions (Shapiro- informed consents were reviewed, and blood types and Wilk and Levene’s tests). Kolmogorov-Smirnov test was Rh D groups of mothers and newborns, antibody assays performed to identify whether or not parameters are if mothers had alloimmunization, the direct antiglobulin normally distributed. Student’s t-test and Mann- test results and the grades of those whose tests were pos- Whitney U test were used for the comparison between

Volume 28 | Issue 1 | April 2020 43 Tu¤cu AU, Çiftçi FC, Aktepe Keskin E

two groups. The categorical data were analyzed by to the cases with negative DCT result (p=0.003, p=0.015, Fisher’s exact test and Chi-square test. p<0.05 was con- p=0.038 and p=0.026, respectively). It was found that sidered statistically significant in the tests. hemolysis and IVIG treatment were higher in the group with positive DCT and serum total bilirubin level, ecchymosis and polycythemia were higher in the group with Results negative DCT in a statistically significant way (p<0.05). A total of 302 newborns were born during the study peri- No significant difference was found between the groups od. Of the infants, the blood type was A in 132 (43.7%), in terms of rehospitalization and nourishment method B in 47 (15.5%), 0 in 102 (33.7%), and AB in 21 (6.9%). for phototherapy (p>0.05) (Table 1). There was ABO incompatibility between mother and Direct Coombs test positivity was found in 27 (8.9%) newborn in 64 (21.1%) cases (53 newborns with the newborns. It was found that all of the cases with positive blood type of A, and 11 newborns with the blood type of result had ABO incompatibility (the newborn was A and B). Rh incompatibility was found in 4 cases. The result of the mother was 0 in 21 cases, and the newborn was B and direct Coombs test was positive in 27 cases. Of these the mother was 0 in 6 cases). Rh and minor blood type cases, the test result was +1 in 18, +2 in 8, +3 in 1, but no incompatibility was not detected in none of the newborns case with +4 was found. The phototherapy rates of the with positive Direct Coombs test. While 15 (55.6%) of cases with positive result for the direct Coombs test was the cases were female, 12 (44.4%) of them were male. 74% (20/27) (Table 1). Gestational diabetes, maternal Their mean weight was 3130±468 g, and the mean week infection during pregnancy, maternal alloimmunization of gestation was 37.7±1.5 weeks. It was found that 20 of and fetal hydrops were not observed in both groups. the cases were delivered by C/S and 7 of them by NSVD. There was no statistically significant difference between It was found that the total serum bilirubin levels of 11 the groups in terms of the week of gestation and birth newborns with positive direct Coombs test, who did not weight (p=0.445 and p=0.280, respectively). undergo phototherapy within the first 48 hours and dis- It was found that the cases with positive result in the charged, were high enough to receive phototherapy. direct Coombs test underwent more phototherapy, the Thirty-seven (13.4%) newborns (37/275) with nega- phototherapy was initiated earlier, they were hospitalized tive direct Coombs test underwent phototherapy. Of for a longer time and had lower levels of serum total these cases, 19 (51.3%) were female and 18 (48.7%) were bilirubin values in a statistically significant way compared male. Their mean weight was 2980±516 g, and mean

Table 1. The demographic and clinical characteristics of the groups.

DCT positive DCT negative Demographic and clinical characteristics n=27 n=275 p-value

Week of gestation (week) 37.8±1.5 37.4±1.8 0.445 Birth weight (g) 3130±468 2980±516 0.280 Cases who underwent phototherapy 20 (74%) 37 (13.4%) 0.003* Hospitalization day (day) 2.26±1.34 5.34±1.12 0.015* Hospitalization duration (hour) 34.9±6.06 27.9±9.06 0.038* Serum bilirubin level at hospitalization (mg/dl) 12.89±4.46 18.45±2.78 0.026* Second hospitalization 2 (7.4%) 15 (5.4%) 0.365 Nourishment method Breastfeeding Breastfeeding Breastfeeding + formula Formula Breastfeeding + formula Formula 15 (55.6%) 10 (37%) 2 (7.4%) 20 (54%) 14 (37.8%) 3 (8.2%) 0.235 Hemolysis 5 (18.5%)0 0.01* Ecchymosis 0 4 (1.4%)0.02* Polycythemia 0 2 (0.7%) 0.037* Intravenous 3 (11.1%)0 0.03*

*p<0.05 was considered statistically significant.

44 Perinatal Journal Coombs test positivity in cord blood: early detection of risky newborns and the assessment of their follow-up results

week of gestation was 37.4±1.8 weeks. It was found that Our study found DCT positivity in 8.9% of all new- 25 (67.6%) of the cases were delivered by C/S and 12 borns born in our hospital. This is above the rates (32.4%) of them by NSVD. The blood type was A in 18 reported by the various studies in the literature. Diloon (48.6%) newborns, 0 in 11 (29.7%) newborns, B in 6 et al. found this incidence 2.3% while Valsami et al. (16.2%) newborns and AB in 2 (5.4%) newborns. ABO reported it 2.59%.[12,13] This rate was 6.6% in the study incompatibility was detected in 14 newborns who had of Altuntaﬂ et al., and it was similar with the rate we negative direct Coombs test and underwent photothera- found in our study.[14] py (A in newborns and 0 in mothers in 12 cases, and B in ABO incompatibility is the most common reason for newborns and 0 in mothers in 2 cases) while 4 newborns the hemolytic disease of the newborn. Of all pregnan- had Rh incompatibility and negative DCT. Minor blood cies, 15–20% have ABO incompatibility.[15] The rate of type incompatibility was not observed in none of our ABO incompatibility was 21.1% in our study. Together cases. Of the cases, 4 (14.8%) had ecchymosis (history of with Rh immunization, minor blood type incompatibil- difficult labor) and 2 (7.4%) had polycythemia (newborn ities have become one of the most important reasons of polycythemia). It was found that the siblings of three the hemolytic disease of the newborn. In our study, we cases underwent phototherapy upon the preliminary did not detect any minor blood type incompatibility in diagnosis of indirect hyperbilirubinemia. the groups. Narter et al. found that 38.1% of the cases with DCT positivity developed hyperbilirubinemia that [16] Discussion needs treatment, this rate was 74% in our study. It is known that the indirect hyperbilirubinemia which is In our study, all newborns with positive DCT were not diagnosed early and on time and treated properly followed-up closely by the same physician in terms of leads to various early and late (kernicterus) neurological hyperbilirubinemia, serum bilirubin levels were checked sequels and bilirubin encephalopathy in particular.[6,7] in the newborns with apparent kernicterus. Accordingly, therefore, early detection of elevated bilirubin and start- serum bilirubin levels were over 95 percentile by the age ing treatment process early are important. In our study, in 16 of 27 newborns with positive DCT within the first we aimed to investigate how carrying out direct Coombs 48 hours according to the bilirubin nomogram and they test on all newborns routinely and conducting close clin- started to undergo phototherapy. We reevaluated eleven ical follow-up on the newborns with positive and nega- newborns, who had Coombs test positivity and did not tive test results affect the outcomes. undergo phototherapy in the first 48 hours, within the first 24–48 hours after the discharge in accordance with For the decision on who will undergo DCT in cord the directive, and we found that the serum total bilirubin blood, hyperbilirubinemia sub-committee recommends values were at a level that requires phototherapy in 4 of 11 testing all pregnant women in terms of ABO and Rh (D) newborns. We believe that the higher hyperbilirubinemia groups, screening in terms of potential antibodies seen rate that requires treatment in our study than other stud- rarely, (i) conducting blood type test, Rh assay and direct Coombs test on cord blood if blood type of pregnant ies is because we followed up risk group more closely and woman is not known during prenatal period or if it is Rh systematically, and this showed that the patients with pos- (-), (ii) deciding to perform blood type test and DCT on itive DCT should be followed up more closely. cord blood by considering the risk factors.[4] It is known that the serum bilirubin level of new- [17] As required by our hospital policy, we carry out borns reaches to the peak level at 3rd–6th days. blood type test and DCT on the cord blood of all new- Therefore, it is recommended calling the cases, who are borns. Various studies showed that carrying out DCT discharged early after the delivery and in the risk group in terms of hyperbilirubinemia, for check-up within on the cord blood of the newborns with ABO and Rh [18] incompatibilities help to detect potential hemolysis and 24–48 hours after discharge. In our hospital, we carry its complications early.[8,9] There are also studies showing out postnatal follow-up of mothers and newborns in 48 that detecting and following up bilirubin level in the hours. We ask families to bring their infants for follow- cord blood predict hyperbilirubinemia development up within 24–48 hours after evaluating the risk factors. better but carrying out DCT on the cord blood routine- Direct Coombs test is a very useful examination to ly is not helpful in terms of cost-efficiency.[10,11] predict when indirect hyperbilirubinemia reaches

Volume 28 | Issue 1 | April 2020 45 Tu¤cu AU, Çiftçi FC, Aktepe Keskin E

pathological threshold and hospitalization for pho- References totherapy.[14] Therefore, the test being positive makes 1. Issitt PD. Hemolytic disease of the newborn. In: Issitt PD, edi- clinicians be more cautious in terms of the potential tor. Applied blood group serology. 3rd ed. Durham, NC: clinical conditions (hemolytic anemia) and their compli- Montgomery Scientific, 1985. p. 571–98. cations (hyperbilirubinemia, hydrops, heart failure etc.). 2. Tugcu AU. Ince DA, Turan O, Belen B, Olcay L, Ecevit A. In terms of the newborns who are not in the risk group, Hemolytic anemia caused by non-D minor blood incompati- delays may occur in the diagnosis and treatment bilities in a newborn. Pan Afr Med J 2019;33:262. processes. In line with this, the day of initiating pho- 3. Moran P, Robson SC, Reid MM. Anti-E in pregnancy. BJOG totherapy was earlier and phototherapy duration was 2000;107:1436–8. shorter in the cases with positive DCT compared to the 4. American Academy of Pediatrics Subcommittee on cases with negative DCT. Hospitalization bilirubin Hyperbilirubinemia. Management of hyperbilirubinemia in threshold for phototherapy was shorter in the cases with the newborn infant 35 or more weeks of gestation. Pediatrics positive DCT who were hospitalized earlier was shorter 2004;114:297–316. due to the presence of risk factors. 5. Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a pre- discharge hour-specific serum bilirubin for subsequent signifi- The rates of indirect hyperbilirubinemia risk factors cant hyperbilirubinemia in healthy term and near-term new- (ABO and Rh incompatibility, ecchymosis, poly- borns. Pediatrics 1999;103:6–14. cythemia, the history of sibling which underwent pho- 6. deHaas M, Thurik FF, Koelewijn JM, van der Schoot CE. totherapy) in the cases with negative DCT are similar Haemolytic disease of the fetus and newborn. Vox Sang 2015; with the previous studies (in this group, only the routine 109:99–113. physical examination was performed for icterus in the 7. Kaplan M, Bromiker R, Hammerman C. Hyperbilirubinemia, postnatal 48-hour follow-up period beside their moth- hemolysis, and increased bilirubin neurotoxicity. Semin ers).[19] Perinatol 2014;38:429–37. In terms of the limitations of our study, it is unclear 8. Baptista-González H, Hernández-Martínez JA, Galindo- if the newborns which were born in our hospital under- Delgado P, Santamaría-Hernández C, Rosenfeld-Mann F. Usefulness of direct antiglobulin test in neonatal screening. went phototherapy in another center with the diagnosis [Article in Spanish] Bol Med Hosp Infant Mex 2009;66:502– of indirect hyperbilirubinemia except the newborns in 10. our study which underwent phototherapy. Since know- 9. Kaplan M, Hammerman C, Vreman HJ, Wong RJ, Stevenson ing these data may affect the results of our study, our DK. Direct antiglobulin titer strength and hyperbilirubinemia. study has the limitation of being single-centered. Our Pediatrics 2014;134:e1340–4. data cannot be generalized as they are the results of a 10. Shahid R, Graba S. Outcome and cost analysis of implementing single-centered study. Therefore, it is needed to evalu- selective Coombs testing in the newborn nursery. J Perinatol ate the risk factors associated with national photothera- 2012;32:966–9. py through detailed and larger samples. 11. Leistikow EA, Collin MF, Savastano GD, de Sierra TM, Leistikow BN. Wasted health care dollars. Routine cord blood type and Coombs’ testing. Arch Pediatr Adolesc Med 1995;149: Conclusion 1147–51. Today, there is no specific method to prevent jaundice 12. Dillon A, Chaudhari T, Crispin P, Shadbolt B, Kent A. Has particularly for the newborns with a risk factor. The anti-D prophylaxis increased the rate of positive direct only thing to do for newborns at this point is to detect antiglobulin test results and can the direct antiglobulin test if they have risk factors or not, and to follow up new- predict need for phototherapy in Rh/ABO incompatibility? J Paediatr Child Health 2011;47:40–3. borns with risk factors appropriately. Direct Coombs test has still been playing an important role to predict 13. Valsami S, Politou M, Boutsikou T, Briana D, Papatesta M, Malamitsi-Puchner A. Importance of direct antiglobulin test hemolytic anemia and potential manifestation of (DAT) in cord blood: causes of DAT (+) in a cohort study. hyperbilirubinemia in association with hemolytic ane- Pediatr Neonatol 2015;56:256–60. mia in the newborns, and to initiate treatment process 14. Altuntaﬂ N, Taﬂç› Çelebi D, Koçak M, And›ran N. Yenido¤an as soon as possible. bebeklerde direkt Coombs testi taramas› ve pozitifli¤inin mor- bidite üzerine etkisi; tek merkez deneyimi. Pamukkale T›p Conflicts of Interest: No conflicts declared. Dergisi 2015;8:39–44.

46 Perinatal Journal Coombs test positivity in cord blood: early detection of risky newborns and the assessment of their follow-up results

15. Sarici SU, Yurdakök M, Serdar MA, Oran O, Erdem G, 17. Maisels MJ, Newman TB. Jaundice in full-term and near-term Tekinalp G, et al. An early (sixth-hour) serum bilirubin meas- babies who leave the hospital within 36 hours. The pediatri- urement is useful in predicting the development of significant cian’s nemesis. Clin Perinatol 1998;25:295–302. hyperbilirubinemia and severe ABO hemolytic disease in a 18. Braveman P, Egerter S, Pearl M, Marchi K, Miller C. selective high-risk population of newborns with ABO incompatibility. Pediatrics 2002;109:e-53. Problems associated with early discharge of newborn infants. Early discharge of newborns and mothers: a critical review of 16. Narter F, Ergüven M. Direkt Coombs pozitif ABO uygunsu- the literature. Pediatrics 1995;96:716–26. zlu¤unda do¤um sonras› on ikinci saatte bilirubin persentilin- in profilaktik intravenöz immünglobülin kullan›m›nda belir- 19. Bratlid D. Bilirubin toxicity: pathophysiology and assessment leyici rolü. Çocuk Dergisi 2009;9:22–4. of risk factors. N Y State J Med 1991;91:489–92.

Volume 28 | Issue 1 | April 2020 47 A L J O A T U N R I N R A E L P Case Report

Isolated levocardia with situs inversus without cardiac abnormality in fetus: prenatal diagnosis and management

Mucize Eriç ÖzdemirİD , Oya Demirci İD Department of Perinatology, Zeynep Kamil Maternity and Children’s Diseases Training and Research Hospital., Health Sciences University, Istanbul, Turkey

Abstract Özet: Kardiyak anomalisi olmayan fetüste situs inversuslu izole levokardi: Prenatal tan› ve yönetim Objective: Isolated levocardia is a situs abnormality that the heart is Amaç: ‹zole levokardi, kalbin normal levo pozisyonunda oldu¤u in the normal levo position, but the abdominal viscera are in dextro fakat abdominal iç organlar›n dekstro pozisyonunda oldu¤u bir si- position. Most cases are accompanied by structural heart anomalies. tus anomalisidir. Ço¤u olguda yap›sal kalp anomalileri de efllik et- In this case, we aimed to present a fetus with isolated levocardia with- mektedir. Çal›flmam›zda, kardiyak anomalisi olmayan izole levo- out cardiac abnormality. kardili bir fetüsü sunmay› amaçlad›k. Case: The mother was referred to our clinic with a suspicion of fetal Olgu: Olgumuz, 22. gebelik haftas›nda fetal dekstrokardi flüphe- dextrocardia at 22 weeks of gestation. When detailed examination was siyle klini¤imize sevk edildi. Planlanan detayl› ultrason muayene- planned by ultrasonography isolated levocardia was detected in fetus. sinde, fetüste izole levokardi tespit edildi. Fetal ekokardiyografide There were no cardiac abnormalities in fetal echocardiography. Fetus hiçbir kardiyak anomali görülmedi. Fetüs do¤uma kadar takip was followed up until delivery and newborn was examined again at edildi ve yenido¤an, postnatal dönemde yeniden muayene edildi. 2 postnatal period. No problem was detected until the age of 2 years. yafl›na kadar hiçbir sorun tespit edilmedi. Conclusion: Fetal situs should be assessed by ultrasonography in all Sonuç: Fetal situs tüm gebelerde ultrasonografi muayenesi ile de- pregnant women. ¤erlendirilmelidir. Keywords: Fetus, levocardia, ultrasonography. Anahtar sözcükler: Fetüs, levokardi, ultrasonografi.

Introduction mate.[4] According to reports, the incidence of IL is approximately 1 per 22,000 births,[5] and it represents Isolated levocardia (IL) is a kind of situs anomaly that the 0.4–1.2% of all congenital heart disease (CHD).[6] In this heart is in the normal levo position, but the abdominal [1] study, we reported a case of IL with structurally normal viscera are in dextro position. The vast majority of the [2] heart and no rhythm abnormalities. cases have major cardiac anomalies. This condition is rare when it is associated with a normal cardiac structure[3] and the incidence of this anomaly in fetuses is not Case Report known.[1] Most of IL patients who do not have cardiac A 28-year-old woman gravida 3 para 2 with no family and intestinal abnormalities survive with unknown rea- history of congenital anomalies, having consanguineous sons. So, the prenatal incidence of IL is difficult to esti- marriage and a normal medical history had routine pre-

Correspondence: Mucize Eriç Özdemir, MD. Department of Perinatology, Zeynep Kamil Maternity and Children’s Diseases Training and Research Hospital., Health Sciences University, Istanbul, Turkey. e-mail: [email protected] / Received: January 15, 2020; Accepted: February 17, 2020 Please cite this article as: Eriç Özdemir M, Demirci O. Isolated levocardia with situs inversus without cardiac abnormality in fetus: prenatal diagnosis and management. Perinatal Journal 2020;28(1):48–51. doi:10.2399/prn.20.0281004

ORCID ID: M. Eriç Özdemir 0000-0002-2177-0771, O. Demirci 0000-0001-5578-4437 Isolated levocardia with situs inversus without cardiac abnormality in fetus: prenatal diagnosis and management

natal ultrasound with suspicion of dextrocardia. The Discussion patient rejected to have any of aneuploidy screening tests. The fetal side and axis must be examined carefully for The patient was referred for fetal echocardiography at 22 diagnosis of cardiac malpositions. Özkutlu et al. sug- weeks of gestation. On ultrasound, the fetus had a left- gested that Cordes technique provides a simple deter- sided heart and a right-sided stomach (Fig. 1). The gall- mination of the fetal situs.[7] Situs anomalies are the least bladder was located at right side to the umbilical vein in common forms of CHD.[8] ‘Situs’ defines the arrange- the midline. Fetal echocardiography showed situs solitus ment of the viscera, atria, and vessels within the body. of the atria, the ventricles, and the main arteries. The ‘Situs solitus’ refers to normal arrangement; ‘situs inferior vena cava (VCI) and aorta were both on the left, inversus’ refers to inverted arrangement; and ‘situs and the main portal vein was on the right side. The VCI ambiguus’ (heterotaxy) refers to abnormalities in was running on the left side, and returning to the anteri- arrangements that can neither be described as solitus or right side of the diaphragm (Fig. 2). Portal venous nor inversus.[9] Univentricular physiology and transpo- structures and ductus venosus were normal. Sonographic sition of the great arteries are more common in fetuses evaluation of the fetus revealed no additional abnormalities. With these findings, the case was considered as IL. with levocardia, whereas abnormal pulmonary venous Amniocentesis showed normal male karyotype. At 38 connection, double outlet of right ventricle and left ventricle outlet obstruction are more frequent in fetus- weeks of gestation, a planned cesarean section was per- [10] formed secondary to fetal macrosomia. A male infant was es with dextrocardia. IL is a subtype of situs inversus [11] born with a birth weight of 4100 g and an Apgar score of that was first defined by Taussing in 1947. Then, Van [2] 9 at 1 min and 8 at 5 min. The neonate’s electrocardio- Praagh et al. classified this condition as a partial situs gram showed normal sinus rhythm and postnatal inversus in which the heart remains in levocardia. In [2] echocardiography confirmed the prenatal diagnosis. 95% of the cases, major cardiac anomalies are detect- Abdominal ultrasonography of the baby after birth ed and only 5–13% of the cases survive for longer than [12,13] revealed right-sided spleen and stomach and confirmed 5 years. IL is one of the heterotaxy syndromes and left-sided VCI. The baby was in good condition and oral should be carefully evaluated in terms of associated feeding was started. The boy was stable and discharged organ anomalies. Splenic abnormalities like asplenia home after a week. He was regularly followed up by a and polysplenia are usually encountered with this pediatrician and there were no major problems recorded anomaly.[2] Vaccination against Streptococcus pneumoniae with his health at 2 years. and Neisseria meningitidis and daily antibiotic prophylax-

Left VCI

Right

Fig. 1. A right-sided stomach of the case with left-sided heart case Fig. 2. The vena cava inferior (VCI) returns to the anterior right is shown on ultrasound image. side of the diaphragm.

Volume 28 | Issue 1 | April 2020 49 Eriç Özdemir M, Demirci O

is can be suggested for asplenic patients to prevent seri- tal period. Families with the baby prenatally diagnosed ous infection.[9] In some cases, IL may be complicated with IL syndrome can be better informed about the by an intestinal malrotation and intestinal obstruction prognosis. In prenatally suspected cases, a more com- due to peritoneal band, intraluminal web and an aber- prehensive examination can be performed with postna- rant vessel, commonly the superior mesenteric artery. tal MR (magnetic resonance) imaging. MR provides These cases cannot be detected for years until an more detailed information about the anatomy of the abdominal surgery.[14,15] Interrupted VCI with azygous abdominal organs and provides a more detailed exami- continuation can be detected in cases of IL.[16] and intes- nation of bowel problems.[20] Newborns with IL should tinal malrotation is generally related to interrupted be followed-up closely especially after feeding. The [3] VCI. Also, double inferior vena cava (DVCI) has been families of uncomplicated cases should be also warned reported in some IL cases. DVCI may be important for in terms of gastrointestinal pathologies and cardiac a retroperitoneal surgery and management of a throm- arrhythmias that may develop in future. For the abdom- [17] boembolic disease. Rhythm abnormalities such as inal surgeries that may be encountered in the future, it atrioventricular nodal reentry tachycardia and sick sinus is important to inform the surgical team about the syndrome are reported in cases of IL. Therefore, long- anatomy in advance. term monitorization is recommended for these patients against new-onset arrhythmias.[18] Since there were no asplenia detected in our case, the neonatologist did not Conclusion recommend vaccination and daily antibiotherapy. In In the absence of associated cardiac anomaly and chro- the neonatal period there was no sign of primary ciliary mosomal abnormality, IL cases have low risk for mor- dyskinesia and the change in respiratory sounds was bidity and mortality. Anatomical investigation and care- associated with gastroesophageal reflux. Findings of ful observation may improve the outcome of IL. intestinal malrotation and obstruction were not observed, there was no pathology associated with VCI. Conflicts of Interest: No conflicts declared Cardiac arrhythmia did not develop during the neona- References tal period and subsequent follow-ups. 1. Gindes L, Hegesh J, Barkai G, Jacobson JM, Achiron R. The pathogenesis of IL is not entirely clear but it is Isolated levocardia: prenatal diagnosis, clinical importance, associated with the abnormalities in the embryological and literature review. J Ultrasound Med 2007;26:361–5. development process. Genetic studies do not define a 2. Van Praagh S, Santini F, Sanders SP. Cardiac malpositions specific gene mutation, but there are studies investigat- with special emphasis on visceral heterotaxy (asplenia and ing the primer ciliary dyskinesia (PCD) gene. The lack polysplenia syndromes). In: Fyler DC, editor. Nadas’ pediatric of the PCD gene is thought to be resulting in IL when cardiology. Philadelphia, PA: Hanley & Belfus; 1992. p. 589– 608. it is absent in the regions associated with the development of abdominal visceral organs.[4] Heterotaxic syn- 3. Ghawi H, Zghouzi MM, Emahbes TM, Avad SM. Prenatal diagnosis of isolated levocardia and a structurally normal heart: dromes are more common in diabetic pregnancies, first two case reports and a review of the literature. Pediatric trimester cocaine use, and in those with family history Cardiol 2013;34:1034–7. [19] of CHD. In our case there were no risk factors under- 4. Katsuya S, Yamada S, Ukita M, Nishimura H, Matsumura N, lying IL. Prognosis of IL mostly depends on the sever- Fukuhara K, et al. Isolated levocardia: prenatal diagnosis and ity of associated cardiac anomalies.[9] In addition, intes- management. Congenit Anom (Kyoto) 2009;49:56–60. tinal malrotation and associated obstructions may be 5. Campbell M, Deuchar DC. Dextrocardia and isolated laevo- life-threatening, requiring immediate surgical interven- cardia. I. Isolated laevocardia. Br Heart J 1965;27:69–82. tion.[4] The IL patients with no CHD and no intestinal 6. Liberthson RR, Hastreiter AR, Sinha SN, Bharati S, Novak malrotation are considered healthy and may not be GM, Lev M. Levocardia with visceral heterotaxy – isolated diagnosed until later ages. It is important to diagnose levocardia: pathologic anatomy and its clinical implications. Am Heart J 1973;85:40–54. fetuses with IL prenatally. Although accompanying no 7. Ozkutlu S, Bostan OM, Deren O, Onderoglu L, Kale G, cardiac anomalies, it is important to follow the neonate Gucer S, et al. Prenatal echocardiographic diagnosis of cardiac carefully for the complications like intestinal malrota- right/left axis and malpositions according to standardized tion and bowel obstruction may develop during postna- Cordes technique. Anadolu Kardiyol Derg 2011;11:131–6.

50 Perinatal Journal Isolated levocardia with situs inversus without cardiac abnormality in fetus: prenatal diagnosis and management

8. Lin AE, Krikov S, Riehle-Colarusso T, Frias JL, Belmont J, 15. Tryfonas GI, Chaidos C, Avtzoglou PP, Zioutis J, Klokaris A, Anderka M, et al.; National Birth Defects Prevention Study. Papanastasopoulos A. Partial situs inversus: duodenal obstruc- Laterality defects in the national birth defects prevention study tion in a neonate with isolated levocardia. J Pediatr Surg 1992; (1998–2007): birth prevalence and descriptive epidemiology. Am 27:1584–6. J Med Genet A 2014;164A:2581–91. 16. Alt›n H, Alp H, Karataﬂ Z, ﬁap F, Baysal T, Karaslan S. 9. Lambert TE, Kuller J, Small M, Rhee E, Barker P. Abnormalities Isolated levocardia, a rare situs anomaly: report of different of fetal situs: an overview and literature review. Obstet Gynecol two patients. Türkiye Klinikleri Cardiovascular Sciences 2013; Surv 2016;71:33–8. 25:118–22. 10. Wang X, Shi Y, Zeng S, Zhou J, Zhou J, Yuan H, et al. 17. Ng WT, Ng SS. Double inferior vena cava: a report of three Comparing levocardia and dextrocardia in fetuses with heterotaxy syndrome: prenatal features, clinical significance and out- cases. Singapore Med J 2009;50:e211–3. comes. BMC Pregnancy Childbirth 2017;17:393. 18. Alberto Lopez J, Angelini P, Lufschanowski R. Successful 11. Taussig HB. Congenital malformation of the heart. New York, ablation of atrioventricular node reentry tachycardia in a NY: Commonwealth Fund; 1947. patient with crisscross heart and situs inversus levocardia. J 12. Annamalai AL, Ramakrishnan T. Levocardia with partial sub- Interv Card Electrophysiol 2006;17:133–7. diaphragmatic heterotaxia. Indian Heart J 1967;19:268–74. 19. Belmont JW, Mohapatra B, Towbin JA, Ware SM. Molecular 13. Harris TR, Rainey RL. Ideal isolated levocardia. Am Heart J genetics of heterotaxy syndromes. Curr Opin Cardiol 2004;19: 1965;70:440–8. 216–20. 14. Budhiraja S, Singh G, Miglani HP, Mitra SK. Neonatal intes- 20. Nemec SF, Brugger PC, Nemec U, Bettelheim D, Kasprian tinal obstruction with isolated levocardia. J Pediatr Surg 2000; G, Amann G, et al. Situs anomalies on prenatal MRI. Eur J 35:1115–6. Radiol 2012;81:e495–501.

Volume 28 | Issue 1 | April 2020 51 A L J O A T U N R I N R A E L P Case Report

A rare complication developing after delivery: septic pelvic thromboembophlebitis

Ersin Çintesun1 İD , Denizhan Bayramo¤lu1 İD , Emine Uysal2 İD , Çetin Çelik1 İD 1Department of Obstetrics and Gynecology, Faculty of Medicine, Selçuk University, Konya, Turkey 2Department of Radiology, Faculty of Medicine, Selçuk University, Konya, Turkey

Abstract Özet: Do¤um sonras› geliflen ender bir komplikasyon: Septik pelvik tromboemboflebit Objective: In this case report, we aimed to discuss a septic pelvic Amaç: Bu olgu bildiriminde, geçirilmifl sezaryen öyküsü olan ve thromboembophlebitis (SPT) case detected 20 days later who had vajinal yolla 30. haftada intrauterin ölü do¤um yapm›fl bir hastada, the previous history of cesarean section and had an intrauterine still- 20 gün sonra tespit edilen septik pelvik tromboemboflebit (SPT) birth vaginally at 30 weeks of gestation. olgusunun tart›fl›lmas›n› amaçlad›k. Case: A 24-year old patient, who admitted to the emergency service Olgu: 24 yafl›nda, atefl ve sa¤ alt kar›n a¤r›s› ile acil servise baflvu- with the complaints of fever and pain in the lower right abdomen and ran ve bilgisayarl› tomografi (BT) görüntülemesinde sa¤ ovaryen was reported to have a 4 cm formation consistent with thrombus on ven duvar›nda 4 cm ebat›nda segmente trombüs ile uyumlu görü- the right ovarian vein wall in the computed tomography (ST), was hos- nüm raporlanan hasta takip ve tedavi amac›yla yat›r›ld›. Genifl pitalized for follow-up and treatment. The patient whose thrombus spektrumlu antibiyoterapi ve antikoagülan tedavisi sonras› kontrol showed remission in the check-up tomography scan after the broad- tomografi görüntüsünde trombüsü gerileyen hasta 10. gün tabur- spectrum antibiotherapy and anticoagulant treatment was discharged cu edildi. Takiplerinde komplikasyon geliflmeyen hastan›n tedavi- on the 10th day. The treatment of the patient who did not develop any si flifa ile sonuçland›. complication in the follow-ups was completed with recover. Sonuç: Sonuç olarak, SPT hem obstetrik hem de jinekoloji prati- Conclusion: In conclusion, SPT is a complication which is seen rarely ¤inde oldukça ender rastlanan bir komplikasyondur. SPT, geç ta- in both obstetric and gynecologic practices. SPT is a disease which n›n›n ölümcül sonuçlar do¤urabildi¤i ancak erken tan› ile de yüz may lead to fatal outcomes by late diagnosis but satisfying results with güldürücü sonuçlar al›nabilen bir hastal›kt›r. Do¤um veya operas- early diagnosis. Abdominal pain and fever symptoms should come to yon sonras› kar›n a¤r›s› ve atefl bulgular› olan her olguda mutlaka mind in all cases after delivery or operation. akla gelmelidir. Keywords: Septic pelvic thromboembophlebitis, pregnancy, fever. Anahtar sözcükler: Septik pelvik tromboemboflebit, gebelik, atefl.

Introduction thrombophlebitis (OVT) and deep septic pelvic thromboembophlebitis (DSPT). SPT is observed in Septic pelvic thromboembophlebitis (SPT) is a quite one out of 3000 deliveries and it is more frequent in rare but significant complication seen after pelvic [4] cesarean sections. Its risk factors are the cesarean sec- infection. While it usually develops after delivery in tion, chorioamnionitis, induced abortions, multiple association with endometritis, it may also occur due to pregnancies and maternal age being <20.[3,5] Most of the [1–3] malignity and pelvic inflammatory diseases. It has cases have pain in the lower right abdomen and fever two different clinical forms, which are ovarian vein 48–96 hours after the delivery.[6] Rarely, it may have

Correspondence: Ersin Çintesun, MD. Department of Obstetrics and Gynecology, Faculty of Medicine, Selçuk University, Konya, Turkey. e-mail: [email protected] / Received: March 5, 2020; Accepted: April 10, 2020 Please cite this article as: Çintesun E, Bayramo¤lu D, Uysal E, Çelik Ç. A rare complication developing after delivery: septic pelvic thromboembophlebitis. Perinatal Journal 2020;28(1):52–55. doi:10.2399/prn.20.0281010

ORCID ID: E. Çintesun 0000-0001-8507-5850, D. Bayramo¤lu 0000-0002-6183-8398; E. Uysal 0000-0001-8533-4939; Ç. Çelik 0000-0001-6165-5092 A rare complication developing after delivery: septic pelvic thromboembophlebitis

persistent fever and lower abdominal pain despite the intrauterine stillbirth vaginally at 30 weeks of gestation 20 antibiotherapy. Although imaging methods are used in days ago in another center. Sensitivity was observed in the the diagnosis of the disease, the success rates are rela- right lower quadrant in the abdominopelvic examination. tively limited. Sometimes, the response to an anticoag- No pathology was found in the examinations carried out ulant treatment already initiated may help to diagnose on other systems. The highest temperature during admis- SPT. Today, it can be treated with antibiotics and anti- sion was 37.8ºC, and arterial pressure and pulse were coagulants. The important issue in this disease is to within normal range. In the laboratory analyses, it was recognize and remember that such a clinic condition found that Hgb was 12.2 g/dL, WBC was 9.2 K/mm3, may develop. When the diagnosis of the disease is late, liver and kidney function tests were normal, and CRP was it may progress fatally. 8.20 mg/L. It was observed that the procalcitonin was In this case report, we aimed to discuss a SPT case <0.5 μg/L. Samples were collected from the patient for which has the potential for morbidity and mortality in vaginal cervix culture. No formation consistent with case of late diagnosis but satisfying results can be thrombus was observed in the lower extremities in the achieved by the treatment during diagnosis, and to raise bilateral lower extremity Doppler USG. Antibiotherapy × awareness on this disease. Therefore, we discussed a (intravenous [IV] ampicillin-sulbactam 1 g 4 1) and anticoagulant (subcutaneous enoxaparin 4000 IU 2×1) treat- SPT case detected 20 days later who had the previous ments were initiated. history of cesarean section and had an intrauterine stillbirth vaginally at 30 weeks of gestation in our study. Beginning from the 24th hour of the treatment, the pelvic pain and fever of the hospital regressed to the normal levels. As the venous line could not be seen Case Report clearly on the pelvic MRI on the 7th day, computed A 24-year old patient, who admitted to the emergency tomography (CT) was repeated upon the recommen- service with the complaints of fever and pain in the lower dation of the radiology department. It was reported right abdomen and was reported to have a 4 cm formation that thrombus regressed at a high level (Fig. 2). As consistent with thrombus on the right ovarian vein wall in WBC and CRP values were within the normal limits the computed tomography (ST), was hospitalized for fol- and there was no reproduction in the cervix culture low-up and treatment (Fig. 1). After checking her histo- according to the laboratory analysis, the patient was ry, it was found that the case underwent a cesarean section discharged on the 10th day by oral antibiotherapy and previously, had a unilateral loss of hearing and had an anticoagulant treatments. It was also recommended to

a b

Fig. 1. (a) In the CT image with axial contrast, elevated diameter in the right ovarian vein and thrombus (white/light colored arrow) in it, and (b) the thrombus (red/dark colored arrow) in the inferior vena cava can be seen.

Volume 28 | Issue 1 | April 2020 53 Çintesun E et al.

perform the anticoagulant treatment for 6 weeks. The by imaging methods.[8,10,11] In DSPT, there is an intense informed consent was received from the patient to use condition manifesting itself with fever resistant to her medical data in scientific studies. antibiotics a few days after delivery or surgical procedure and mostly before discharge, and usually there is no pain.[6] In these cases, thrombus is not observed usu- Discussion ally in the screening.[8,10,11] While reproduction is not Although SPT develops rarely in the obstetric patient usually observed in the culture in OVT and DPST [7,8] population, its mortality is 4.4%. The pathogenesis cases which is an advanced form of SPT, a study con- of SPT is explained by Virchow’s triad. The venous sta- ducted on a series of 158 postpartum OVT cases sis due to venous dilation during pregnancy and reported that reproduction occurred in the cultures of reduced venous pressure or hypercoagulopathy second- 22% of the cases, where it was mostly streptococcus.[12] ary to the pregnancy causes endothelial cell injury Since our case did not have high fever, we did not exam- which occurs directly or due to infection by delivery or ine blood culture, and there was no reproduction in the surgical procedures. In addition, SPT is observed most cervix culture. Our case delivering stillbirth vaginally 20 frequently in the right ovary due to the presence of sig- days ago made us think that she had OVT due to an moid colon in the left ovary, right ovarian vein being infection after delivery as a risk factor. longer and uterus making more pressure on the right Septic pulmonary emboly (SPE) (13%) and metasta- [9] side during pregnancy. In our case, we observed tic abscess were reported as the two important compli- thrombus on the right ovarian vein during her admis- cations of SPT.[13] Also, some studies reported other sion. Also, observing on the 20th day after delivery complications such as the clot clogging iliofemoral or make us think that pregnancy-associated impacts have a renal vein by reverse flow.[14,15] In addition, septic throm- contribution on this condition. bi and embolies are the source of bacteremia and they [15] The two different forms of SPT, which are OVT can be fatal if not treated. and DSPT, differ from each other in terms of clinical In the suspected cases whose fever does not go down findings and diagnosis. While there are fever and pain despite the antibiotic treatment, receiving fever in the right lower quadrant one week after delivery or response 48 hours after anticoagulant treatment can be surgical procedure, the mass can be palpated on the used for the diagnosis.[8] SPT diagnosis can be estab- right lower quadrant in some cases. It is possible to lished specifically by detecting palpable intravenous observe right ovarian vein thrombus in 20% of the cases thrombus and purulent fluid in the exploratory laparo-

a b

Fig. 2. (a) It can be seen in the axial CT images with control contrast that the diameter of the right ovarian vein became normal, and the thrombus in the right ovarian vein (white/light colored arrow) and (b) in the inferior vena cava (red/dark colored arrow) regressed partially.

54 Perinatal Journal A rare complication developing after delivery: septic pelvic thromboembophlebitis

tomy, but it is rarely used. In the treatment of the dis- 3. Collins CG, MacCallum EA, Nelson EW, Weinstein BB, ease, it seems appropriate to add anticoagulant treat- Collins JH. Suppurative pelvic thrombophlebitis. I. Incidence, pathology, and etiology; a study of 70 patients treated by liga- ment to the broad-spectrum antibiotherapy which con- [16] tion of the inferior vena cava and ovarian vessels. Surgery tains potential bacteria. Although there is no certain 1951;30:298–310. rule for the type and duration of anticoagulant treat- 4. Wysokinska EM, Hodge D, McBane RD 2nd. Ovarian vein ment in the relevant literature, unfractionated heparin thrombosis: incidence of recurrent venous thromboembolism and low molecular weight heparin are the options used and survival. Thromb Haemost 2006;96:126–31. most commonly. In our case, we administered low 5. Dotters-Katz SK, Smid MC, Grace MR, Thompson JL, molecular weight heparin in the dose of 1 mg/kg with Heine RP, Manuck T. Risk factors for postpartum septic pelvic thrombophlebitis: a multicenter cohort. Am J Perinatol 12-hour interval, and observed that the complaints of 2017;34:1148–51. the patient regressed completely by continuing the 6. Eser A, Aday G, ‹negöl ‹, Sürgit Ö, Karatafl G, Gonca MO. treatment for six weeks as the thrombus was confirmed Septic pelvic thrombophlebitis in differential diagnosis of post- radiologically. As we observed the distinct regression in partum acute abdomen: case report. [Article in Turkish] the check-up tomography scan performed previously, Türkiye Klinikleri Journal of Clinical Obstetrics & Gynecology MRI was not effective in the diagnosis of this patient 2015;25:287–91. and for the purpose of protecting the patient for re- 7. Cunningham F, Leveno K, Bloom S, Spong CY, Dashe J. exposure to the radiation, we considered the full regres- Williams obstetrics, 24e. New York, NY: Mcgraw-Hill; 2014. sion of the clinical results as recovery. 8. K›r M, Üstün C, Kökçü A, Çokflenim fi. Septic pelvic thrombophlebitis: a case report. [Article in Turkish] Journal of Experimental and Clinical Medicine 1992;9:283–5. Conclusion 9. Hodgkinson C. Physiology of the ovarian veins during pregnancy. Obstet Gynecol 1953;1:26–37. In conclusion, SPT is a complication which is seen rarely 10. Kadanal› A, Karagöz G. Puerperal enfeksiyonlar. In: Çiçek NM, in both obstetric and gynecologic practices. SPT is a dis- Akyürek C, Çelik Ç, Haberal A, editörler. Kad›n hastal›klar› ve ease which may lead to fatal outcomes by late diagnosis do¤um bilgisi. Vol 1. 3rd ed. Ankara: Atlas Kitapç›l›k; 2012. p. but satisfying results with early diagnosis. Our case 323–8. exhibited an atypical progress in general, and her condi- 11. Garcia J, Aboujaoude R, Apuzzio J, Alvarez JR. Septic pelvic tion was detected by coincidence. As seen in our case, it thrombophlebitis: diagnosis and management. Infect Dis Obstet is essential to remember and rule out SPT diagnosis in Gynecol 2006:15614. the cases with fever and abdominal pain in the postpar- 12. Dunnihoo DR, Gallaspy JW, Wise RB, Otterson WN. tum period. Unfortunately, this rare disease has severe Postpartum ovarian vein thrombophlebitis: a review. Obstet Gynecol Surv 1991;46:415–27. outcomes and it should always come to mind in the dif- 13. Nezhat C, Farhady P, Lemyre M. Septic pelvic throm- ferential diagnosis. bophlebitis following laparoscopic hysterectomy. JSLS 2009;13: 84–6. Conflicts of Interest: No conflicts declared 14. Hassen-Khodja R, Gillet JY, Batt M, Bongain A, Persch M, Libo L, et al. Thrombophlebitis of the ovarian vein with free- References floating thrombus in the inferior vena cava. Ann Vasc 1. Y›ld›z K, Soyalp C. The cause of persistent fever after the cae- Surg1993;7:582–6. sarean section: ovarian vein thrombosis. [Article in Turkish] 15. Witlin AG, Sibai BM. Postpartum ovarian vein thrombosis after Van T›p Dergisi 2017;24:47–9. vaginal delivery: a report of 11 cases. Obstet Gynecol 1995;85: 2. Çintesun E, Gül A, fiahin G, Bayramo¤lu D, Uysal E, Çelik Ç. 775–80. Ovarian vein thrombophlebitis after pelvic inflammatory dis- 16. Josey WE, Staggers SR Jr. Heparin therapy in septic pelvic ease: a case report. [Article in Turkish] Ege T›p Dergisi 2019; thrombophlebitis: a study of 46 cases. Am J Obstet Gynecol 58:313–5. 1974;120:228–33.

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