J O U R N a L O F P E R I N a T a L a N D N E O N a T a L C A

Vol. 13 • No. 1 ISSN: 0972-2408 Apr–Jun 2012

PerinatologyJournal of Perinatal and Neonatal Care

Indexed in EMBASE and CINAHL

Vol. 13 • No. 1 Apr–Jun 2012

PerinatologyJournal of Perinatal and Neonatal Care

Editor in chief Dr Ranjan Kumar Pejaver Bangalore

Managing Editor Dr Jayashree B Keshav Bangalore

Editorial Board

Dr Kamini A Rao, Bangalore Dr Arvind Shenoi, Bangalore Dr Prathima Radhakrishnan, Bangalore Dr Sulochana Gunasheela, Bangalore Dr Meenakshi Bhat, Bangalore

National Advisory Committee

Dr DK Guha, Delhi Dr MKC Nair, Trivandrum Dr Uma Ram, Chennai Dr Purnima Satoskar, Mumbai

International Advisory Committee

Dr Hisham Mirghani, UAE Dr Rajam S Ramamurthy, USA Dr RS Prasad, UK Dr Koravangattu Sankaran, Canada Dr Ravi GP Krishnan, USA Dr Bhavani Sriram, Singapore Dr David Ellwood, Australia

Indexed in EMBASE and CINAHL Vol. 13 • No. 1 • Apr–Jun 2012 General Information PerinatologyJournal of Perinatal and Neonatal Care

The Journal address of a subscriber on two consecutive Perinatology (ISSN 0972-2408), one of the occasions, names of such members will be few journals dedicated to the emerging deleted from the mailing list of the journal. multidisciplinary field of perinatal medicine, Providing complete, correct, and up-to-date is published and distributed quarterly (in the address is the responsibility of the subscriber. months of January, April, July, and October Information regarding change of address every year) at The Himalaya Drug Company. should be communicated to the publisher at The journal publishes original research articles, [email protected]. review articles, brief reports on clinical and Copyright laboratory observations, case reports, and clinical studies. The journal is indexed in The entire contents of Perinatology are EMBASE, the Excerpta Medica database, protected under Indian and international CINAHL® database, and Cumulative Index copyrights. The journal, however, grants its to Nursing and Allied Health Literature® print subscribers the right of access and a license index. to copy, use, distribute, perform, and display the information/article publicly and to make Information for Authors and distribute derivative works in any digital There are no page charges for Perinatology medium for any reasonable noncommercial submissions. Please see the last section of the purpose. For commercial use, one has to journal for guidelines to be followed while obtain permission from the publisher. In either preparing and submitting a manuscript. case, the authorship and ownership of the information/article should be attributed Subscription Information properly. For permission to reproduce articles/ Perinatology allows its readers to recommend information published in this journal, please this journal to two of their friends/colleagues write to publications@himalayahealthcare. using the invitation/free subscription form com. provided in every issue. The readers can send Address for Correspondence the invitation/free subscription form attached in the journal to the editor with complete The Managing Editor – Perinatology postal addresses of two of their friends/ Scientific Publications Division colleagues. The Himalaya Drug Company Makali, Bangalore – 562 123 Subsequent issues of the journal will be sent to the invitees on a regular basis, without any Email: [email protected] subscription charges. Published at Copies of the journal are sent directly from The Himalaya Drug Company the publisher’s address. It is illegal to acquire Makali, Bangalore – 562 123 copies from any other source. If a copy is received for personal use, one cannot resale Printed at or give away the copy for commercial or M/s Sri Sudhindra Offset Process library use. The copies of the journal are sent #97, DT Street, 8th Cross, Malleswaram, by ordinary post/courier. If a copy returns Bangalore – 560 003 due to incomplete, incorrect, or changed Vol. 13 • No. 1 • Apr–Jun 2012 Contents PerinatologyJournal of Perinatal and Neonatal Care

Research Articles Cord Blood Bilirubin Level as an Early Predictor of Neonatal Hyperbilirubinemia— A Hospital-based Prospective Study Singhal V, Kamath N, Baliga BS, Unnikrishnan B 1

Study of Changing Trend in Maternal Mortality Jyothi GS, Umadevi K, Nandakumar BS, Sujani BK 9

Cystic Fibrosis: Are we Missing the Diagnosis in India? Menon PG 16

Fetal Medicine Update Outcome of Isolated Congenital Diaphragmatic Hernia Diagnosed in the Second Trimester Namashivaya A, Radhakrishnan P 20

Picture Quiz 26

Self-assessment Quiz 27

Abstracts from Literature 30

Short Communications Popliteal Pterygium Syndrome Devdas S, Belvadi GB, Premlatha R, Ramya S 32

Sirenomelia with Polycystic Kidneys: A Rare Anomaly Yelamali BC, Pol RR, Kolagi S, Bhagawati M 34

A Simple Approach to Pneumothorax in Newborns Duong HH, Sankaran K 36

Instructions to Authors 39 Vol. 13 • No. 1 • Apr–Jun 2012 Editorial PerinatologyJournal of Perinatal and Neonatal Care

Dear friends,

It is indeed great that our journal Perinatology, in its new look, released by the new publishers M/s The Himalaya Drug Company, has entered its second year. I am glad to present you the first issue of Volume 13 of the journal. My sincere thanks to the publisher, who has been persistently striving toward raising the academic standard and circulation of Perinatology. I would also like to acknowledge the managing editor and her team for the constant support, cooperation, and help.

I would like to bring to your notice that the editorial board, and the national and international advisory committees have been revised. Some of the erstwhile members had to discontinue due to various reasons. I acknowledge their contribution toward the growth of Perinatology since its inception. Active, enthusiastic members who are pioneers in the various disciplines of perinatal medicine have been inducted. The members of the editorial board will be introduced to you in this and subsequent issues.

This issue of Perinatology features articles on interesting topics such as changing trend in maternal mortality in India and current scenario of diagnostic services for cystic fibrosis and case reports on rare congenital disorders such as sirenomelia and popliteal pterygium syndrome. The theme page gives you the current scenario on breast feeding practices, particularly in India.

I recently had an opportunity to attend the Joint Congress of the Federation of Asian Oceania Perinatal Societies and the Perinatal Society of Australia and New Zealand, held in Sydney, Australia. The conference primarily emphasized on improving the situation of “still births” in various countries of the region. Still births in India is a poorly recorded and reported event. It is estimated that the stillbirth rate in India is between 30 and 35 per 1000 births and perinatal mortality rate is between 60 and 70 per 1000 births. Approximately, 0.8 million stillbirths and 1.7 million perinatal deaths occur every year. It is crucial to improvise perinatal audit, which helps to identify suboptimal care related to perinatal deaths and take appropriate measures for its reduction.

I hope you will enjoy reading this issue.

Dr Ranjan Kumar Pejaver Editor in chief Email: [email protected] Vol. 13 • No. 1 • Apr–Jun 2012 Know your Editorial Board PerinatologyJournal of Perinatal and Neonatal Care

Dr Ranjan Kumar Pejaver is a Senior Consultant Neonatologist at KR Hospital, Honorary Professor of Neonatology at Kempegowda Institute of Medical Sciences, and Head of the Department of Pediatrics at St Philomenas Hospital in Bangalore, India.

Dr Pejaver has been associated with various esteemed organizations/committees both at Dr Ranjan Kumar Pejaver the national and international levels. He is the (FRCP, FRCPCH [UK], FIAP, FNNF) president of Federation of Asia Oceania Perinatal Editor in chief Societies; member (International committee) of World Association of Perinatal Medicine; secretary at the Neonatal Chapter of Indian Academy of Pediatrics; Joint National Coordinator of Indian Academy of Pediatrics, Neonatal Resuscitation Program, and First Golden Minute Project; and Fellow of the Royal Society of Tropical Medicine and Hygiene, London.

Dr Pejaver has been the founder editor of Perinatology. In addition, he is an associate editor of Journal of Neonatology, member of national advisory board for Indian Pediatrics, and member of the editorial board for Journal of Perinatal Medicine. He has published over 60 scientific papers in national and international journals and delivered more than 75 presentations at various scientific meetings held across the globe. He has also authored and contributed for various medical text books. Dr Pejaver has participated in and guided more than twenty major multicenter research trials. He is a well traveled person, having worked in several places including Africa, United Kingdom, Germany, Middle East, and India. Vol. 13 • No. 1 • Apr–Jun 2012 Theme PerinatologyJournal of Perinatal and Neonatal Care

Breast Milk is Best for Newborn

Breastfeeding is one of the most effective ways to ensure good health and survival of infants and young children. The World Health Organization recommends exclusive breastfeeding up to 6 months of age and continued breastfeeding along with complementary foods up to 2 years of age or beyond. The American Academy of Pediatrics advises that breastfeeding be continued for at least 1 year, and thereafter for as long as mother and baby desire.

Globally, <40% of infants under 6 months of age are exclusively breastfed. Latest statistical reports have shown that breastfeeding within 1 hour of birth could avert 22% newborn deaths (which numbers to 250,000 newborns). Exclusive breastfeeding from 0 to 6 months can reduce the incidence of deaths due to diarrhea by 4.6 times and pneumonia by 2.5 times. It helps to cut down 13% (350,000) of deaths among children below 5 years of age. Overall Situation of Early and Exclusive Breastfeeding in India The status of optimal breastfeeding and complementary feeding practices is reported to be very dismal in India. According to an assessment done by the Government of India and National Family Health Survey (NFHS-3), the initiation of breastfeeding within 1 hour of birth is only 24.5%. A more recent data from the District Level Household and Facility Survey (DLHS-3) showed slight improvement, which is encouraging, wherein the initiation of breastfeeding was reported to be about 40% (data obtained from 534 districts). The value however varied from 4.2% to 93.3% across these districts. Exclusive breastfeeding up to the age of 6 months, according to NFHS-3, was found to be only 46.3%. However, as per the data provided by DLHS, the percentage varied substantially across the states and districts. Not even a single district recorded >90% exclusive breastfeeding.

Further analysis of age wise data also revealed that exclusive breastfeeding rapidly declined from first month to sixth month, and only about 20% children were exclusively breastfed at 6 months, while the goal of planning commission for 10th plan was 80%. Introduction of complementary feeding along with continued breastfeeding between 6 and 9 months of age was 55.8% in NFHS-3 as compared to 35% in NFSH-2.

Overall, the most unfortunate part of feeding practices is that there is very little, if any improvement, over the past 2 decades, except in the rate of initiation of breastfeeding showing a worthwhile increase over the past 3 years from 20% to 40%.

The success rate among mothers who want to breastfeed could be greatly improved by educating all the prospective mothers about the health benefits and management of breastfeeding and drawbacks of formula feeding. Research RESEARCH ARTICLES PERINATOLOGY • Vol. 13 • No. 1 • Apr–Jun 2012 Articles

Cord Blood Bilirubin Level as an Early Predictor of Neonatal Hyperbilirubinemia—A Hospital- based Prospective Study Vikram Singhal, Nutan Kamath,* Baliga BS, Unnikrishnan B

Abstract Background: Neonatal hyperbilirubinemia, a condition characterized by elevated bilirubin level in blood, is a common, complicated, and controversial clinical problem. The American Academy of Pediatrics (AAP) recommends a follow-up visit, after 2 to 3 days of birth, to detect significant jaundice in all newborns discharged within 48 hours of delivery. The present study was carried out to evaluate cord blood bilirubin levels as an early predictor of neonatal hyperbilirubinemia. Methods: The study group consisted of 500 term, appropriate for gestational age (AGA) neonates with an Apgar score of ≥7. Total bilirubin of ≥15 mg/dL was defined as significant hyperbilirubinemia. Umbilical cord serum bilirubin (UCSB) was estimated and followed up daily for evidence of neonatal hyperbilirubinemia up to 5 postnatal days. Prevalence of hyperbilirubinemia was found to be 14% in the study population. In case of clinical jaundice presenting before 5 days, serum bilirubin level was estimated on the day of detection. Values of bilirubin on fifth day were related with that of cord blood bilirubin. Blood groups of both mothers and newborns were evaluated. Direct Coomb’s test was done in presence of ABO incompatibility. Data were analyzed using chi-square, and receiver operating characteristics (ROC) curve. Results: Mean UCSB was reported to be 1.56 ± 0.70 mg/dL. There *Correspondence was a significant association between route of delivery, birth Dr Nutan Kamath order, and hyperbilirubinemia requiring phototherapy (P<.005). Professor, Kasturba Medical College Using UCSB level of 31.9 mg/dL, hyperbilirubinemia could be pre- Mangalore - 576104, Karnataka dicted with sensitivity of 90% and specificity of 82.55% and pos- India itive predictive value of 45.65% and negative predictive value of Email: [email protected] 98.07%. There was no significant association found between the

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SinghalRESEARCH V, et al. CordARTICLES blood bilirubin level, an early predictor of neonatal hyperbilirubinemia

mothers’ blood groups and increased risk of hyperbilirubinemia in neonates in this study. Conclusion: This study suggests that the measurement of UCSB is a useful tool for early prediction of the subsequent course of jaundice in healthy term newborns in Indian population. It may help to improve the management of newborns. Key words: Hyperbilirubinemia, cord bilirubin, neonates

Introduction However, taking a blood sample causes pain and needs skilled staff. Umbilical cord blood can be easily Neonatal hyperbilirubinemia is an interesting, compli- sampled in almost all newborns for various screening cated, and controversial clinical condition. Jaundice procedures. The hypothesis—“the umbilical cord in newborn affects nearly 70% of term and 80% of serum bilirubin may be a promising marker” to assess preterm neonates during the first week of life and in 1–3 the risk of subsequent excessive hyperbilirubinemia, majority of the infants, it is a physiological event. was first published in 1950s by Vest.13 Several studies Total serum bilirubin (TSB) in infants discharged from Western countries have assessed the predictive within 48 hours of life, generally shows an increasing ability of cord blood bilirubin in neonatal hyperbiliru- trend and some of these infants later develop significant binemia.14–19 hyperbilirubinemia. It is necessary to know the usefulness of UCSB in The conjugated bilirubin is not absorbed from the intes- prediction of neonatal hyperbilirubinemia in Asian tine in the newborn, but the small amount of uncon- population as racial differences are known to exist.6 jugated bilirubin that appears in the bile is partially Hence the present study was conducted to evaluate reabsorbed. In the newborn, enterohepatic circula- the cord blood bilirubin levels as an early predictor of tion of bilirubin is due to the presence of an enzyme, neonatal hyperbilirubinemia in a cohort of newborns in β -glucuronidase, which converts bile glucuronide into South India. unconjugated bilirubin. This circulation of bilirubin is important in neonates who are not fed from birth, Aims and Objectives as with introduction of feeds, bacterial colonization To evaluate cord blood bilirubin levels in predicting the destroys this enzyme. Meconium also contains a signifi- risk of subsequent hyperbilirubinemia in healthy term cant amount of bilirubin, half of which is unconjugated newborns. and reabsorbed.4 The American Academy of Pediatrics (AAP) recom- Methodology mends that newborns discharged within 48 hours of A prospective cohort study was carried out at the delivery should have a follow-up visit after 2 to 3 days neonatal unit of a tertiary referral hospital affiliated to detect significant jaundice.5 Early prediction of jaun- to a medical college in South India, for a period of 12 dice using umbilical cord serum bilirubin (UCSB) months. offers an attractive option to detect neonates who are at the risk of developing hyperbilirubinemia. Study population Reliable prediction can reduce hospital stay for normal The initial sample comprised 530 newborns, sequen- neonates and help in identifying those who are at an tially born, from any type of delivery, both genders, increased risk of developing pathological jaundice.6–12 gestational age of >37 weeks measured by Ballard’s

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Singhal V, et al. Cord blood bilirubin level, an early predictor of neonatalRESEARCH hyperbilirubinemia ARTICLES method,20 birth weight of >2500 g and Apgar scores of Roche automated clinical chemistry analyzers by a >7 at the first and fifth minute of life, with or without method developed by Wahlefeld, et al.22 blood group incompatibility between mother and child (ABO or Rh). Working indices The exclusion criteria of the study were any newborn The main outcome of the study was analyzed in terms requiring neonatal intensive care unit (NICU) admis- of bilirubin level of ≥15 mg/dL, which was consid- sion (with an exception of phototherapy); emergency ered as hyperbilirubinemia requiring phototherapy, cesarean section; birth weight of <2.5 kg; gestational age according to AAP guidelines. of <37 weeks or >41 weeks; pregnancy-induced hypertension; gestational diabetes mellitus; Rh–ve blood Analysis of data group; history of previous abortion; maternal intake of The analysis was carried out using the Statistical drugs like antimalarials, sulfonamides, or nitrofuran- Package for the Social Sciences (SPSS 16.0.2) program toin; and those babies who required neonatal resuscita- for Windows. The critical bilirubin level, measured tion or had clinical sepsis, as all the above contributed from the umbilical cord blood having the highest sensi- to exaggerated neonatal hyperbillirubinemia. Thus, 30 tivity, was determined with the receiver operating char- cases were excluded from the 530 in the initial sample. acteristic (ROC) curve analysis. Statistical test using The final sample, therefore, comprised 500 newborns. chi-square test of significance was applied and the predictive values (sensitivity, specificity, positive predic- Study tools tive value (PPV), and negative predictive value (NPV) were calculated using the conventional formulae. Maternal interview, cord blood sample, and venous P values with significance of <5% were considered blood of all neonates statistically significant. All infants were classified into Data collection 4 groups depending on the UCSB levels <0.9mg/dL (group-I), 1.0 to 1.9 mg/dL (group-II), 2.0 to 2.9 mg/ Delivered mothers who fulfilled the inclusion criteria dL (group-III), and >3 mg/dL (group-IV). were recruited and clinical history in a specially designed proforma was recorded. The inclusion of the Results newborns in the study was done after receiving written A total of 530 newborns were initially enrolled and consent from their parents. Cord blood samples were 30 of these were excluded during the study period. collected from all newborns who complied with the protocol inclusion criteria. The newborns were followed The prevalence of hyperbilirubinemia in this study up for 5-day period with daily physical examination population was 14%. In this study, male infants consti- according to Kramer dermal zones.21 In case of clin- tuted 290 (58%) and females constituted 210 (42%). ical jaundice presenting before 5 days, serum bilirubin Among 70 newborns requiring phototherapy, 45 level was rechecked on the same day. Values of bilirubin (64.29%) were males and 25 (35.71%) were females on fifth day were related with those of UCSB. Blood (Table 1). Among the males, 15.5% required photo- grouping tests of both the mothers and their newborns therapy as compared to only 11.9% in the females. were done. Direct Coomb’s test was done in case of In this study, 385 (77%) were delivered by normal ABO incompatibility. vaginal delivery (NVD) and 115 (23%) by lower segment cesarean section (LSCS). The number of Laboratory investigation infants born by LSCS who developed hyperbiliru- The umbilical cord blood samples were collected and binemia were almost double (22.6%) as compared subjected to hemoglobin, hematocrit, blood grouping to those who required phototherapy born by NVD and Rh typing, and total and direct serum bilirubin (11.4%) and this was statistically significant P ( <.005) estimation. Serum bilirubin estimation was done using (Table 1).

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SinghalRESEARCH V, et al. CordARTICLES blood bilirubin level, an early predictor of neonatal hyperbilirubinemia

Table 1. Correlation of Various Factors and Table 2. Predictive Ability of Hyperbilirubinemia Requirement of Phototherapy Requiring Phototherapy Using UCSB Level Phototherapy Phototherapy Total Yes No Yes No Number Number % Number % Number % Number % Gender (c² = 1.32 P = .251 Not significant) Association between UCSB Level and Requirement of Phototherapy Male 45 64.29 245 56.98 (c² = 168.4 P<.001 Highly significant) First group 1 0.91 109 99.09 110 Female 25 35.71 185 43.02 (0.0–0.9 mg/dL) Route of Delivery (c² = 9.19 P = .002 Significant) Second group 6 2.36 248 97.64 254 Normal vaginal delivery 44 62.86 341 79.31 (1.0–1.9 mg/dL) Lower segment cesarean Third group 26 37.14 89 20.69 47 42.74 63 57.26 110 section (2.0–2.9 mg/dL) Fourth group Birth Order (c² = 8.20 P = .04 Significant) 16 61.54 10 38.46 26 (≥3 mg/dL) Association between UCSB and requirement of phototherapy with First 41 58.57 180 41.86 taking >1.9 mg/dL level as cut-off Second 20 28.57 140 32.56 (c² = 158.61 P<.0001 highly significant) Third 5 7.14 63 14.65 ≥1.9 63 46 73 54 136 Above third 4 5.72 47 10.73 <1.9 7 1.9 357 98.1 364 Mother’s age (c² = 3.00 P = .39 Not significant) <25 Years 31 44.29 233 54.19 Newborns of mothers between 26 and 30 years of age 26–30 Years 32 45.71 152 35.35 who required phototherapy were 32 (45.71%) and that 31–35 Years 6 8.57 36 8.37 above 36 years was 1 (1.43%) and this was found not to >36–40 Years 1 1.43 9 2.09 be statistically significant (Table 1). Total 70 100 430 100 In this study, there was no statistically significant correlation between requirement of phototherapy and cord A total of 221 (44.2%) newborns were first in birth blood hemoglobin and hematocrit levels. The mean order and 51 (10.2%) were above third in birth order in this study (Table 1). There was a statistical significance hemoglobin and hematocrit levels in infants requiring between birth order and children requiring photo- phototherapy were 15.514 and 46.3429, whereas those therapy. About 264 (52.8%) mothers were below the age of 25 years and 10 (2.00%) were above the age of 35 years.

Figure 1. Association between UCSB level and Figure 2. ROC Curve requirement of phototherapy.

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Singhal V, et al. Cord blood bilirubin level, an early predictor of neonatalRESEARCH hyperbilirubinemia ARTICLES who did not require phototherapy were 15.394 and breath corrected for ambient carbon monoxide and 46.3930, respectively. tried to predict early onset of neonatal hyperbilirubinemia.20,25 Others like Seidman, et al have estimated Among 70 newborns who required phototherapy, the predictive value of serum bilirubin concentrations majority were in group-III (67.7%) and only one in during initial postnatal days.26 Transcutaneous esti- group-I (1.5%). There was statistically highly signifi- mation of bilirubin during the first 24 hours is a good cant (P<.001) association between requirement of predictor of neonatal jaundice as shown by Bilgeu, et phototherapy and increasing UCSB levels. This study al and Bhat, et al.25,27 However, the values vary with shows that number of infants requiring phototherapy parameters like color and thickness of the skin. Most proportionately increased as the UCSB increased ie, of these studies investigated postnatal serum bilirubin from 0.91% in group-I to 61.54% in group-IV (Figure specimens which can be obtained only by painful blood 1). The values characterizing the predictive ability of sampling. In contrast, umbilical cord blood can be UCSB as predictor for the future development of signif- easily collected in all newborns. Furthermore, it keeps icant hyperbilirubinemia are shown in Table 2. the newborn free from pain and most important is that With ROC analysis, a mean umbilical cord bilirubin the data are available immediately after birth. Stratifi- level of >1.9 mg/dL was determined to have the highest cation of high-risk neonates is possible based on UCSB sensitivity to predict the newborns who would develop for early discharge. significant hyperbilirubinemia (Figure 2). In this In this regard in 1986, Rosenfeld analyzed a group of study, using UCSB level of ≥1.9 mg/dL, hyperbiliru- 108 full-term newborns according to the risk of devel- binemia could be predicted with sensitivity of 90.00%, oping severe hyperbilirubinemia and concluded that specificity of 82.55%, positive predictive value (PPV) newborns with an UCSB level of lower than 2 mg/dL of 45.65%, and negative predictive value (NPV) of had only 4% chance of developing significant jaun- 98.07%. At this critical mean serum bilirubin level, dice, in comparison to a 25% chance presented by the NPV was very high and the PPV was fairly low. Of those neonates with levels higher than 2 mg/dL.16 The the 136 newborns who had a UCSB level of >1.9 mg/ latter group presented a higher chance of phototherapy dL, 63 (46%) developed significant hyperbilirubinemia requirement. in first 5 days of life, whereas only 7 (1.9%) of the 364 Knudsen carried out a similar study to demonstrate that newborns who had UCSB level of <1.9 mg/dL devel- jaundiced newborns presented higher UCSB levels than oped significant hyperbilirubinemia later on. newborns without clinical jaundice, but they consid- 29 Discussion ered the cut-off of 2.3 mg/dL. The prevalence of hyperbilirubinemia in this study was The growing practice of early discharge of newborns has 14%, which is comparable to 10% to 15% in various resulted in a re-emergence of bilirubin-related neurolog- other studies.15–18 Minor differences in prevalence may 7 ical sequelae. Prevention of morbid outcomes is based be attributable to ethnic and geographic variations in on the early detection of jaundice in neonates who are different populations. Higher prevalence in this study at risk of developing significant hyperbilirubinemia. can be explained by percentage of mothers receiving Studies are focused to identify these high-risk neonates oxytocin. Oxytocin used for induction of labor has at the earliest age.11,20,23–26 Bhutani, et al defined hour- been known to be associated with neonatal hyperbiliru- 30–32 specific bilirubin values of newborns and plotted binemia. percentile curves that are very useful for detecting Sex ratio in this study was 1.38:1. The prevalence of newborns at risk.11 Aplay, et al identified that bilirubin hyperbilirubinemia was more in males as compared to value below 6 mg/dL after 24 hours correlated with females, but this was not found to be significant which low postnatal bilirubin values.23,24 Stevenson, et al and is comparable with studies by Bernaldo, et al; Seidman, Okyama, et al measured carbon monoxide in end-tidal et al; and Newman, et al.18,26,33

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Majority of the deliveries in this study were normal risk group children with UCSB level of <1.9 mg/dL. (77%), while 23% were cesarean sections and was statis- NPV in this low risk group can prove useful in using tically significant. This is in agreement to a study done this parameter for making decisions regarding early by Phelan, et al; however in a study done by Suchonska, discharge or request for review of the newborns for et al, no significant relation was found between route of evaluating neonatal hyperbilirubinemia. delivery and neonatal hyperbilirubinemia.36,17 In this study, there was no association found between In this study, most infants were first in birth order with the blood group of the mother and neonate and devel- significant association between hyperbilirubinemia and opment of neonatal hyperbilirubinemia, which is in birth order. This is similar with the findings of a study agreement with other studies.18,26,42 The results of this by Phelan, et al where primiparous mothers are more study differ from a study done by Sarici, et al, in which likely to have jaundiced infants.36 there were more number of mothers with O+ve blood group.43 This may be due to very small number of In this study, no significant association was found mothers having O+ve as blood group in this study. between maternal age and development of hyperbilirubinemia in newborns. This is in agreement with a study Although there has been a decrease in the length of done by Srivastav, et al.35 However, studies done by postdelivery hospital stays for newborns and their Seidman, et al; Newman, et al; and Rakesh, et al have mothers in recent years, there is still much contro- found that there is a significant association between versy about how early (<48 hours after delivery) or jaundice and increasing maternal age.26, 33, 37 late (>72 hours after delivery), a mother–child dyad should be discharged. Opponents of the early discharge The mean UCSB was 1.56 ± 0.70 mg/dL and the suggest that various risks are associated such as hyper- number of newborns with significant hyperbilirbinemia bilirubinemia; breast-feeding difficulties; feeding prob- increased with increasing UCSB levels in this study lems leading to dehydration and malnutrition; missed (Table 2). identification of congenital anomalies and newborn 2-4,34,44 In the present study, UCSB value of 1.9 mg/dL was screening; and increased rate of readmission. In considered as cut-off to predict subsequent hyperbiliru- contrast, proponents of the early discharge regard it as safe and advantageous because of various medical, binemia requiring phototherapy in view of an increase 1–3,45 in the percentage of neonates developing hyperbiliru- social, and economic reasons. binemia above this value (2.36% – 42.36%) between To optimize utilization of the limited neonatal care the two groups. This value is higher than that in the facility available in our country, it is essential to have study by Knuffer, et al and lower than that used in the practical guidelines to predict which newborn would study by Knudsen, et al.19,15 With lower cut-off value (as develop significant hyperbilirubinemia and to avoid with the study by Knupfer, et al), sensitivity and NPV preventable neurological damage. From the present increases, but specificity and PPV decreases (Figure 2). study, it can be concluded that estimation of UCSB, If a higher cut-off value is considered (as with the study considering the critical bilirubin level of >1.9 mg/dL at by Knudsen, et al), specificity and PPV increases, but birth will help predict nearly all healthy term newborns sensitivity and NPV decreases. Hence, considering a who would have significant hyperbilirubinemia and cut-off of 1.9 mg/dL in this study has resulted in fairly will require a phototherapy treatment later during first comparable sensitivity and NPV to that of the study by few days of life. It can also be concluded that newborns Knupfer, et al and higher specificity and PPV (Table 3). with UCSB level of <0.9 mg/dL are unlikely to have neonatal hyperbilirubinemia. The main limitation of All studies (Table 4) show significant association this study was small sample size. between rising UCSB and development of jaundice in subsequent postnatal days. Present study shows that Conclusion UCSB is an useful indicator of subsequent neonatal This study suggests that the measurement of UCSB is hyperbilirubinemia and aids in identifying the low- a useful tool for risk stratification due to hyperbiliru-

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Singhal V, et al. Cord blood bilirubin level, an early predictor of neonatalRESEARCH hyperbilirubinemia ARTICLES

Table 3. Statistics and Predictive Ability of UCSB 3. Kivlahan C, Jame EJP. The natural history of neonatal jaundice. Pediatrics. 1984;74:364-370. Present Study by Knupfer, Study by Knudsen, Study 4. Xiawang, et al. Bilirubin metabolism applied physiology. study (%) et al (%) et al (%) Curr Pediatr. 2006;16(1):70-74. UCSB ³1.9 ³1.74 ³2.33 5. American Academy of Pediatrics. Practice parameter: Sensitivity 90 97.0 13.0 Management of hyperbilirubinemia in the healthy term newborn. Pediatrics. 1994;94:558-567. Specificity 82.55 41.40 99.0 6. Madan A, et al. Neonatal hyperbilirubinemia. Taeusch PPV 45.65 4.80 85.0 HW, et al. eds. Avery’s diseases of the newborn. 8th Edn. NPV 98.07 99.80 72.00 Philadelphia:WB Saunders Company;2005:1226-1256. 7. Stanely L. An evidence based review of important issues Table 4. Relationship between UCSB and Postnatal concerning neonatal hyperbilirubinemia. Pediatrics. Jaundice 2000;114:130-153. 8. Valaes T. Problems with predictions of neonatal Study (no. of Hyperbilirubi- UCSB Incidence of hyperbilirbinemia. Pediatrics. 2001;108:175-177. cases) nemia (%) (mg/dL) jaundice (%) 9. Thomas N, et al. Predictions and prevention of extreme 0–0.9 0.91 neonatal hyperbilirubinemia in a health maintenance Present study 1–1.9 2.36 organization. Acta Pediatr Adolesc Med. 2000;154:1140‑1147. 14 (500) 2–2.9 42.74 10. Maisles MJ, et al. Jaundice in the healthy newborn >3 61.54 infant: A new approach to an old problem. Pediatrics. 1988;81:505‑511. Rataj, et al.14 <1 2.4 11. Bhutani VK, et al. Predictive ability of predischarge (800) >2.5 89 hour specific serum bilirubin for subsequent significant Bernaldo AJ, et <2 0 hyperbilirubinemia in healthy term and near term newborns. 19.86 al.18 (380) >2 53 Pediatrics. 1999;103:6-14. <1.17 0 12. Tan KL. Transcutaneous bilirubinometry in full term Chinese and Malay infants. Acta Pediatr Scand. 1982;71:593-596. Knupfer, et al.19 1.17–1.75 0.30 10.60 13. Vest M. Physiologic and pathologic des Neugeborenen (1100) 1.75–2.34 3.4 icterus. Pediatrics.1959:33-36. >2.34 8.6 14. Rataj J, et al. Usefulness of measuring bilirubin levels in Zakia N, et al.38 <2.5 4.1 cord blood for predicting hyperbilirubinemia in newborns. 15.5 (84) >2.5 90.9 Ginekol Pol. 1994;65(6):429-432. 15. Knudsen A. Prediction of the development of neonatal 39 >4 100 Preethi, et al. jaundice by increased umbilical cord blood bilirubin. Acta (50) <4 2.2 Pediatr Scand. 1989;78:217-221. Taksande, et <2 2 16. Rosenfeld J. Umbilical cord bilirubin levels as a 9.5 al.41 (200) >2 17 predictor of subsequent hyperbilirubinemia. J Fam Pract. 1986;23:556‑558. binemia. It may help by facilitating the decision time 17. Suchonska B, et al. Concentration of bilirubin in the umbilical blood as indicator of hyperbilirubinemia in newborns. for early discharge. Establishing such screening proce- Ginekol-Pol J. 2004;75(10):749-753. dures using UCSB will also minimize the risk of 18. Bernaldo AJ, Segre CA. Bilirubin dosage in cord blood could missing diagnosis in the case continuum of neonates in it predict neonatal hyperbilirubinemia? Sao Paulo Med J. the community. 2004;122(3):99-103. 19. Knupfer M, et al. Predictive value of umbilical cord blood References bilirubin for postnatal hyperbilirubinemia. Acta Pediatrica. 2005;94:581-587. 1. Agarwal R, Deorari AK. Unconjugated hyperbilirubinemia in newborns: Current prospective. Indian Pediatr. 20. Stevenson DK, Faranoff AA. Prediction of hyperbilirubinemia 2002;39:30‑42. in near term and term infants. Pediatrics. 2001;108:31-39. 2. Singhal PK, et al. Spectrum of hyperbilirubinemia: An 21. Kramer LI. Advancement of dermal icterus in the jaundiced analysis of 454 cases. Indian Pediatr. 1992;29:319-325. newborn. Am J Dis Child. 1969;118:454-458.

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SinghalRESEARCH V, et al. CordARTICLES blood bilirubin level, an early predictor of neonatal hyperbilirubinemia

22. Wahlefeld AW, et al. Modification of the Malloy-Evelyn 35. Srivastava N, et al. A study of serum bilirubin in neonates method for a simple, reliable determination of total bilirubin in relation to the maternal age. Indian J Med Sci. in serum. Scand J clin Lab Invest. 1972;29 Supplement 126. 1999;53:158‑161. 23. Alpay F, et al. The value of first day bilirubin measurement 36. Phelan J, et al. Early newborn hospital discharge and in predicting development of significant hyperbilirubinemia readmission for mild and severe jaundice. Arch Pediatr in healthy term newborn. Pediatrics. 2000;106:16. Adolesc Med. 1999;153:1283-1288. 24. Agarwal R, et al. Early neonatal hyperbilirubinemia using first 37. Rakesh L, et al. Non-invasive estimation of total serum day serum bilirubin level. Indian Pediatr. 2002;39:724-730. bilirubin by multi wavelength spectral reflectance in neonates. 25. Okuyana H, et al. End tidal CO in prediction of neonatal non- Indian Pediatr. 2000;37:771-775. hemolytic hyperbilirubinemia. Pediatr Int. 2001;43:329-333. 38. Zakia N, et al. The value of umbilical cord bilirubin 26. Seidman DS, et al. Predicting the risk of jaundice in full-term measurement in predicting the development of significant healthy newborns – A prospective population based study. J hyperbilirubinemia in healthy newborn. Bangladesh J Child Perinatal. 1999;19:564-567. Health. 2009;33(2):50-54. 27. Risemberg A. Value of measuring cord blood bilirubin 39. Preethi BP, et al. Correlation of cord bilirubin levels with concentration in ABO incompatibility. Brit Med J. hyperbilirubinemia in ABO incompatibility. Int J Pharma 1990;1:980-986. and Bio Sci. 2011;2(2):257-262. 28. Knudsen A. Prediction and non-invasive assessment of 40. Camilla K, et al. Neonatal hyperbilirubinemia In: Cloherty neonatal jaundice in the term healthy newborn infant. Acta JP, et al. eds. Manual of Neonatal Care (5th edn). Pediatr. 1996;85:393-397. Philadelphia:Lippincott Williams and Wilkins; 2004:185-221. 29. Knudsen A. Predicting the need of phototherapy in healthy 41. Taksande A, et al. Prediction of the development of neonatal mature neonates using transcutaneous bilirubinometry on the hyperbilirubinemia by increased umbilical cord bilirubin first postnatal day. Biol Neonate. 1995;68:398-403. level. Curr Pediatr Res. 2005;9(1&2):5-9. 30. Khuram A, Zulfiquor A. Risk factor and spectrum of 42. Palmer DC, Drew JH. Jaundice: A 10 year review of 41000 neonatal jaundice in a birth cohort in Karachi. Indian Pediatr. live born infants. Aust Pediatr. 1983;19(2):86-89. 1999;36:487-493. 43. Sarici SU, et al. An early (sixhour) serum bilirubin 31. Maisles MJ, et al. Normal serum bilirubin levels in the measurement is useful in predicting the development newborn and the effect of breast-feeding. Pediatrics. of significant hyperbilirubinemia and severs ABO 1986;78:837-843. incompatibility. Pediatrics. 2002;109:e53. 32. Suchonska B, et al. Maternal and umbilical bilirubin 44. Bhutani VK, Johnson LH. Managing the assessment of concentration at the time of delivery depending on the course neonatal jaundice importance of timing. Indian J Pediatr. of pregnancy and labor. Ginekol Pol. 2003;74:618-623. 2000;67:733-737. 33. Newman M, et al. Jaundice noted in first 24 hours after birth 45. Perlstein MA. The late clinical syndrome of posticteric in a managed care organization. Arch Pediatr Adolesc Med. encephalopathy. Pediatr Clin North Am. 1960;7:665-687. 2002;156:1244-1250. 34. Friedman L, et al. Factors influencing the incidence of neonatal jaundice. Br Med J. 1978;1:1235-1237.

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RESEARCH ARTICLES

Study of Changing Trend in Maternal Mortality Jyothi GS,* Umadevi K, Nandakumar BS, Sujani BK

Abstract Objective: To review the changing trend in maternal mortality rate (MMR) and specific causes of maternal deaths. Methods: This is a retrospective analysis of maternal deaths (occurred over a decade from 1998 to 2008) carried out at the Department of Obstetrics and Gynecology, M S Ramaiah Medical College, Bangalore, a referral tertiary center. The data has been analyzed in 2 comparable time frames from Sep- tember 1998 to August 2003, and September 2003 to August 2008. Results: Maternal mortality rate (MMR) per 100,000 live births has shown a decrease from 1066 between 1998 and 2003 to 931 between 2003 and 2008. It was noted that 56% to 61% deaths across both groups occurred in primigravidas. The duration from admission to death was >24 hours in 52% death cases that occurred in the first half of the decade while 71% occurred in the later half of the decade, reflecting improvement in emer- *Correspondence gency obstetric care. Hemorrhage, hypertensive disorders, and Dr Jyothi GS septicemia emerged as the greatest killers. The proportion of all Associate Professor maternal deaths due to indirect causes increased with liver dis- Department of Obstetrics and Gynecology orders (with jaundice) being the leading cause. M S Ramaiah Medical College Conclusion: The MMR in this institution is still high due to emer- Bangalore - 560054, Karnataka gency referrals. Unfortunately, direct causes continue to be the India primary killers. Emphasis should be laid on regular and quality Phone: +91 8023484422, +91 9845257772 antenatal care, and availability of emergency obstetric care in Email: [email protected] tertiary care centers. Key words: Meternal mortality, meternal death, hemorrhage, hypertensive disorders, septicemia

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JyothiRESEARCH GS, et al. ARTICLESChanging trend in maternal mortality

Table 1. Changing Trends in Maternal Mortality Over Introduction and Aim a Decade Maternal death is recognized as the most crucial area of No. of Total MMR/100,000 Year maternity care, necessitating urgent medical attention. maternal deaths live births live births Nothing illustrates the contrast between well resourced 1998–2003 25 2345 1066 (developed) and under resourced (developing) coun- 2003–2008 41 4403 931 tries more starkly than maternal mortality rate (MMR). According to recent estimates by the World Health Table 2. Distribution of Subjects by Their Various Organization, the overall maternal mortality ratio per Demographic Characteristics 100,000 live births is 13 in industrialized countries, Year Residence and 440 in developing countries, and 890 in least developed 1998–2003 2003–2008 nature countries.1 Institutional data, though not an index of Total no. Total no. of admission % % maternity care of the nation as a whole, still highlights n = 25 n = 41 the magnitude of the problem. All teaching referral Emergency 23 92 40 97.6 hospitals have inflated rates of morbidity and mortality, Booked 02 08 01 2.4 as they serve a very wide area of referrals and most of the cases present with complications. The objective of Urban 21 84 30 73.2 this study is to review and analyze the changing trend in MMR and specific causes of maternal deaths over a Rural 04 16 11 26.80 decade in a tertiary care center. Year Primigravida/ 1998–2003 2003–2008 Multigravida Total no. Total no. Methodology % % A retrospective analysis of maternal deaths occur- n = 25 n = 41 ring over a decade from 1998 to 2008 was carried out Primigravida 14 56 26 63.4 in the Department of Obstetrics and Gynecology, M S Ramaiah Medical College, Bangalore, which Multigravida 10 40 15 36.6 is a teaching and referral hospital catering to high- Grand multigravida 01 04 - - risk obstetric patients. The data has been analyzed in Year 2 comparable time frames from September 1998 to 1998–2003 2003–2008 August 2003 and September 2003 to August 2008. Age group in years Total no. Total no. % Data for the present review includes all maternal deaths n = 25 n = 41 which occurred during the period as mentioned above. < 20 (teenage) 03 12 06 All the death records of women in the reproductive 20–30 19 76 34 age groups were reviewed individually to discuss the specific cause of death. MMR was computed as the total >30 03 12 01 number of maternal deaths per 100,000 live births and the causes of maternal deaths were classified as deaths Table 3. Distribution of Subjects by Admission to Death Interval due to direct/indirect/unrelated causes. A cause-specific mortality ratio was used to determine whether there Year 1998–2003 2003–2008 has been an increase or decrease in any specific cause of Hours/days Total no. of Total no. of death. The total number of live births was also obtained. deaths % deaths % Statistical analysis was carried out with SPSS version 18 n = 25 n = 41 <24 hours 12 48 12 29.3 software. Descriptive statistics was computed to present the baseline data of the study population. The level of 24 hours to 7 days 11 44 24 58.5 significance was fixed atP <.05. >7 days 02 08 05 12.20

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Jyothi GS, et al. Changing RESEARCHtrend in maternal ARTICLES mortality

Table 4. Distribution of Subjects by Causes of Death first half of the decade (between 1998 and 2003), there Year were 25 maternal deaths with 2345 live births giving a 1998–2003 2003–2008 Causes of maternal deaths MMR of 1066 per 100,000 live births. In the second Total no. Total no. % % half of the decade (between 2003 and 2008), there n = 25 n = 41 were 41 maternal deaths and 4403 live births giving an I: Direct MMR of 931 per 100,000 live births (Table 1). 1) Hemorrhage 07 28 06 14.63 a) Atonic 02 - 05 - Emergency admissions accounted for 23 (92%) of the b) Traumatic + atonic 02 - 01 - death cases between 1998 and 2003 and 40 (98%) of c) Placenta previa 02 - - - the death cases between 2003 and 2008. It was also d) Retained placenta 01 - - - noted that 21 (84%) of maternal deaths in the first half e) Abruptio placenta 00 - - - of the study period and 30 (73.2%) in the second half 2) Hypertensive disorders 06 24 07 17.07 of the study period were from urban areas. a) Severe pregnancy-induced The age of mothers ranged from 18 to 45 years. Mothers hypertension (PIH) with under the age of 30 years constituted 22 (88%) deaths hemolysis, elevated liver 02 - 03 - enzymes, low platelet count in the 1998 to 2003 period and 40 (97.6%) deaths syndrome (HELLP syndrome) between 2003 and 2008, suggesting that the third b) Eclampsia with HELLP 04 - 04 - decade of life is the potential age group for maternal syndrome complications to occur. Distributions of subjects by 3) Septicemia 04 16 06 14.63 age, parity, and other demographic characteristics at the 4) Early pregnancy deaths 04 16 04 10 time of admission are shown in Table 2. a) Ruptured ectopic 01 - 01 - It was noted that 56% of the deaths in 1998 to 2003 b) Termination of pregnancy 03 - 03 - period and 63.4% of the deaths in 2003 to 2008 period 5) Amniotic fluid embolism 01 4 03 7.5 were of primiparous women. Primigravidae are iden- 6) Acute fatty liver of pregnancy - - 01 2.5 tified as the vulnerable group, needing high-risk care II: Indirect during pregnancy and labor. One (4%) of the deaths 1) Cerebral venous thrombosis + 01 4 - - that occurred in the 1998 to 2003 period was a grand meningitis multipara, whereas no deaths of grand multiparas were 2) Severe anemia 01 4 01 2.5 recorded in the 2003 to 2008 period. Fourteen (56%) 3) Viral infection with hepatorenal - - 02 5 syndrome maternal deaths in the first half and 19 (46.34%) 4) Infective hepatitis - - 04 10 maternal deaths in the second half of the decade had irregular or no antenatal visits, reflecting poor aware- 5) Cerebrovascular diseases - - 01 2.5 ness of antenatal care. 6) Pulmonary embolism - - 02 5 7) Respiratory diseases - - 01 2.5 The admission to death time interval of maternal death III: Unrelated cases is shown in Table 3. Twelve (48%) subjects in the 1) Blood transfusion reaction - - 01 2.5 1998 to 2003 period and 12 (29.3%) in the 2003 to 2) Trauma 01 4 01 2.5 2008 period died within 24 hours of admission. Two (8%) subjects in the first half and 5 (12.2%) cases in the 3) Cerebral malaria - - 01 2.5 second half died after 7 days of hospital stay. Timely and prompt referrals could have saved many lives. Results During the entire 10-year study period, the hospital Causes of maternal deaths registered 6748 live births and 66 maternal deaths The MMR (per 100,000 live births) has shown a giving an MMR of 978 per 100,000 live births. In the decrease from 1066 in 1998 to 931 in 2003 to 2008.

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JyothiRESEARCH GS, et al. ARTICLESChanging trend in maternal mortality

Direct causes of death accounted for 22 (88%) cases nursing homes and district hospitals, and two primary in the first half as compared to 27 (65.85%) cases in health care centers (PHCs) covered by the hospital. It is the second half of the study period. The list of various equipped with super specialty services, adult and pedi- causes of death is enumerated in Table 4. atric intensive care unit (ICU) and intensive therapy Hemorrhage, hypertensive disorders, and septicemia unit (ITU), and 24 hours functioning blood bank serv- have emerged as the greatest killers, resulting in 7 ices. Ambulatory services exist, mostly used for inpa- (28%), 6 (24%), and 4 (16%) deaths, respectively, in tient services. the first half of the study period and 6 (14.63%), 7 Discussion (17.07%), and 6 (14.63%) deaths respectively, in the second half of the study period. The International Conference on population and development in 1994 recommended reduction in maternal There was a decline in the hypertensive disorders of mortality by at least 50% of the level recorded in 1990 pregnancy as a cause of maternal death from 24% to by the year 2000 and further one half by the year 17%. This could be due to the practice of an uniform 2015. The Millennium Development Goals (MDG) evidence-based protocol for the management of preg- of the United Nations has set the target of reducing nancy-induced hypertension (PIH) and eclampsia, and the number of maternal deaths to 200/100,000 of live increased awareness of the disorder with early referral. births by 2007 and 109/100,000 of live births by 2015. The proportion of all indirect causes leading to maternal Sample Registration Survey is the largest demographic deaths increased with liver disorders (07[17.5%]) being sample survey in the country that amongst other indi- the leading cause. It was also noted that 56% to 63% of cators provide direct estimates of maternal mortality maternal deaths across both groups occurred in primi- through a nationally representative sample. gravidae. The admission to death interval was >24 hours It is heartening to know that the MMR of India has in 52% death cases that occurred in the first half of the declined from 254 in 2004 to 2006 period to 212 in study period as compared to 71% in the second half of 2007 to 2009 period. The decline has been most the study period, reflecting improvement in emergency significant in EAG (Empowered Action Group states obstetric care. Almost all patients received fresh frozen comprising Bihar, Jharkhand, Madhya Pradesh, Chhat- plasma and platelet transfusions. tisgarh, Orissa, Rajasthan, Uttar Pradesh, Uttarakhand, Comparison of proportion of causes for maternal and Assam) from 375 to 308. Among the southern deaths between the first and second half was done using states (Andhra Pradesh, Karnataka, Kerala, and Tamil chi-square test of proportion. Owing to small propor- Nadu) the decline has been from 149 to 127, and in tions, the causes were combined to ensure compa- other states from 174 to 149. It is worth noting that rability between the 2 groups. It was observed in the the number of states that have realized MDG target in present study that differences in the total proportions of 2007 to 2009 period has gone up to 3 against 1. Kerala causes for maternal mortality was found to be statisti- (81) was the sole state with this distinction in 2004 to cally not significant, chi-square = 1.106, df = 3,P = .78. 2006 period, and now Tamil Nadu (97) and Mahar- In addition, the trends for linearity with regard to 2 ashtra (104) are the new entrants. Andhra Pradesh comparable durations of the study was also found to be (134), West Bengal (145), Gujarat (148), and Haryana statistically not significant, chi-square = 3.02,P = .08. (153) are in close proximity to the MDG target.2 Table 5 shows the comparative MMR and causes of Our hospital is a well-known tertiary care center maternal deaths at different institutions in India and catering to high-risk obstetrics. Patient population the changing trends. here comprises low-income group from urban slums; referred patients from surrounding rural areas of 100 This decade review of maternal mortality in to 200 km radius; patients referred from private clinics, M S Ramaiah Memorial and Teaching Hospital

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Jyothi GS, et al. Changing RESEARCHtrend in maternal ARTICLES mortality

Table 5. Comparative Maternal Mortality Rates and Causes of Maternal Deaths at Different Institutions in India - Changing Trends Hemorrhage Hypertensive Sepsis Anemia Jaundice Institution Year MMR (%) disorders (%) (%) (%) (%) Khare S, et al. Netaji Subhash Chandra Bose Medical College and 1986–2000 2642.77 9.01 21.41 13.41 23.92 16.8 Hospital, Jabalpur Shanti Roy, et al. Patna Medical College and Hospital, Bihar 1990–1998 1692.55 20.4 26.04 9.79 18.64 4.37 Sarmishtha, et al. Silchar Medical College and Hospital, Assam 1994–1995 2089 20.0 20 39.3 9.83 - Kulkarni SR, et al. Vani Vilas Hospital, Bangalore 1988–1997 879 24.4 25.8 17.7 11.6 9.4 Shankar J, et al. Vijayanagara Institute of Medical Sciences, Bellary 1988–1997 1723 23.5 23.7 21.3 17.5 12.4 Patel DA, et al. Rural Medical College, Gujarat 1994–1997 4286 31.03 13.79 20.69 17.24 3.45 Bedi N, et al. Indian Council of Medical Research 1993–1994 582 23.6 24 7.2 11.5 7.1 Census India 2001–2003 301 38 05 11 - - Jadav AJ, et al. 1995–2005 320 67 32 06 - 06 Bhatt R, et al. (FOGSI–WHO study) 1992–1994 572 19.8 25.5 20.6 - 8.7 Amitava, et al. 1994–2004 623 9.72 50.56 18.17 4.18 1.8 Sule OAO 1988–1997 1936 12.6 4.9 21.4 9.8 - Onwuhafua PI 1990–1997 652 17.39 36.95 6.52 - - Jyothi GS, et al. (present study) 1998–2003 1066 28 24 28 4 - Jyothi GS, et al. (present study) 2003–2008 931 14.63 17.07 22.5 2.5 17.5

(MSRMTH) shows only a 13% reduction of MMR, that every woman has a ready access to an SBA during 1066 in 1998 to 2003 period to 931 in 2003 to 2008 delivery and emergency obstetric care (EmOC) in period. The very high maternal mortality in our case of complications. In developing countries, more hospital is due to several reasons. First, our institu- than half of pregnant women deliver at home without tion serves as a tertiary center and deals with exclu- an SBA. The International Federation of Obstetrics sively high-risk patients in good numbers as compared and Gynecology and International Confederation of to so-called normal deliveries, because of its reputed Midwives recommend that there be 1 skill provider for blood bank and ICU services. Second, the majority of every 5000 individuals. But with current brain drain, maternal deaths are late referrals brought in a mori- the average physician to population ratio is as low as 1 bund state with end stage events, where it is difficult to for every 100,000 in developing countries and far less salvage the maternal life. in rural areas where 80% of the population reside.3 Maternal deaths are highest in the most difficult to The causes of maternal death vary between developed access areas, that is, in rural settings where women are and developing countries. Embolism, cardiomyopathy, unable to reach either a skilled birth attendant (SBA) and acute respiratory distress syndrome followed by or appropriate facilities in times of complications hypertensive disorders and hemorrhage are the major during labor or delivery. This burden is compounded causes of maternal deaths in developed countries, by the fact that most complications occur at the time whereas in developing countries it is hemorrhage and of delivery and cannot be predicted beforehand. Many hypertensive disorders followed by septicemia. When pregnancies identified as high-risk deliver normally compared with other studies in India, study by Bhatt et and most life-threatening complications occur in low al shows MMR of 572 (1992–1994), Jadav, et al docu- -risk women. The primary strategies to reduce MMR ments 320 (1995–2005), and study by Amitava P, et al by the international community have been to ensure (Burdwan) reports MMR of 623 (1994–2004). When

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JyothiRESEARCH GS, et al. ARTICLESChanging trend in maternal mortality compared with other developing countries, study done by Dinesh, et al and Maitra, et al.14,15 There was by Sule from Sagamu, Nigeria shows MMR of 1936 1 case of acute fatty liver of pregnancy (AFLP), 2 cases (1988–1997). Study by Onwuhafua from Nigeria shows of viral infection with hepatorenal syndrome, and 4 MMR of 652 (1990–1997).4 cases of infective hepatitis. This is due to delayed refer- An ICMR study from 31 teaching hospitals from 16 rals from various centers in terminal stages of hepatic states of India shows that the major causes of maternal failure. Severe anemia as an indirect cause of maternal death were hypertensive disorders, hemorrhage, death was seen in the second half amounting to 5%. and sepsis including early pregnancy deaths due to postabortal sepsis, anemia, and hepatitis. The ICMR Conclusion study shows 24% death due to hypertensive disorder MMR at tertiary care institutions is still high due to between 1993 and 1994, which was double that of emergency referrals coming in moribund state. MS previous ICMR study (12% in 1990).5 In the present Ramaiah Hospital is a recognized tertiary care center study, deaths due to hypertensive disorder decreased for high-risk obstetrics. Unfortunately, direct causes from 24% between 1998 and 2003 to 17.07% between still continue to be the primary killers. Importance 2003 and 2008 as compared to FOGSI-WHO study of should be given to regular and quality antenatal care. Bhatt (1997); and studies by Khare, et al; Kulkarni, et Training should be made available in EmOC amongst al; Roy, et al; and Sharma, et al.6–10 This difference is doctors and midwives which should also percolate to attributed to the use of magnesium sulphate for all cases the level of interns, residents, and health guides. Inten- of eclampsia and impending eclampsia and also because sive efforts should be directed towards policy, program, of early resort to emergency cesarean section in cases of and training and research activities. Provision of effec- severe PIH with other complications and eclampsia. tive contraception and safe abortion services should be Deaths due to sepsis have been reduced from 28% in made available at first referral units in order to reduce between 1998 and 2003 to 22.63% between 2003 and maternal deaths due to unsafe abortion. Confiden- 2008. This is much higher in comparison with ICMR tial enquiries into maternal deaths as adopted in devel- task force study (7%); study by Registrar General in oped countries should be encouraged. The sole purpose census India (11%); Khare, et al 1986–2000 (13.41%); of confidential enquiries is to improve patient care by Roy, et al 1990–1998 (9.79%); Kulkarni, et al 1988– gathering and analyzing information and learning and 1997 (17.7%); and Jadav, et al (6%).11 disseminating appropriate lessons. Abortion-related deaths have decreased from 12% in the first half to 7.5% in the second half of the study References period. This may be due to reduction in illegally 1. Drife J. Maternal mortality in well resourced countries: is there still a need for confidential enquiries? Best Pract Res induced abortion due to increased awareness and also Clin Obstet Gynaecol. 2008;22(3):501-515. because of early presentation with complications due 2. Special Bulletin on Maternal Mortality in India 2007-09. to post abortal sepsis. Deaths due to hemorrhage has Office of the Registrar General, India, Ministry of Home decreased from 28% in the first half to 14.63% in the Affairs, Government of India. 2011. second half as compared to studies done by Patel, et 3. Prata N, et al. Saving maternal lives in resource poor settings: al (31.03%); Shankar, et al (23.5%); Kulkarni, et al facing reality. Health Policy. 2009;89(2):131-148. (24.4%); Jadav, et al (67%); Census India (38%); and 4. Sahu L, et al. Changing trends in maternal mortality- Bedi, et al - ICMR (23.6%).12,13 This is due to quality (MMR is a good healthcare index). Int J Gynaecol Obstet. emergency obstetric care, good blood bank facilities 2008;12(6):24-29. providing component therapy round the clock at our 5. Bedi N, et al. Maternal deaths in India-preventable tragedies, hospital, and availability of ICU and ITU services. An ICMR task force study. J Obstet Gynaecol India. 2001;51(2):86-92. Deaths due to liver disorders have increased in the 6. Bhatt R. Maternal Mortality in India-FOGSI- WHO Study. second half amounting to 17.07% similar to the studies J Obstet Gynaecol India. 1997;47; 207-214.

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7. Khare S, et al. Maternal mortality in Jabalpur medical 12. Shankar J, Seetharam S. Maternal mortality- 10 years review; College-(A 15 years Study). J Obstet Gynaecol India. a decade of safe motherhood. J Obstet Gynaecol India. 2002;52:51-54. 2001;51;108-110. 8. Kulkarni SR, Huligol A. Maternal mortality- 10 years study. 13. Patel DA, et al. Maternal mortality at Karamsad - The only J Obstet Gynaecol India. 2001;51;73-76. Rural Medical College in Gujarat. J Obstet Gynaecol India. 9. Roy S, et al. Maternal mortality in Apex Hospital in Bihar. J 2001;51:63-66. Obstet Gynaecol India. 2002;52:100-104. 14. Dinesh P, et al. Changing trends of maternal mortality: A 10. Sharma N. Maternal mortality - A retrospective study of ten comparative study. J Obstet Gynaecol India. 2011:161-165. years. J Obstet Gynaecol India. 2001;51:60-62. 15. Maitra N, et al. Changing trends in the cumulative and cause 11. Jadav AJ, Govind RP. J Obstet Gynaecol India. 2007;57: specific maternal mortality ratio over three decades. J Obstet 398‑400. Gynaecol India. 2000;50-53.

Evaluation of Diagnostic Role of Cardiac Troponin T (cTnT) in Newborns with Heart Defects Tarkowska A, Furmaga-Jablonska W.

Scientific World Journal. 2012;2012:682538.

Heart diseases are a significant cause of morbidity and mortality in newborns. Diagnostic methods are often not sufficient or, in many cases, cannot be used. There is a great advance in medical knowledge concerning biomar- kers in the diagnosis of circulatory system in adult patients. Among them, cardiac troponins play the main role. In current literature, there is not enough data concerning the possibility of using them in neonatal cardiac diag- nostics. The aim of this study was to evaluate diagnostic usefulness of cardiac troponin T (cTnT) in correlation with other markers of circulatory failure and myocardial damage in newborns with heart defects. The study involved 83 newborns up to 46 weeks of postmenstrual age. The exclusion criteria were severe perinatal asphyxia and presence of severe noncardiac diseases. Patients were divided into 2 main groups: Group I included 54 patients with congenital heart defects (CHDs) and group II (control) included 29 healthy neonates. All patients underwent a detailed examination of circulatory system. cTnT concentrations were evaluated by Roche Cardiac T quantitative test. Performed studies revealed that cTnT levels in newborns with heart pathology were significantly higher than in healthy ones. However, cTnT concentrations in patients with CHD did not correlate with clinical symptoms of heart failure and neither with echocardiographic markers of left ventricular function. Type of heart defect did not influence cTnT levels as well. Only hemodynamic significance evaluated by echocardiography influenced the cTnT levels with statistical significance. Statistically significant differences in cTnT levels between newborns with heart defects and healthy subjects were shown. CTnT levels in newborns with heart defects referred only to hemodynamic significance of the defect.

PERINATOLOGY • Vol. 13 • No. 1 • Apr–Jun 2012 • 15 Research Articles

RESEARCH ARTICLES

Cystic Fibrosis: Are We Missing the Diagnosis in India? Pramila G Menon*

Abstract Introduction: This study was undertaken to evaluate and improve the availability and accessibility of cystic fibrosis (CF) services in Pune (Maharashtra), India. Material and Methods: Tool used in this study was a questionnaire (Annexure I) which was prevalidated by the departmental faculty and distributed to pediatricians (n = 40) who participated in the training workshop at Pune Regional Centre, Aundh, Pune, Maharashtra, India. The questionnaire comprised 15 items, which included their qualification and experience regarding CF patients based on factors such as knowledge about diagnosis and prognosis of CF patients, and availability of diagnostic and management services of CF. Results: About 92.5% of pediatricians agreed CF is now a panethnic disease and 100% accepted that factors associated with decreased survival of CF patients from developing countries are early age of onset of symptoms, severe malnutrition at the time of diagnosis, and frequent episodes of pneumonia. In cases of severe malnutrition and not responding to nutritional therapy, neonatal meconium ileus, and recurrent pneumonia, 87.5%, 100%, and 85% of the pediatricians suspect CF, respectively. *Correspondence It was noted that 90% of the pediatricians did not have facilities Dr Pramila G Menon for diagnosis of CF (such as sweat chloride test and genetic Associate Professor and Head studies) and 87.5% felt that unavailability of the facilities makes Department of Genetics, Immunology the diagnosis of CF difficult. About 90% agreed that educating Biochemistry, and Nutrition pediatricians about the disease can improve quality of life and Maharashtra University of Health Sciences survival in CF. Aundh Civil Hospital Building Conclusion: Inadequacy of diagnostic services for CF could be Pune - 411 027, Maharashtra the reason for missing CF cases in India. It is crucial to sensitize India health professionals for CF diagnosis and develop better diag- Phone: 91-20-27286143/27285695, 9960255611 nostic and patient support services for CF. Fax: 91-20-27280454 Key words: Cystic fibrosis, autosomal genetic disorder, diagnostic services

16 • PERINATOLOGY • Vol. 13 • No. 1 • Apr–Jun 2012 Research Articles

Menon PG. DiagnosisRESEARCH of cystic fibrosis ARTICLES in India Introduction an effort to find out the knowledge about CF and availability of genetic services for CF in Maharashtra before Cystic fibrosis (CF) is an autosomal recessive genetic starting full-fledged genetic services for CF. disorder, thought to be prevalent in Caucasians. However, recent reports suggest the incidence of CF Aim of the Study in Indian children, too. The estimated prevalence The aim of this study was to find out the availability in migrant populations in the United Kingdom and and accessibility of CF genetic services in Maharashtra, United States vary from 1 in 10,000 to 1 in 40,000.1,2 It and create and support a CF Services Network to share is very important to understand the basic genetics and strategies for providing quality, accessible, and compre- pathophysiology of CF which will help in diagnosing hensive services to CF patients consequently. more CF patients. Precise incidence of CF in the Indian population is not known. Even if the prevalence of CF Material and Methods in India is 1 in 10,000 births, there may be 3000 chil- The faculty who participated in the study was pedia- dren born with CF annually in different parts of India. tricians from various medical colleges, with experience Therefore, India would hold the largest population of ranging from 2 to 25 years. Tool used in this study was CF patients in the world today.3 a questionnaire (Annexure I) which was prevalidated by Maharashtra University of Health Sciences (MUHS) the departmental faculty and distributed to 40 pedia- is an apex university in the state of Maharashtra, tricians who participated in the training workshop at India. The Department of Genetics, Immunology, and Pune Regional center, Aundh, Pune, Maharashtra, Biochemistry of this university endeavors to be the key India. The questionnaire comprised 15 items, which center for diagnosing genetic disorders using modern included their qualification and experience regarding molecular biology and genetic techniques. The study is CF patients based on factors such as knowledge about

Annexure I

Dear participant, 4. Factors that are associated with decreased survival in CF 9. Aggressive physiotherapy with nutritional management This questionnaire is an effort to find out problem of cystic fibrosis (CF) patients from developing countries are age of onset of and judicious use of antibiotics can improve the quality of in our society. We would be thankful to you, if you can give us the feed- symptoms <2 months, severe malnutrition at the time of life and survival in CF. back from your clinical practice about this disease. diagnosis, and frequent episodes of pneumonia. a. Strongly agree b. Agree a. Strongly agree b. Agree c. Neutral d. Disagree Name: ______c. Neutral d. Disagree e. Strongly disagree Designation with qualification: ______e. Strongly disagree 10. I do come across CF patients in my practice. ______Years experience: _____ 5. Absence of facilities for diagnosis (sweat chloride esti- a. Strongly agree b. Agree mation and genetic studies), makes the diagnosis of CF c. Neutral d. Disagree Address: ______difficult. e. Strongly disagree ______a. Strongly agree b. Agree c. Neutral d. Disagree 11. Many of the above mentioned hurdles can successfully be Phone no: ______Signature:______e. Strongly disagree solved by establishing CF services. a. Strongly agree b. Agree 1. CF earlier believed to be nonexistent in non Caucasians, 6. Education of pediatricians about the disease, early diag- c. Neutral d. Disagree is now a panethnic disease, having been reported from nosis can improve the quality of life and survival in CF. various regions of the world over last one decade. a. Strongly agree b. Agree e. Strongly disagree a. Strongly agree b. Agree c. Neutral d. Disagree 12. In cases of recurrent pneumonia I do suspect CF. c. Neutral d. Disagree e. Strongly disagree a. Strongly agree b. Agree e. Strongly disagree 7. Using indigenous technology in sweat chloride test may be c. Neutral d. Disagree 2. Care of children with CF is not a priority for governments in alternative to diagnosis and is the need of hour. e. Strongly disagree developing countries a. Strongly agree b. Agree 13. I do have facilities for diagnosis of CF like sweat chloride a. Strongly agree b. Agree c. Neutral d. Disagree test. c. Neutral d. Disagree e. Strongly disagree a. Yes b. No e. Strongly disagree 8. In cases of severe malnutrition not responding to nutri- 14. CF is never considered in my practice. 3. Cystic fibrosis is rare in India tional therapy, I do suspect CF. a. Yes b. No a. Strongly agree b. Agree a. Strongly agree b. Agree c. Neutral d. Disagree c. Neutral d. Disagree 15. In cases of neonatal meconium ileus, do you suspect CF? e. Strongly disagree e. Strongly disagree a. Yes b. No

PERINATOLOGY • Vol. 13 • No. 1 • Apr–Jun 2012 • 17 Research Articles

MenonRESEARCH PG. Diagnosis ARTICLES of cystic fibrosis in India diagnosis and prognosis of CF patients, and availability care professionals to enhance awareness and build of diagnostic and management services of CF. competencies which will help them in proper manage- Results ment of CF patients. The pattern of genetic education was studied in different About 92.5% of the pediatricians agreed that CF is parts of world. Genetic services in the United Kingdom now a panethnic disease and almost all pediatricians are among the most highly developed in Europe, having (100%) agreed that the factors that are associated with evolved from academic departments into regional decreased survival in CF patients from developing centers, serving a population of 26 million.6 With a very countries are early age of onset of symptoms, severe large population and high birth rate and due to prac- malnutrition at the time of diagnosis, and frequent tice of consanguineous marriages, there is a high preva- episodes of pneumonia. In cases of severe malnutri- lence of genetic disorders in India. Due to inadequate tion not responding to nutritional therapy, 87.5% diagnostic, management, and rehabilitation facilities, of the study population suspected CF. Similarly in the burden of these disorders is greater than in Western cases of neonatal meconium ileus and recurrent pneu- countries.7 Indian scenario of genetic education is also monia (not responding to nutritional therapy), 100% not different. Survey results about genetics education in and 85% of the pediatricians suspect CF, respectively. this study show that the number of hours of teaching About 90% do not have facilities for diagnosis of CF genetics is inadequate (<5) at both undergraduate level like sweat chloride test and 87.5% felt absence of diag- (64.65%) and postgraduate level (69.31%). However, nostic facilities such as sweat chloride estimation and nursing schools in India have 15 hours of teaching in genetic studies would make the diagnosis of CF diffi- genetics (unpublished data). Medical genetics course cult. Approximately 85% of the pediatricians enrolled represents 54 hours of the fourth semester of Medicine in the study felt that caring of children with CF is not and it is also taught in dentistry, nursing, and health 8 a priority for government in developing countries; 80% technology. Guttmacher, et al (2007) summarized required indigenous technology in sweat chloride test disconnect between basic sciences and clinical experi- which may be alternative to diagnosis which is the need ences during training. The study reported that failure to of hour; and 90% agreed that educating pediatricians integrate genetics across the curriculum and inadequate about the disease and early diagnosis can improve the representation of genetics on certifying exams are other important factors leading to dearth of genetics profes- quality of life and survival in CF. sionals.9 Discussion Surveys of health professionals demonstrate a lack of This study highlights the need to improve genetic serv- basic knowledge and confidence to deal with genetics- ices in India. Many advances in genetics, from mapping related issues that arise in the clinical setting. Confir- the human genome through the Human Genome mation for those findings about the genetics knowledge Project continue to have significant impact on public and competence of health professionals also comes health policy and service delivery.4 The changing from survey data of 5915 consumers of genetics services scenario in genetics suggests that every physician would (Harvey, et al. 2007). Data collected by the Genetic need to apply genetic knowledge on patients presenting Alliance and the National Coalition for Health Profes- with specific symptoms and genetic testing will be sional Education in Genetics (NCHPEG) show that increasingly important to aid in prescribing and clin- 32% of respondents rated the genetics knowledge of ical management of patients with genetic disorders.5 their providers as poor, across all disciplines, and 78% Genetic service experts feel that integration of genetics reported that they received no genetics-education mate- with healthcare will help improve health by reducing rials from the provider designated as most important to morbidity and mortality in genetic disorders. It is the family.10 The results of the survey done in this study important to provide education and training to health also give similar results.

18 • PERINATOLOGY • Vol. 13 • No. 1 • Apr–Jun 2012 Research Articles

Menon PG. DiagnosisRESEARCH of cystic fibrosis ARTICLES in India A strategic plan developed by the Genomics Directorate Conclusion in consultation with the Western Australian Genetics Inadequacy of diagnostic services for CF may be reason Council allocate resources stressed on the need to for missing CF cases in India. It is imperative to sensi- improve genetics knowledge of health professionals and tize the health professionals for CF diagnosis and the community. In western countries, CF services are develop better diagnostic and patient support serv- well developed, which has resulted in better survival of ices for CF. Early diagnosis will help improve patient CF patients, but CF services in India are still in a devel- management and reduce mortality. oping state. There are few centers which offer diagnostic facilities and clinical care to CF patients. It is impor- References tant to develop early diagnostic and better treatment 1. Goodchild MC, et al. Cystic fibrosis in three Pakistani facilities for patients with CF to prevent mortality and children. Arch Dis Child. 1974;49(9):739-741. morbidity. It is very much the need of the hour to have 2. Powers CA, et al. Cystic fibrosis in Asian Indians. Arch a database of CF and recognize pattern of mutational Pediatr Adolesc Med. 1996;150(5):554-555. analysis of CF for Indian patients. This is also empha- 3. Noke C, Kabra SK. Country Close Up: India Cystic Fibrosis sized by Kabra et al. Appropriate strategies for patient in India. Last accessed March 16, 2012. 4. Kaye CI, et al. Integrating Genetic Services into Public identification, diagnosis, and molecular study need to Health –Guidance for State and Territorial Programs from the be devised which will help in planning strategies for National Newborn Screening and Genetics Resource Center prenatal diagnosis.11 The present study brings out a very (NNSGRC). Community Genet. 2001;4:175-196. important point that pediatricians do suspect CF, but 5. Roses A. Pharmacogenetics and the practice of medicine. unavailability of CF-related diagnostic services is the Nature. 2000;405(6788):857-865. hindrance for further management of CF. 6. Harris R, ed. Genetic services in Europe. A comparative study of 31 countries by the Concerted Action on Genetic Services Despite the availability of the sweat test, it is difficult in Europe. Eur J Hum Genet. 1997; 5(Suppl 2):1-220. to diagnose CF in early childhood and delays in diag- 7. Verma IC, Bijarnia S. The burden of genetic disorders in India and a framework for community control. Community nosing CF can lead to severe malnutrition, lung disease, Genet. 2002;5(3):192-196. or even death. screened group had a higher proportion 8. Dra. Araceli Lantigua Cruz, Dra. María Teresa Lemus Valdés of patients with pancreatic insufficiency, their growth y Dra. Beatriz Marcheco Teruel Rev Cubana Genet Comunit indices were significantly better than those of the 2007;1(1):15-9 Medical genetic services in Cuba. control group during the 13-year follow-up evaluation, 9. Guttmacher AE, et al. Educating health-care professionals and therefore this randomized clinical trial of early about genetics and genomics. Nat Rev Genet. 2007;8:151‑157. CF diagnosis must be interpreted as unequivocally 10. Harvey EK, et al. Providers’ knowledge of genetics: A survey of 5915 individuals and families with genetic conditions. 12 positive. Genet Med. 2007;9(5):259-267. This study highlights the need for establishing good 11. Kabra SK, et al. Cystic fibrosis in India. Pediatr Pulmonol. 2007;42(12):1087-1094. services for diagnosis of CF. It also brings out that 12. Farrell PM, et al. Early diagnosis of cystic fibrosis through pediatricians do suspect CF in practice, but further neonatal screening prevents severe malnutrition and improves confirming diagnosis and proper management of CF long-term growth. Wisconsin Cystic Fibrosis Neonatal patients in India is difficult due to poor genetic services Screening Study Group. Pediatrics. 2001;107(1)1-13. for CF.

PERINATOLOGY • Vol. 13 • No. 1 • Apr–Jun 2012 • 19 Fetal Medicine RESEARCH ARTICLES Update PERINATOLOGY • Vol. 13 • No. 1 • Apr–Jun 2012

Outcome of Isolated Congenital Diaphragmatic Hernia Diagnosed in the Second Trimester Namashivaya A, Prathima Radhakrishnan*

Abstract Congenital diaphragmatic hernia (CDH) is the most common developmental abnormality of the diaphragm which occurs in 1 out of every 2000 to 5000 live births. CDH is diagnosed prenatally when an ultrasound scan shows a herniation of abdominal viscera into the thorax. CDH is associated with a mass effect that causes mediastinal shift, lung compression which leads to pulmonary hypoplasia and pulmonary hypertension. As a result, CDH is associated with high neonatal mortality. Antenatal prediction of postnatal outcome depends essentially on the degree of intratho- racic compression of the lungs. The most widely used method is ultrasonographic measurement of the fetal lung area-to-head *Correspondence circumference ratio (LHR). This has a major implication in counseling parents regarding available options for subsequent man- Dr Prathima Radhakrishnan agement of pregnancy including expectant management and Bangalore Fetal Medicine Centre fetal endoscopic tracheal occlusion (FETO), and termination of Richmond Road, pregnancy. Bangalore - 560025, Karnataka India Key words: Congenital diaphragmatic hernia (CDH), fetal CDH, Email: drprathima@bangalorefetalmedicine. fetal endoscopic tracheal occlusion (FETO), lung-to-head ratio com (LHR)

20 Fetal Medicine Update

Namashivaya A. Congenital diaphragmatic hernia diagnosisRESEARCH in second ARTICLES trimester Aim Table 1. Total number of isolated CDH 13 To determine the postnatal outcome of antenatally cases diagnosed isolated congenital diaphragmatic hernia (CDH) in a tertiary referral setting. Live births 7/13 (53.8%) Study Design 6/13 (45%) Abnormal karyotype All the fetuses that presented or were diagnosed to have Terminations Severe CDH isolated CDH at Bangalore Fetal Medicine Centre from 2005 and 2011 were included and postnatal follow-up Parents opted to terminate Postnatal death before surgical was performed. 1/7 (14.2%) correction

Results Postnatal surgery and doing well 5/6 (83.3%) A total number of 13 fetuses presented with isolated CDH diagnosed in the second trimester of pregnancy. Conclusions After counseling regarding antenatal karyotyping and postnatal outcome, 6 pregnant women (45%) had The results suggest that antenatal diagnosis of CDH chosen to terminate the pregnancy. The remaining 7 and optimal counseling regarding prognosis bears a (55%) decided to continue with the pregnancy. One huge impact on the outcome of pregnancy. Karyo- among them underwent fetal endoscopic tracheal typing is important even when CDH appears to be occlusion (FETO) at the Harris Birthright Research apparently isolated. The assessment of lung area-to- Centre of Fetal Medicine (HBRC), London and the head circumference ratio (LHR) guides the manage- rest 6 underwent postnatal correction in India. ment of pregnancy with respect to severity of the defect. In severe cases, parents may either opt for termination Only 1 neonate of the 6 who had surgical repair of the of pregnancy or prenatal fetal intervention. When the primary defect died postoperatively due to sepsis. The LHR is good, that is >1, postnatal outcomes are favo- remaining 5 who underwent surgical correction have rable. However, the baby needs to be delivered in a been followed up until the age of 2 to 4 years and are tertiary centre, which has facilities for neonatal ICU doing well. and surgery. The fetus with severe degree of CDH was the one who underwent FETO at 28 weeks of gestation at HBRC. Discussion An ex-utero intrapartum treatment (EXIT) was done Embryology at 37 weeks and the infant did well in the immediate postnatal period. The infant however died after 6 The gut returns from the yolk sac between 10 to 12 hours of birth due to pulmonary hemorrhage, which weeks of gestation and by then the diaphragm forma- was confirmed on autopsy. Antenatal ultrasound scan tion is complete. If there is a delayed closure in the had shown expansion of the fetal lungs which was communication between the thorax and abdomen, the confirmed postnatally by autopsy. abdominal contents pass into the thoracic cavity and thus prevent closure of the diaphragm. On the other Out of the 6 who had chosen to terminate pregnancy, hand, it could be a primary diaphragmatic defect.1 4 opted to undergo prenatal diagnosis for karyotypic anomalies. One fetus among them was diagnosed with In about 50% of the cases, CDH may not occur before abnormal karyotype. 24 weeks and therefore there is low detection rate between 18 and 20 weeks. The prevalence of CDH is 1 in 2000 to 5000 live births with male:female ratio of

PERINATOLOGY • Vol. 13 • No. 1 • Apr–Jun 2012 • 21 Fetal Medicine Update

NamashivayaRESEARCH A. ARTICLES Congenital diaphragmatic hernia diagnosis in second trimester

2:1. There are 4 types of CDH which include: (Figure 2): Posterolateral or Bochdalek hernia (90%) - This is the - Loops of bowel and/or stomach in the thoracic cavity most common form of CDH, which is usually left sided - Mediastinal shift/cardiac compression with stomach, bowel, and spleen as herniated contents. - Abnormal positioning of gallbladder, hepatic veins Parasternal or Morgagni hernia (2%) – Morgagni hernia is located on the anterior portion of the diaphragm and Polyhydramnios may develop in the third trimester is usually right sided or bilateral with liver herniation. secondary to esophageal compression. Septum transversum defect – This occurs due to herni- Fetal Magnetic Resonance ation of the central tendon. Imaging and CDH Hiatal hernia - Hiatal hernia is a congenital herniation occurring through large esophageal orifice. Magnetic Resonance Imaging (MRI) has been identified as an additional imaging modality that can assist Inheritance in deriving accurate antenatal diagnosis and also in Generally sporadic but isolated defects in siblings do have a recurrence risk, which is about 2%. Rare autosomal recessive syndrome with diaphragmatic agenesis has been described.2 Association of CDH with Fryns syndrome, Beckwith-Wiedemann syndrome, and Pierre Robin syndrome is established. Diagnosis The diagnosis is usually first suspected when there is an absence of the fetal stomach bubble at its usual place. Instead, it will be seen as a cystic mass in the chest cavity and the heart is further “pushed” to the right side Figure 2. Mediastinal shift to the right due to herni- (Figure 1). ation of the stomach and intestines into the left chest cavity Prenatal ultrasound diagnosis assessment of perinatal outcome. Among fetuses with Prenatal ultrasound diagnosis shows the following left-sided CDH, assessment of pulmonary hypoplasia based on MRI relative fetal lung volume and MRI relative LHR is excellent in prediction of neonatal survival and extracorporeal membrane oxygenation (ECMO) requirement.11 The prognostic accuracy is slightly better than that of sonographic relative LHR ratio. MRI was found to be superior than ultrasound in demon- strating the position of the fetal liver above or below the diaphragm and to reliably visualized fetal lung tissue. These findings are important for parental counseling, selection of fetal surgical candidates, and estimation of prognosis. Figure 1. Fetal abdomen showing absence of the stomach bubble which is seen as a cystic area in Associated anomalies the thorax adjacent to the heart which has shifted In about 25% cases of CDH, there is a chromosomal further to the right abnormality, usually trisomy 21 and 18. A further 25%

22 • PERINATOLOGY • Vol. 13 • No. 1 • Apr–Jun 2012 Fetal Medicine Update

Namashivaya A. Congenital diaphragmatic hernia diagnosisRESEARCH in second ARTICLES trimester cases are likely to have major defects, which include: Prognosis • Cardiovascular defects (atrial septal defect [ASD], The primary determinant of survival is the presence of ventricular septal defect [VSD], hypoplastic left associated anomalies, degree of pulmonary hypoplasia, heart, tetralogy of Fallot, and transposition) and development of postnatal pulmonary hypertension. • Facial defects (oral clefts) The mortality, especially in undiagnosed CDH has • Gastrointestinal defects (exomphalos, duodenal remained high, despite optimal postnatal management atresia) and the introduction of ECMO.3 • Renal anomalies (hydronephrosis, renal agenesis, polycystic kidneys, and duplex kidneys) Antenatal prediction of pulmonary hypoplasia remains • Neural tube defects (anencephaly, cephalocele, one of the main challenges of prenatal diagnosis spina bifida) because this would be vital in both counseling parents and also in selecting those cases that may benefit from Differential diagnosis prenatal surgery. Poor prognostic signs are: The differential diagnosis includes cystic chest 1. Associated chromosomal abnormalities lesions like 2. Associated anomalies • Cystic adenomatoid malformation of the lung 3. Major mediastinal shift (CCAM), especially with right sided CDH 4. Severe polyhydramnios leading to preterm delivery • Bronchogenic cysts Lung-to-head ratio • Lung tumors • Neurenteric cyst In CDH, LHR increases, while “observed to expected LHR” (O/E LHR) is independent of gestational age. Management of In fetuses with both left- and right-sided CDH, measurement of the O/E LHR provides a useful predic- pregnancy tion of subsequent survival. The observed LHR is Management of pregnancy includes essential tests and expressed as a percentage of the expected normal mean consultations such as: for gestational age.4 In CDH, prenatal prediction of 1. Detailed ultrasound examination, including fetal postnatal survival relies on the indirect assessment of echocardiography lung size. The LHR was initially thought to be inde- 2. Fetal karyotyping pendent of the gestational age at assessment.5 However, 3. Counseling which includes consultation with studies with normal fetuses, between 12 and 32 weeks pediatric surgeon to discuss the postnatal course of gestation, have shown that there is an 18-fold increase the condition in lung area but only a 4-fold increase in head circum- 4. Fetal MRI, which could help in the assessment of ference.3 In fetuses with CDH, LHR changes with ipsilateral lung gestational age and this effect is removed by intro- 4 These investigations should be performed at the first ducing the observed to expected LHR. available opportunity. This will guide the parents to The most commonly used method for such assessment make decisions regarding continuing the pregnancy or is measurement of the two-dimensional lung area to termination even if the diagnosis is made later in preg- head circumference ratio.10 If the LHR is ≤1, the prog- nancy. Appropriate mode, place, and timing of delivery nosis is guarded, despite ECMO, whereas if it is >1.4, can be planned by the obstetrician in consultation with it is much better. LHR values between 1.0 to 1.4 were the parents. If the fetus is found to be chromosomally associated with 38% survival and in majority of cases abnormal, obstetric intervention such as cesarean they required ECMO. Overall, survivors have a mean section may be avoided. LHR of 1.4 ± 0.33 and nonsurvivors, 1.05 ± 0.3. Post-

PERINATOLOGY • Vol. 13 • No. 1 • Apr–Jun 2012 • 23 Fetal Medicine Update

NamashivayaRESEARCH A. ARTICLES Congenital diaphragmatic hernia diagnosis in second trimester natal survival is significantly less in cases where liver stomach bubble in its usual place, instead a cystic has herniated.6 area adjacent to heart in the chest cavity “pushing” the heart to the opposite side. Right-sided CDH Prenatal surgery may show only mediastinal shift and there may be The main objective of intrauterine surgery is to mini- erratically diagnosed as CCAM of the right lung. mize abnormal development of vital organs rather than • Following detection of CDH, a detailed USS to correction of an abnormal defect. The observation that assess the extent of herniation, other anomalies and in congenital laryngeal obstruction there is massive fetal echocardiography is mandatory. overgrowth of the fetal lungs, the same principle was • Fetal karyotyping must be offered to parents. applied as an alternative to intrauterine surgical correc- • USS determination of O/E LHR helps to prognos- tion of the primary defect.9 Postnatal complications in ticate these pregnancies. cases with CDH result from a mechanical space-occu- • Fetal MRI has shown to be useful in determining pying lesion effect, with lung hypoplasia and pulmo- the extent of hypoplasia of the ipsilateral lung and nary hypertension, as well as decreased lung expansion the presence or absence of liver herniation. with respiration. Based on these observations, prenatal • Prenatal fetal intervention appears to be prom- treatment has been proposed to avoid pulmonary hypo- ising especially in left CDH with a very low LHR, plasia. where the mortality is nearly 100% by improving the survival of these babies by 50%. Hence, this FETO, a minimal access approach, has been performed option must be further explored. between 26 and 30 weeks with the rationale of • Delivery of these fetuses must be in a tertiary care preventing outward movement of pulmonary fluid; unit where there are adequate facilities for care of retention of the fluid within the lungs and their expan- neonates with pulmonary hypoplasia, and neonatal sion could cause reduction of the visceral contents back surgical expertise in order to maximize survival. into the peritoneal cavity. In addition, the placement • Risk of recurrence depends upon the cause of of a “tracheal clip” accelerates lung growth and avoids CDH and hence even in pregnancies that are 7 the often-fatal pulmonary hypoplasia. Preterm labor terminated, complete fetal investigation should and other complications of open fetal surgery may in include karyotyping, and autopsy followed by turn be avoided by using FETO. This approach would postnatal and preconceptional counseling with the obviate the need for a large uterine incision and hence help of a geneticist. possibly reduce the overall risks of open surgery.8 The best candidates for this procedure are fetuses with a References left CDH who have liver herniation and a low LHR 1. Sanders RC, et al. Structural fetal abnormalities –The Total that are at high risk of neonatal demise. Tracheal clip Picture. St Lois-Baltimore-Boston: Mosby;1996:122-126. placement via endoscopic fetal surgery appears to 2. Gibbs DL, et al. Familial diaphragmatic agenesis: an have better results than those in fetuses operated with autosomal-recessive syndrome with a poor prognosis. J Pediatr Surg. 1997;32(2):366-368. open fetal surgery. A minimally-invasive intraluminal 3. Harrison MR, et al. Correction of congenital diaphragmatic tracheal occlusion technique, which avoids laparotomy, hernia in utero VII: a prospective trial. J Pediatr Surg. hysterotomy, and fetal neck dissection, has been accom- 1997;32(11):1637-1642. plished. 4. Jani J, et al. Observed to expected lung area to head circumference ratio in the prediction of survival in foetuses Summary of Antenatally with isolated diaphragmatic hernia. Ultrasound Obstet Diagnosed CDH Gynecol. 2007;30(1):67-71. 5. Laudy JA, et al. Congenital diaphragmatic hernia: An CDH can present in any of the trimesters. evaluation of the prognostic value of the lung-to-head ratio • Ultrasound scan (USS) appearances are usually typical, especially in left CDH - absence of the

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Namashivaya A. Congenital diaphragmatic hernia diagnosisRESEARCH in second ARTICLES trimester

and other prenatal parameters. Prenat Diagn. 2003;23:634– 9. Harrison MR, et al. Correction of congenital diaphragmatic 639. hernia in utero VII: a prospective trial. J Pediatr Surg. 6. Lipshutz GS, et al. Prospective analysis of lung-to- 1996;31:1339-1348. head ratio predicts survival for patients with prenatally 10. Peralta CFA, et al. Assessment of lung area in normal diagnosed congenital diaphragmatic hernia. J Pediatr Surg. fetuses at 12–32 weeks. Ultrasound Obstet Gynecol. 1997;32(11):1634-1636. 2005;26:718–724. 7. VanderWall KJ, et al. Fetendo-clip: a fetal endoscopic 11. Kilian AK, et al. Congenital diaphragmatic hernia: predictive tracheal clip procedure in a human fetus. J Pediatr Surg. value of MRI relative lung-to-head ratio compared with MRI 1997: 32(7):970-972. fetal lung volume and sonographic lung-to-head ratio. AJR 8. VanderWall KJ, et al. Fetal endoscopic (“Fetendo”) tracheal Am J Roentgenol. 2009;192(1):153-158. clip. J Pediatr Surg. 1996;31(8):1101-1103 (discussion 1103-1104).

Serum procalcitonin: Early Detection of Neonatal Bacteremia and Septicemia in a Tertiary Healthcare Facility Nnanna II, et al.

N Am J Med Sci. 2011;3(3):157-160.

The benefits of procalcitonin measurement in neonatal bacteremia/septicemia with suspected nosocomial infection are unclear and unresearched. The aim of this study was to assess procalcitonin value as an early or first line diagnosis/prognosis for bacterial neonatal septicemic infection in selected critically ill neonates. An observational cohort study in a 10-bed intensive care unit was performed. A total of 60 neonates, with either proven or clinically suspected (but not confirmed) bacterial neonatal septicemic infection were included. Procalci- tonin measurements were obtained on the day when the infection was suspected. Neonates with proven septicemic infection were compared to those without the infection. The diagnostic value of procalcitonin was determined through the area under the corresponding receiver operating characteristic curve (AUROCC). In addition, predictive value of procalcitonin variations preceding the clinical suspicion of infection was also assessed. The results of the study showed that procalcitonin is the best early predictor of proven infection in this population of neonates with a clinical suspicion of septicemia (AUROCC = 0.80; 91.6% CI, 0.68 - 0.91). In contrast, eleva- tion of C-reactive protein, leukocyte count, and fever had a poor predictive value in this population. Monitoring the level of procalcitonin could be helpful in the early diagnosis of neonatal septicemic infection in the intensive care unit. Both absolute values and variations should be considered and evaluated in further studies.

PERINATOLOGY • Vol. 13 • No. 1 • Apr–Jun 2012 • 25 RESEARCH ARTICLES Quiz PERINATOLOGY • Vol. 13 • No. 1 • Apr–Jun 2012

Picture Quiz

Can you make the correct diagnosis?

Figure 1 Figure 2

Figure 3 Figure 4

26 Quiz

RESEARCHSelf-assessment ARTICLES Quiz

Self-assessment Quiz

1. In spermatogenesis 5. The ovary a. the Leydig cells are mainly responsible for a. is derived from the paramesonephros sperm production b. is attached to the uterine cornu by the b. spermatids are haploid infundibulo-pelvic ligament c. new sperms develop and mature in 40 days c. lies posterior to the broad ligament d. spermatogonia constantly divide by mitosis d. lies anterior to the ureter e. capacitation in the epididymis is an e. is attached to the distal portion of the fallopian essential step tube 2. Ergometrine, when given at delivery 6. Amniotic fluid embolism a. causes transient hypertension a. is a complication of the puerperium b. is antiemetic b. is complicated by disseminated intravascular c. intramuscularly, works within 1 minute coagulation d. causes rhythmic uterine contractions c. causes cyanosis e. reduces postpartum blood loss d. causes bronchospasm e. leads to maternal death in 30% of cases 3. Cyproterone acetate a. binds to androgen receptors 7. Gross obesity in a pregnant patient causes an increase in the incidence of b. is safe to use in early pregnancy c. is used to treat hirsutism a. leg edema d. is a contraceptive b. malpresentation e. causes acne c. hypertension d. cephalopelvic disproportion 4. The following drugs reduce the efficacy e. multiple pregnancy of combined oral contraceptives a. digoxin 8. A frank or extended breech is b. rifampicin a. easily turned by external cephalic version c. phenytoin b. the commonest type of breech presentation in primigravidae d. ampicillin c. less likely than a flexed breech to be complicated e. diazepam by a cord prolapsed d. the presentation in approximately 2% of women near term e. sometimes known as a footling

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RESEARCH ARTICLES Picture Quiz Answers

Figure 1: Trisomy 21 (Down syndrome) The metacarpals and phalanges are relatively short, resulting in square, stubby hands. Hypoplasia of the mid-phalanx of the fifth finger with incurving is present. The single palmar crease (Simian crease) is not present. Figure 2: Trisomy 21 (Down syndrome) The open mouth and protruding tongue result from hypotonia. There is a low nasal bridge with a tendency to epicanthic folds. Figure 3: Trisomy 21 (Down syndrome) Speckling of the iris is present (brushfield spots). Refractive errors may occur and lens opacities may be seen on slit-lamp examination. Figure 4: Trisomy 18 (Edwards syndrome) The hand is clenched with the index finger overlapping the third finger. The nails are hypoplastic.

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RESEARCH ARTICLES Self-assessment Quiz Answers

Question 1: B, D Question 5: C, D Unlike the female in whom all germ cells are present The ovary is derived from the genital ridge and primor- in the ovary at birth, in the male spermatogonia dial germ cells from the yolk sac. It is not a Mullerian constantly divide to form new germ cells. These are structure. The ovary is attached to the pelvic side wall mitotic divisions, the meiotic division occurring later to by the infundibulo-pelvic ligament which contains its yield haploid spermatids. The process of spermatogen- blood vessels, and to the uterine cornu by the ovarian esis takes approximately 70 days and is mainly under suspensory ligament. It lies posterior to the broad liga- the control of the Sertoli cells. Capacitation in the ment and is anterior to the ureter. There is no connec- epididymis is no longer thought to be a necessary step; tion to the fallopian tube. sperms obtained before this phase have been shown to be capable of fertilizing an ovum. Question 6: B, C Amniotic fluid embolism is a major obstetric emer- Question 2: A, E gency which is estimated to lead to maternal death in Ergometrine causes vasoconstriction and hyperten- up to 95% of cases, although it is difficult to confirm sion as well as causes tonic uterine contraction and the diagnosis if the patient survives. It occurs during increases circulating blood volume by moving blood labor or occasionally at cesarean section when amniotic from the uterus into circulation. The contraction of fluid enters the maternal circulation, causing platelet the myometrium constricts placental bed vessels and and fibrin thrombi to lodge in the lungs leading to reduces blood loss. Gut smooth muscle also contracts respiratory distress and cyanosis. DIC and hypofibrin- and patients usually vomit. Given intramuscularly, it ogenemia occur. Bronchospasm is a complication of takes approximately 7 minutes to work. aspiration. Question 3: A, C Question 7: A, C, D Cyproterone acetate binds to androgen receptors The obese pregnant patient has an increased risk of and acts as a competitive inhibitor. It is used to treat developing hypertensive disorders. She frequently has hirsutism and is likely to cure acne. Patients need to be leg edema. As the fetus is often large, cephalopelvic warned that it is not an effective contraceptive and is a disproportion and shoulder dystocia are more common. teratogenic, and so they must use an effective contra- Malpresentations and multiple pregnancies are no more ceptive when taking this drug. common, but are more difficult to detect. Question 4: B, C, D Question 8: B, C, D Rifampicin increases the rate of metabolism of An extended breech has its leg splinting its body, with combined oral contraceptives, as does phenytoin. The flexed hips and extended knees. It is very difficult to contraceptive effect of oral preparations is reduced turn because of this splinting effect. It is the commonest when taking broad spectrum antibiotics such as ampi- breech presentation. A footling has one leg extended cillin or tetracycline, although the risk of pregnancy is and one leg flexed, presenting with a single foot first. small.

PERINATOLOGY • Vol. 13 • No. 1 • Apr–Jun 2012 • 29 Abstracts from RESEARCH ARTICLES Literature PERINATOLOGY • Vol. 13 • No. 1 • Apr–Jun 2012 Long-term Neurodevelopmental Motor Outcomes After Neonatal Outcomes After Intrauterine and Arterial Ischemic Stroke Related to Neonatal Insults: A Systematic Early MRI Data in a Prospective Study Review Husson B, et al. Mwaniki MK, et al. Pediatrics. 2010;126:912-918. Lancet. 2012;379(9814):445-452. In this prospective cohort study, the authors tried to A systematic review was done by the authors to estimate correlate early imaging data with motor outcomes in the risks of long-term neurocognitive and other sequelae infants with neonatal arterial ischemic stroke (AIS). after intrauterine and neonatal insults, especially in low- From a prospective cohort of 100 children with neonatal income and middle-income countries. The data from AIS, they analyzed the MRI studies performed within the studies published in Medline, Cumulative Index the first 28 days of life for 80 infants evaluated at 2 years to Nursing and Allied Health Literature, the Cochrane of age. The relationships between infarction location Library, and Embase between January 1, 1966 and June and corticospinal tract (CST) involvement and motor 30, 2011 were reviewed. The results were summarized outcomes were studied. Of 73 infarctions involving the with medians and interquartile ranges (IQRs) and the middle cerebral artery (MCA) territory, 50 were super- risk of at least one sequel after insult was calculated. ficial infarctions, 5 deep infarctions, and 18 mixed infarctions. The CST involvement was detected in 24 Of the 28,212 studies identified by search, 153 studies cases. Nineteen patients with MCA infarctions (26%, were suitable to be included and 22,161 survivors of 95% CI: 16%–34%) developed hemiplegia. Mixed intrauterine or neonatal insults were recognized. The infarctions (P<.0001) and CST involvement (P<.0001) overall median risk of at least one sequel in any domain were highly predictive of hemiplegia. From this data, it was 39.4% (IQR 20.0–54.8), with a risk of at least one can be concluded that early MRI scans after neonatal severe impairment in any insult domain of 18.5% (7.7– AIS help in accurate prediction of motor outcomes. 33.3), of at least one moderate impairment of 5.0% (0.0- 13.3%), and of at least one mild impairment of 10.0% (1.4–17.9%). The pooled risk estimate of at least one Dietary Nucleotides and Early sequel (weighted mean) associated with one or more of Growth in Formula-fed Infants the insults studied (excluding HIV) was 37.0% (95% Singhal A, et al. CI: 27.0–48.0%) and this risk was not significantly Pediatrics. 2010;126:e946-e953. affected by region, duration of the follow-up, study design, or period of data collection. The most common In this randomized controlled trial, authors assessed sequelae were learning difficulties, cognition or develop- the role of nucleotide supplementation of the formula mental delay, cerebral palsy, hearing impairment, and in early infant growth. Enrolled neonates, 100 each in visual impairment. intervention and control group, were followed up to 20 weeks of postnatal age. Infants fed with nucleotide- These data suggest that intrauterine and neonatal insults supplemented formula had greater occipitofrontal head have a high risk of causing substantial long-term neuro- circumference at ages 8, 16, and 20 weeks than infants logical morbidity. Hence, comparable cohort studies fed with control formula (mean difference in z scores should be done in resource-poor regions to properly at 8 weeks: 0.4 (95% CI: 0.1–0.7; P = .006) even after assess the burden of these conditions, and long-term adjustment for potential confounding factors (P = .002). outcomes, such as chronic disease, and to inform policy Weight at 8 weeks and the increase in both occipitof- and program investments. rontal head circumference and weight from birth to 8 weeks were also greater in infants fed with nucleotide-

30 Abstracts from Literature

RESEARCH ARTICLES supplemented formula than in those fed with control small-for-gestational age (SGA) preterm infants with formula. Data supports the hypothesis that nucleotide appropriate-for-gestational age (AGA) preterm infants. supplementation leads to increased weight gain and Assessment was made on 15 SGA and 34 AGA preterms head growth in formula-fed infants. (gestational age ≤36 weeks) longitudinally from 34 to 50 weeks postmenstrual age (PMA) using the Neonatal Systemic Hypothermia After Oral-Motor Assessment Scale (NOMAS). Data Neonatal Encephalopathy: suggested that SGA preterms develop a normal sucking pattern later than the AGA preterms (median, 50 vs 44 Outcomes of neo.nEURO.Network weeks PMA, P = .002). Abnormal sucking including RCT “incoordination” and dysfunctional sucking were more Simbruner G, et al. prevalent in SGA preterms than in AGA preterms (median, 11% vs 0% per infant, P<.05). A higher gesta- Pediatrics. 2010;126:e771-778. tional age and z-score for birth weight were predictive This study assessed the efficacy of whole body cooling of normal sucking at 50 weeks PMA. compared to routine care in neonates after perinatal hypoxic-ischemic encephalopathy (HIE). Cooling Cerebral White Matter Blood Flow blanket was used in hypothermia group to reduce the rectal temperature to 33.5°C. All infants received and Arterial Blood Pressure in morphine (0.1 mg/kg) every 4 hours or an equivalent Preterm Infants dose of fentanyl. Neurodevelopmental outcomes were Borch K, et al. assessed at the age of 18 to 21 months. The primary Acta Paediatr. 2010;99(10):1489-1492. outcome was death or severe disability. In this experimental study, 13 normoxic preterm A total of 129 newborn infants were enrolled, and (26–32 weeks ) infants underwent blood flow imaging 111 infants were evaluated at 18 to 21 months (53 in on 16 occasions with single-photon emission computed the hypothermia group and 58 in the normothermia tomography (SPECT) using 99Tc labeled hexam- group). The rates of death or severe disability were 51% ethylpropylenamide oxime (HMPAO) as the tracer. in the hypothermia group and 83% in the normoth- Results showed no statistically significant direct rela- P ermia group ( = .001; OR: 0.21; 95% CI: 0.09–0.54); tion between white matter blood flow percentage number needed to treat: 4, (95% CI: 3–9). Hypo- and any of the variables. Using non-linear regression, thermia also had a statistically significant protective however, assuming a plateau over a certain blood pres- effect in the group with severe HIE (n = 77; OR: 0.17, sure threshold and a positive slope below this threshold, [95% CI: 0.05–0.57]). Systemic hypothermia in the the relation to white matter flow percentage was statis- neo.nEURO.network trial showed a strong neuropro- tically significant P ( = 0.02). The threshold was 29 tective effect and was effective in the severe HIE group. mmHg. Analysis of these data supports the concept that periventricular white matter is selectively vulner- The Development of Sucking able to ischemia during episodes of low blood pressure. Patterns in Preterm, Small-for- gestational Age Infants da Costa SP, et al.

J Pediatr. 2010;157(4):603-609. In this descriptive observational study, authors compared the development of sucking patterns in

PERINATOLOGY • Vol. 13 • No. 1 • Apr–Jun 2012 • 31 Short RESEARCH ARTICLES Communications PERINATOLOGY • Vol. 13 • No. 1 • Apr–Jun 2012

Popliteal Pterygium Syndrome Sahana Devadas,* Gangadhar B Belvadi, Premlatha R, Ramya S

Abstract Popliteal pterygium syndrome (PPS), also termed as popliteal web syndrome or facio-genito-popliteal syndrome, is an autosomal dominant disorder that affects the development of face, limbs, and *Correspondence genitalia. The term PPS was coined by Gorlin, et al in 1968, on Dr Sahana Devadas the basis of the most unusual anomaly, the popliteal pterygium Department of Pediatrics (a web behind the knee). The disorder is very rare, occurring in <1 Bangalore Medical College and in 10,000 individuals. Research Center KR Road Key words: Popliteal pterygium syndrome, multiple pterygium Bangalore - 560002, Karnataka syndrome, popliteal pterygium, ankyloblepharon, syndactyly India

Case Report This study reports a case of 2 siblings, born to a third degree consanguineous Indian family, affected with popliteal pterygium syndrome. The mother’s first pregnancy was a registered and immunized one. At 8 months of gestation, a male child was born with multiple defects—bilateral cleft lip and palate, bilateral ankyloblepharon, total alopecia (Figure 1), and syndactyly of upper and lower limbs (Figure 2). Echocardiogram test revealed a small ventricular septal defect (VSD). The child underwent surgery for ankyloblepharon, cleft lip, and palate (Figure 1). The child is currently 1 year and 7 months old, with developmental Figure 1. First child with total alopecia and bilateral delay. cleft lip operated.

32 Short Communications

Devadas S, et al. PoplitealRESEARCH pterygium ARTICLES syndrome

a b Figure 2. Syndactyly of left lower feet (toes) (a) and Figure 4. Absent scrotum, cryptorchidism, bilateral malformed thumb with ring and middle finger syn- pterygium, and hypoplastic limb. dactyly (b). Second pregnancy was also a registered and immunized Discussion pregnancy. All trimesters were uneventful; however, an antenatal ultrasonography at the eighth month PPS has an autosomal dominant inheritance in gene confirmed mild oligohydramnios. The mother had a map locus of 1q32. PPS is characterized by popliteal spontaneous preterm vaginal delivery at the eighth webbing, cleft lip, cleft palate, lower lip pits, syndac- month of gestation and the birth weight of the neonate tyly, and genital anomalies, which exactly match with was 2.4 kg. On examination, the neonate had total the descriptions of the neonates in this study. This case alopecia, bilateral ankyloblepharon, bilateral cleft lip did not have polyhydramnios as reported in some other and palate, lower lip pit, syndactyly, hypoplasia of digits cases previously. In the absence of a specific genetic of both upper and lower limbs, pterygium extending diagnosis, a careful follow-up by ultrasound remains from ischium to heel (Figure 3), absent scrotum, and the current method of prenatal diagnosis for PPS. cryptorchidism (Figure 4). Investigations revealed pancytopenia (hemoglobin–7.4 g/dL; total count– References 2900; and platelet count–30,000). Results of liver func- 1. Mahalik SK, Menon P. Popliteal pterygium syndrome. J Indian Assoc Pediatr Surg. 2010;15(3):110-111. tion tests, renal function tests, ultrasonography of the 2. James WD, et al. Andrews’ Diseases of the Skin: Clinical abdomen, and infantogram were normal. Dermatology. 10th edn. Philadelphia, USA; Saunders Elsevier:2005. 3. Cole P, et al. Popliteal pterygium: report of an anatomic variant. Ann Plast Surg. 2009;62(6):676-678. 4. Froster-Iskenius UG. Popliteal pterygium syndrome. J Med Genet. 1990;27(5):320-326. 5. Sasidharan CK, Ravi KV. Popliteal pterygium syndrome with unusual features. Indian J Pediatr. 2004;71(3):269-270. 6. Donnelly LF, et al. MR imaging of popliteal pterygium syndrome in pediatric patients. AJR Am J Roentgenol. 2002;178(5):1281-1284. 7. Gardetto A, Piza-Katzer H. A case of familial popliteal pterygium syndrome: early surgical intervention for Figure 3. Second child with bilateral cleft lip and successful treatment. Pediatr Surg Int. 2003;19(8):612-614. palate, bilateral ankyloblepharon, syndactyly, hypo- 8. Ogun TC, et al. A case of a new syndrome or a variant of plasia of digits of both upper and lower limbs, and the rare popliteal pterygium syndrome. J Musculoskelet Res. pterygium extending from ischium to the heel. 2001;5(1):73-77.

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RESEARCH ARTICLES

Sirenomelia with Polycystic Kidneys: A Rare Anomaly Bhuvaneshwari C Yelamali,* Ramesh R Pol, Sanjeev Kolagi, Mahesh Bhagawati

*Correspondence Abstract Dr Bhuvaneshwari C Yelamali This is a case report of a full-term infant born with a rare con- Professor, Department of Pediatrics genital disorder called sirenomelia. The baby was born to a S. Nijalingappa Medical College nondiabetic gravida 2 woman, and died within 1.5 hours after Bagalkot - 587102, Karnataka birth. Prenatal ultrasonography would be helpful in diagnosing India congenital conditions which allows prenatal counseling and subsequent pregnancy termination, if necessary. Phone no: 9448122354 Email: [email protected] Keywords: Sirenomelia, mermaid syndrome, vascular steal theory

Introduction The baby was born to a nondiabetic woman who had not taken any other medications during the antenatal Sirenomelia, also known as mermaid syndrome, is a period, except for iron and folic acid supplementation. rare congenital anomaly of the caudal region charac- The antenatal ultrasonography had shown bilateral terized by fusion of the lower limbs, sometimes with polycystic kidneys with oligohydramnios. Infantogram a single femur bone. It is thought to be an extreme revealed narrow chest with pulmonary hypoplasia and form of caudal regression syndrome. This study is a fused lower limbs made up of two distinct femur, tibia, case report of a newborn with sirenomelia with single and fibula bone. Abdominal ultrasonography showed umbilical artery and bilateral polycystic kidneys. bilateral infantile polycystic kidneys. Case Report The autopsy findings of the newborn were as follows: A full-term infant was born by normal vaginal delivery A single umbilical artery, bilateral polycystic kidneys to a nonconsanguineous couple. Apgar scores at 1 and which were fused to each other at the lower poles, and 5 minutes were 3 and 2, respectively. The newborn had absence of pelvic cavity and any recognizable pelvic fused lower limbs with extreme retroversion and other organs. The rectum and anal canal were absent. The abnormalities such as absence of external genitalia, large intestine was distended with meconium and was imperforate anus, and a single umbilical artery. The connected to the vitellointestinal duct. The coils of baby could not survive beyond 1.5 hours of delivery. small intestine, ascending colon, and appendix were

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Yelamali BC, et al. SirenomeliaRESEARCH with polycystic ARTICLES kidneys present on the left side of the abdominal cavity. Testi- nosis of sirenomelia.7,8 Usually, infants with sirenomelia cles were present in the lower part of the abdominal will present with renal agenesis but in the present case, cavity and measured 0.4 × 0.4 cm. bilateral polycystic kidneys were noted. Early antenatal diagnosis by first trimester is important in order Discussion to allow prenatal counseling so that pregnancy termi- Sirenomelia is a rare, lethal congenital anomaly with nation can be considered earlier and trauma related to a prevalence of 0.1 to 0.25:10,000 in normal pregnan- pregnancy termination at advanced gestational age can cies. It has a strong association with maternal diabetes be reduced. and the relative risk is 1:200–250.1,2 Sirenomelia is characterized by skeletal anomalies, complete fusion References of the lower limbs, absent sacrum, bilateral renal agen- 1. Tanha FD, et al. Sirenomelia (Mermaid Syndrome) in esis or dysgenesis, absent external genitalia, and other an infant of a diabetic mother. Acta Medica Iranica. 2003;4:69-72. gastrointestinal defects.3 2. Mills JI. Malformation in infants of diabetic mothers. The etiology of sirenomelia remains unclear. Sirenom- Teratology. 1984;25:385-394. elia in a baby born to nondiabetic mothers may be 3. Dordoni D, Freeman PC. Sirenomelia sequence. Fetus. caused by abnormal blastogenesis that affects the distri- 1991;1:7553-7560. bution of blood to the caudal region of the fetus. The 4. Stevenson RE, et al. Vascular steal: The pathogenetic mechanism producing sirenomelia and associated defects of vascular steal theory indicates that single umbilical the viscera and soft tissues. Paediatrics. 1986;78:451-457. artery diverts the blood supply from caudal portion 5. Stocker JT, Heifetz SA. Sirenomelia: A morphological study 4,5 of the embryo to the placenta. In case of maternal of 33 cases and review of the literature. Perspect Pediatr diabetes, altered oxidative metabolism may cause Pathol. 1987;10:7. increased production of free oxygen radicals in the 6. Baxi L, et al. Early detection of caudal regression syndrome developing embryo, which is likely to be teratogenic.1 with transvaginal scanning. Obstet Gynecol. 1990;75:486- 490. In the first trimester or early in the second trimester, 7. Adra A, et al. Caudal regression syndrome: etiopathogenesis, prenatal diagnosis can be made by noting the short prenatal diagnosis and perinatal management. Obstet Gynecol crown-rump length and by careful anatomic survey Surv. 1994;49:508-516. on ultrasonography.6,8 Currently, there is no known 8. Sirtori M, et al. Prenatal diagnosis of sirenomelia. J serum marker that may be used for antenatal diag- Ultrasound Med. 1989;8:83-88.

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RESEARCH ARTICLES

A Simple Approach to Pneumothorax in Newborns Heather Hanh Duong*, Koravangattu Sankaran*

*Correspondence Heather Hanh Duong Phone 306 655-1000 Email: [email protected]

Koravangattu Sankaran Divisions of Neonatology and Pediatric Infectious Diseases, Department of Pediatrics, University of Saskatchewan, Saskatoon, Saskatchewan, Canada. Phone 306 655-1000 Email: [email protected]

Introduction into the third intercostal space at the mid axillary line. Eventually, tube thoracostomy has replaced the needle Spontaneous pneumothorax occurs in approximately aspiration method. 0.7% of the newborns.1 The incidence is higher in infants with underlying lung conditions such as hyaline Case Report membrane disease and in conditions requiring positive A late preterm male neonate born at 36 weeks + 5 days pressure ventilation. of gestation was admitted to the neonatal intensive care Tube thoracostomy is a well-accepted treatment in unit (NICU) of Royal University Hospital as respira- neonates requiring ventilation as compared to mechan- tory distress developed at 10 minutes after birth. The ical ventilation that could prevent resolution or intro- male infant was born to a 31-year old G2P1 mother duce a new pneumothorax. with a medical history of essential hypertension and mild asthma managed with methyldopa and intermit- Earlier, needle decompression was used as an emer- tent use of ventolin. During pregnancy, she had per gency procedure for tension pneumothorax while vaginal spotting at 10 to 14 weeks of gestation and a bridging placement of a traditional chest tube thora- threatened preterm labor at 28 weeks of gestation. cotomy. Improvement and ease of insertion with the The mother was group B streptococcus (GBS) posi- Seldinger technique has lead to lesser requirement or tive but the rest of her serology tests were negative. She need for needle aspiration. Needle aspiration method in was induced for hypertension with artificial rupture neonates has never been described since a case report of membrane for clear amniotic fluid. She received was published by Wung, et al in 1978.2 This technique adequate intrapartum antibiotic treatment. The infant was performed on a 30-week old infant receiving posi- had nuchal cord wrapped around neck twice which tive pressure ventilation, when no skilled staff was avail- slipped over and had a true knot. Apgar scores were able to place a chest tube. The Verress needle (16-gauge) 7 and 8 at the first and fifth minute, respectively. At connected to water seal by a venous tubing was placed birth, minimal resuscitation was sufficient. After 10

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Duong HH, et al. PneumothoraxRESEARCH treatment ARTICLES in newborns minutes of birth, grunting and pallor was observed and junction was landmarked for the site of insertion. The the infant was admitted to the NICU. The heart rate chest area was prepped and cleaned with chlorhexi- was above 100 and perfusion improved after receiving a dine in a sterile manner. The needle was directed slowly bolus of normal saline. through the third intercostal space above the rib. A Initial chest x-ray revealed a mild ground-glass appear- trained personnel was instructed to operate the stop ance which did not warrant intubation and surfactant therapy (Figure 1). Subsequently, the infant was subjected to nasal continuous positive airway pressure (NCPAP) at +6 and 25% to 35% O2. A chest x-ray repeated at 24 hours of birth revealed increased opaci- fication in the upper lobe of the right lung (Figure 2). Empiric antibiotic treatment for aspiration pneumonia was started and his feed was stopped. The blood and tracheal secretion cultures were negative for bacterial growth after 48 hours. The infant continued to show Figure 2. Chest x-ray on day one of life signs of respiratory distress such as grunting, mild indrawing, and nasal flaring. Chest x-ray performed at 36 hours after birth revealed left pneumothorax and more evidence of hyaline membrane disease (Figure 3). Subsequently, the infant was intubated and admin- istered a dose of surfactant. Chest decompression by needling was proposed in this case as a simple approach to pneumothorax. Technique The equipments required for the chest decompression procedure included a 23-gauge butterfly needle attached to a 3-way stopcock and 20 mL syringe. Prior to intu- Figure 3. Chest x-ray – lateral decubitus position (left bation, the infant was given a dose of fentanyl. The pneumothorax is more evident) infant was placed in the supine position exposing the chest area. The third intercostal space at the mid axillary

Figure 4. Chest x-ray to confirm placement of chest Figure 1. Chest x-ray on admission tube and visualize residual pneumothorax

PERINATOLOGY • Vol. 13 • No. 1 • Apr–Jun 2012 • 37 Short Communications

DuongRESEARCH HH, et al.ARTICLES Pneumothorax treatment in newborns cock in order to withdraw air. About 39 mL of air was lated patients, it is not a benign procedure and carries its withdrawn during the first needle aspiration. A repeat own risks. Reported complications include lung injury, chest x-ray was done (Figure 4) which revealed residual phrenic nerve paralysis, chylothorax, and hemorrhagic pneumothorax. Further, a repeat needle decompression pericardial effusion.3 A study by Litmanovitz, et al was performed in the second intercostal space at the reported management of pneumothorax without initial midclavicular junction which withdrew 7 mL of air. chest tube placement in a selected group of ventilated neonates.3 These groups of infants were more mature, Another repeat chest x-ray revealed complete resolu- were on lower ventilator setting, and had better blood tion of pneumothorax (Figure 5). There was significant gas results when pneumothorax was diagnosed. The improvement in the symptoms. Further, two additional study reported that infants who were treated initially doses of surfactant were given and the infant was extu- with needle aspiration are more likely to require subse- bated to room air on the sixth day. The infant was also quent chest tube insertion than infants who received given 3 doses of dexamethasone to manage traumatic expectant treatment. intubation. The infant’s respiratory status remained stable and he was discharged home a few days later. There are several advantages of needle aspiration as compared to chest tube insertion. It requires minimal Discussion sedation and has lower risk of injury. The procedure is Significant improvement was observed in the symp- short, easy to master, and requires minimal instrumen- toms which is attributed to both administration of tation, and postprocedure pain management. surfactants and relief of pneumothorax. Although chest In this study, clinical status of the infant improved tube thoracostomy is the treatment of choice for venti- following needle decompression and administration of surfactants and chest tube insertion was not necessary. Air entrapment in the pleural space was resolved by maintaining the infant’s saturation above 95% so that trapped nitrogen gas is washed out. No further complications developed after the procedure. Overall, needle decompression is a safe and simple alternative approach to treat pneumothorax in selective patients so as to avoid more invasive insertion of chest tube. References 1. Gomella TL, et al. Neonatology: Management, Procedures, On-call Problems, Diseases, and Drugs. New York:McGraw- Hill Medical;2009:344-347. 2. Wung JT, et al. A spring-loaded needle for emergency evacuation of pneumothorax. CritCare Med. 1978;6:378-379. 3. Litmanovitz I, Carlo WA. Expectant management Figure 5. Chest x-ray after one dose of surfactant and of pneumothorax in ventilated neonates. Pediatrics. 2 needle decompressions 2008;122:975-979.

38 • PERINATOLOGY • Vol. 13 • No. 1 • Apr–Jun 2012 Vol. 13 • No. 1 • Apr–Jun 2012 Instructions to RESEARCHAuthors ARTICLES PerinatologyJournal of Perinatal and Neonatal Care

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Brief reports and case reports script and also to reduce the length of the manuscript, if should not exceed 1200 words, with not more than two tables and required figures or photographs and six references. Brief accounts of new • Two copies of the journal will be provided to the author free of observations can also be presented as letters not exceeding 400 cost after the issue has been published. No reprints will be sent words. Guidelines to be followed while preparing and submitting a manu- MANUSCRIPT FORMAt script are given below. Titles and subtitles Titles should be short, concise, specific, and informative. MANUSCRIPT CHECKLIST Abstract Typescript and other inputs • Send original (unpublished and not submitted elsewhere) Abstract of a research paper summarizes the main points of an manuscript along with two photocopies to the address* given article: (1) the study objective and background, (2) the study design below and methods, (3) results, and (4) conclusion. • Send a softcopy (CD) of the manuscript in MS Word format Key words • Send two sets of illustrations, photographs, and drawings Key words are descriptors representing the key topics presented in –– Line art/graphs/illustrations should be provided in “.eps” the article. or “.ai” format or in a camera-ready form with redundant Introduction areas trimmed The introduction should provide the objective of the study and state –– Line drawings can be submitted as photographic prints or high-quality photocopies. All other illustrations should be the hypothesis or research question, how and why the hypothesis black-and-white photographic prints was developed, and why it is important. –– Resolution of photographs or their scanned copies should Methods be 300 or more dpi This section includes a description of: –– If the subjects of the photographs are identifiable, either • Study design or type of analysis and period of study their eyes should be masked or their written permission to • Condition, factors, or disease studied use the photograph should be submitted along with the typescripts • Details of sample (eg, study subjects and the setting from which they were drawn) –– Color illustrations can be used if essential to the article • Intervention(s) • Provide complete details of the corresponding author, including address for communication, telephone and fax • Outcome measures numbers, and email address • Statistical analysis • Keep a copy of the manuscript for your reference Results Statements/permissions The results given in the manuscript should be specific and relevant to • Include statements signed by each author on: the research hypothesis. –– Authorship criteria and responsibility Discussion –– Financial disclosure This section should be a formal consideration and critical exami- –– Copyright transfer nation of the study. The results should be considered in this section in • Include statement signed by corresponding author that written the context of other studies. permission has been obtained from all persons named in the Acknowledgment Conclusion • Include research or project support/funding in an acknowl- This section summarizes the consensus statement. It may include edgment benefits and harms of the study. The type of future studies, if appropriate, should be mentioned here. Acknowledgments * The Managing Editor – Perinatology Acknowledgments are considered to be a continuation of the text Scientific Publications Division and precede the references. Only those who have made substantial The Himalaya Drug Company contributions to the study and/or preparation of the paper should Makali, Bangalore, be acknowledged. The source(s) of grant support, equipment, and Karnataka, India – 562123 drugs should be included.

39 Instructions to Authors

RESEARCH ARTICLES

References • Write lowercase abbreviations without period; “et al” and “vs” Authors cite a reference: are examples. Rule of exception: Use lowercase abbreviations, • To support their arguments or lay the foundation for their theses preceded by a comma and followed by a full point at the end of “etc.” For example: sun, moon, etc. • As a source of information or to credit other authors –– Write “for example” or “that is,” preceded and followed General Style Points (US Spelling and Style) by a comma, if it is not the beginning of the sentence, in • Use American English, “ize” spelling a running text. Write “eg” or “ie” followed by a comma • Numbers under 10 are spelled out, except for measurements when used in parenthesis (ie, or eg,) with a unit (8 mmol/L) or age (6-week old), or when in a list with Genus and species other numbers (14 dogs, 12 cats, and 9 gerbils) Italicize when used in singular: Species, variety or subspecies, • Use list comma. For example: The bishops of Durham, Can- genus (eg, first occurrence in text—Escherichia coli; following terbury, Bath and Wells, and York were invited. OR I used to occurrences—E coli—without any period) help my mother with the cooking, cleaning, washing and ironing, and yard work Use lowercase (unless it is not a beginning of the sentence) and • Use double quotes: Generally, quotes are outside punctuation. nonitalic style for plural form of organisms For example: poliomyelitis is commonly referred to as “polio.” Bacillus bacilli • For range use “to” in text, for example 40 to 50 mg, and “–” (en Staphylococcus staphylococci dash) in parenthesis (35–47 cm) Streptococcus streptococci • Use P value as: P = .05, P<.005, P>.05 (no “0” before period and “P” is capital and italics; no space between the symbols (<,>) Units and “P”; rule of exception: insert space before and after the Use standard abbreviations for units of measure. symbol “=”) References • Closed-up em dash “—” should be used for parenthetical All references should be cited in the text, tables, or figures in con- phrases secutive numerical order (as presented in the text) by means of • Parenthesis style: First priority is parenthesis followed by square superscript Arabic numerals, outside punctuation. bracket, that is, ([]), (World Health Organization [WHO]) Article in journals • Date: December 5, 2008 (US style) Typical entry for journal with more than two authors (if more than • Foreign words listed in “Merriam-Webster’s” online dictionary two authors, list first author, then et al). should not be italicized and hyphenated (in vitro, in vivo, etc.) For example: Tables Hunter DJ, et al. Plasma organochlorine levels and the risk of breast • All tables should be cited in the text and it should be in cancer. N Engl J Med. 1997;337(suppl 1):1253-1258. sequential order • Table should be cited as Table 1/Tables 1 and 2/Tables 1 to 3 (or Morris LA. The risk revolution: an experimentation of the regulatory Tables 1–3, inside parenthesis) environment [editorial]. J Am Pharm Assoc. 2001;41:S5-S10. • Table caption should be provided and its first part should be in Books bold form as given below Author name: Same as journal. For example: Aronoff GR, et al. Drug Prescribing in Renal Failure. Vol. 1. 4th edn. Table 1. Table Caption in Title Case (no full point at the end) Philadelphia, PA: American College of Physicians; 1999:39. Figures Dukes MNG, Aronson JK, eds. Meyler’s Side Effects of Drugs. 14th • All figures should be cited in the text and it should be in edn. Amsterdam, Netherlands: Elsevier; 2000:xvi-xvii. sequential order • Figure should be cited as Figure 1/Figures 1 and 2/Figures 1 to 3 Other published material (or Figures 1–3, inside parenthesis) Electronic media • Figure caption should be provided and its first part should be in Perneger TV, et al. Randomized trial of heroin maintenance pro- bold form as given below gramme for adults who fail in conventional drug treatments. TBMJT For example: [serial online]. 1998;317:20-24. Available at: http://www.bmj.com/ cgi/content/full/317/7150/13. Accessed March 4, 2003. Figure 1. Figure caption in sentence case. (Note the full point at the end.) Rennie D, Guyatt G, eds. Users’ Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice [book online]. Abbreviations Chicago, IL: AMA Press; 2002. Available at: http://www.usersguides. Most abbreviations should be spelled out at first mention (in text); org/textbooks.asp. Accessed February 26, 2004. some very common abbreviations need not be expanded. Abbre- Unpublished material viations should not be introduced in titles. Do not include material that has been submitted for publication but Some notes on the use of abbreviations are given below. has not yet been accepted. This material, with its date, should be • In general, use uppercase letters without period for acronyms noted in the text as “unpublished data,” as follows: and initialisms such as CHF, GFR, and WBC and also for routes of For example: administration and dosage schedules such as PO, IV, BID, and TID. Some abbreviations—such as PhD and pH—do contain These findings have recently been corroborated (Mariman, unpub- lowercase letters lished data, January 1996). • Use abbreviations consistently. In general, write out the term or phrase at first mention, followed by the abbreviation in paren- theses; use only the abbreviation thereafter

40 • PERINATOLOGY • Vol. 13 • No. 1 • Apr–Jun 2012

RNI Regd No. KARENG/1999/35 MAG (3) NPP/43/2011/12

Printed and published by Dr Pralhad S Patki on behalf of The Himalaya Drug Company, Makali, Bangalore - 562123. Published at The Himalaya Drug Company, Makali, Bangalore - 562123. Printed at Sri Sudhindra Offset Process, No. 27/28, DT Street, 8th Cross, Malleshwaram, Bangalore - 560003. Edited by Dr Ranjan K Pejaver.