Parent’s Communication with Children about CAH ORIGINAL ARTICLE Etiology at the PGH

6. Metcalfe A, Plumridge G, Coad J, Shanks A, Gill P. Parents’ and diagnosed by newborn screening and treated with low doses of children's communication about genetic risk: a qualitative study, hydrocortisone. Horm Res Pædiatr. 2011;75(1):32-7. doi:10.1159/000316973. Etiology of Hydrops Fetalis at the Philippine General Hospital: learning from families' experiences. Eur J Hum Genet. 2011; 19(6):640-6. 18. Janjanin N, Dumic M, Skrabic V, Kusec V, Grubic Z, Spehar Uroic A. doi:10.1038/ejhg.2010.258. Five patients with congenital adrenal hyperplasia due to 21-hydroxylase A Retrospective Study 7. Rowland E, Metcalfe A. Communicating inherited genetic risk between deficiency (one with associated neuroblastoma) discovered in three parent and child: A meta-thematic synthesis. Int J Nurs Stud. 2013; generations of one family. Horm Res. 2007; 67(3):111-6. doi:10.1159/ 50(6):870-80. doi:10.1016/j.ijnurstu.2012.09.002. 000096420. Michelle E. Abadingo and Maria Melanie Liberty B. Alcausin 8. McConkie-Rosell A, Del Giorno J, Heise EM. Communication of genetic 19. Newborn Screening Reference Center. Prevalence of Disorders Among risk information to daughters in families with fragile X syndrome: The Filipino Newborns (1996-2014) [Online]. 2014 [cited 2015 May]. Department of Pediatrics, College of Medicine and Philippine General Hospital, University of the Philippines Manila parent’s perspective. J Genet Couns. 2011; 20(1):58-69. doi:10.1007/ Available from http://www.newbornscreening.ph/images/stories/ s10897-010-9326-9. ResourcesPrevalence/prevalence-2014.pdf. 9. Plumridge G, Metcalfe A, Coad J, Gill P. Parents’ communication with 20. Braun V, Clarke V. Using thematic analysis in psychology. Qual Res siblings of children affected by an inherited genetic condition. J Genet Psychol. 2006; 3(2):77-101. ABSTRACT Introduction Couns. 2011; 20(4):374-83. doi:10.1007/s10897-011-9361-1. 21. Smith JA, Dancyger C, Wallace M, Jacobs C, Michie S. The development Objective. Hydrops fetalis (HF) is a diagnosis with significant Hydrops fetalis (HF) is defined as abnormal 10. Pentz RD, Peterson SK, Watts B, et al. Hereditary nonpolyposis of a methodology for examining the process of family communication of morbidity and mortality. It is the objective of this study to colorectal cancer family members’ perceptions about the duty to inform genetic test results. J Genet Couns. 2011; 20(1):23-34. doi:10.1007/s10897- accumulation of serous fluid in two or more fetal identify common etiologic causes of HF in the Philippine General and health professionals' role in disseminating genetic information. 010-9317-x. compartments; such as skin, pleura, pericardium, Hospital (PGH). Genet Test. 2005; 9(3):261-8. doi:10.1089/gte.2005.9.261. 22. McConkie-Rosell A, Heise EM, Spiridigliozzi GA. Genetic risk peritoneum, placenta and amniotic fluid. There are two 11. Aktan-Collan KI, Kääriäinen HA, Kolttola EM, et al. Sharing genetic risk communication: experiences of adolescent girls and young women from with next generation: Mutation-positive parents’ communication with families with Fragile X Syndrome. J Genet Couns. 2009; 18(4):313-25. Methods. This is a retrospective review of hydrops fetalis cases categories of hydrops fetalis: isoimmune (IHF) and non- their offspring in Lynch Syndrome. Fam Cancer. 2011; 10(1):43-50. 23. Gallo AM, Angst D, Knafl KA, Hadley E, Smith C. Parents sharing delivered at the PGH from 2010 to 2014. There was a total of 75 isoimmune (NIHF). IHF results in erythroblastosis fetalis, doi:10.1007/s10689-010-9386-x. information with their children about genetic conditions. J Pediatr identified cases of hydrops fetalis. However, only 58 of these, or where there is an increased rate of red blood cell (RBC) 12. Wilson BJ, Forrest K, van Teijlingen ER, et al. Family communication Health Care. 2005;19(5):267-75. doi:10.1016/j.pedhc.2005.05.008. 77.33% have available medical charts for review. destruction due to transplacental passage of maternal about genetic risk: the little that is known. Community Genet. 2004; 24. Boyd DR, Bee HL, Johnson PA. Lifespan Development. Pearson/A and 7(1):15-24. doi:10.1159/000080300. B; 2006. antibody active against paternal RBC antigens of the infant; 13. Hay J, Dibonaventura M, Baser R, Press N, Shoveller J, Bowen D. 25. Rosenthal DA, Gurney RM, Moore SM. From trust on intimacy: A new Results. The median gestational age at birth was 31 (range 21- this entity is approximately 3 times more frequent in the Personal attributions for melanoma risk in melanoma-affected patients inventory for examining Erikson’s stages of psychosocial development. J 40) weeks. There were 19 identified cases (32%) of stillbirth. Of Caucasian population.1 NIHF on the other hand develops in and family members. J Behav Med. 2011; 34(1):53-63. doi:10.1007/s10865- Youth Adolesc. 1981; 10(6):525-37. the 32 patients born alive, 30 (93.75%) died in the immediate the absence of maternal antibody-fetal antigen mediated 010-9286-4. 26. Zimmer-Gembeck MJ, Collins WA. Autonomy Development during neonatal period. The etiologies of HF were identified in 15 cases, 2 14. Hughes IA. Congenital adrenal hyperplasia--a continuum of disorders. Adolescence. Oxford: Blackwell Publishers; 2003. which included congenital anomalies (n=4), cardiac anomalies RBC destruction. At present, NIHF comprise 76-90% of all 3, 4 Lancet. 1998; 352(9130):752-4. doi:10.1016/S0140-6736(98)22037-X. 27. Meyer-Bahlburg HF, Dolezal C, Baker SW, Ehrhardt AA, New MI. (n=3), infectious problems (n=3), hematologic anomalies (n=2), described HF cases.3, 4 15. Merke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet. 2005; Gender development in women with congenital adrenal hyperplasia as Several studies were done elucidating the possible 365(9477):2125-36. doi:10.1016/S0140-6736(05)66736-0. a function of disorder severity. Arch Sex Behav. 2006; 35(6):667-84. placental anomalies (n=2) and congenital tumor (n=1). Cases of 16. Collett-Solberg PF. Congenital adrenal hyperplasia: from genetics and doi:10.1007/s10508-006-9068-9. congenital anomalies were only detected by congenital anomaly causes of NIHF. While there are many identified causes of biochemistry to clinical practice, part 2. Clin Pediatr (Phila). 2001; 28. Gallo AM, Knafl KA, Angst DB. Information management in families scan; no further work-ups were done. Fifteen (15) mothers NIHF, increase in central venous pressure (CVP) is common 40(3):125-32. doi:10.1177/000992280104000301. who have a child with a genetic condition. J Pediatr Nurs. 2009; presented with microcytic, hypochromic on complete in the pathophysiology of NIHF. This leads to accumulation 17. Bonfig W, Schmidt H, Schwarz HP. Growth patterns in the first three 24(3):194-204. doi:10.1016/j.pedn.2008.07.010. blood count (CBC). The cause of HF was not confirmed in the of interstitial fluid, leading to hydrops fetalis.5 years of life in children with classical congenital adrenal hyperplasia remaining 43 (74%) cases. Cardiovascular anomalies was identified as a main etiologic

factor for NIHF.3,6,7 However, certain populations may have Conclusion. It is important to fully investigate the causes of HF to aid in the proper management and counseling. Further work-up increased propensity for NIHF due to particular medical must be done for mothers presenting with microcytic, conditions inherent in the population. An example would hypochromic anemia. This is an important feature of alpha be HB Bart’s hydrops fetalis syndrome wherein the absence thalassemia. Partners of women suspected to have alpha of four alpha-globin genes would result into a severe form thalassemia should also have a hematologic screening. The of anemia. If left untreated, this condition will result to deletion of the four alpha genes will result to HB Bart’s hydrops death in the second or third trimester of gestation, or fetalis; a major cause of hydrops fetalis in Southeast Asian neonatal period.8-8-10 The most severe forms of alpha- countries. thalassemia are restricted in the Southeast Asian region,

11 Key Words: Hydrops fetalis, etiology, fetal outcome which includes the Philippines and China. In Southeast Asia, alpha-t-thalassemia is the most common cause of fetal hydrops, accounting to 60% to 90% of cases.8,9 In a 2003 retrospective study done in MCU-Filemon D. Tantoco

______Medical Foundation (MCU-FDTMF) in the Philippines,

thalassemias ranked third in the most common cause of Paper presented as a poster at the 28th International Pediatrics Association hydrops fetalis.12 Conference, August 17-22, 2016, Vancouver Convention Center, Vancouver, In a national database in the United States, 598 neonates BC, Canada. of 253,651 discharges from neonatal ICUs (NICU), or 0.23%

Corresponding author: Michelle E. Abadingo, MD of discharges were identified with hydrops fetalis. Thirty-six Department of Pediatrics percent of these patients died before hospital discharge.6 In a Philippine General Hospital 2003 study done at the Philippine General Hospital (PGH), University of the Philippines Manila th Taft Avenue, Ermita, Manila 1000 Philippines hydrops fetalis ranked 5 in the most common congenital Telephone: +632 5261710 anomalies.13 In a more recent study done in the same Email: [email protected] institution, results shoshowedwed that hydrops fetalis was one of

180 ACTA MEDICA PHILIPPINA VOL. 51 NO. 3 2017 VOL. 51 NO. 3 2017 ACTA MEDICA PHILIPPINA 181 Etiology Hydrops Fetalis at the PGH

the frequently encountered congenital anomalies detected by and Gynecology; and Section of Neonatology under the prenatal ultrasound. However, most of the hydropic fetuses Department of Pediatrics. As a tertiary referral center, it did not have a complete work-up as to the possible receives patient referrals needing specialized medical and etiology.14 Recent advances in prenatal ultrasound made it surgical care from other institutions all over the country. possible to identify hydrops fetalis early in gestation. However, despite this, fetuses with hydrops fetalis die Study Design and Population antepartum or intrapartum with a mortality rate of 20- For the purpose of this study, hydrops fetalis is defined 90%.14,15 According to the 2012 health statistics of the as excessive fluid accumulation within at least 2 Department of Health (DOH), conditions originating in the extravascular compartments of the body. The study was perinatal period (P00-P99) ranked tenth in the 10 leading reviewed and approved by the University of the Philippines causes of overall mortality.16 Hydrops fetalis is included in Manila Research Ethics Board (UPMREB). Names and this cluster. personal information were anonymized and kept Hydrops fetalis is a diagnosis with significant morbidity confidential. The lists of hydrops fetalis deliveries were and mortality. An epidemiologic profile of hydrops fetalis in obtained from the Section of Perinatology, Department of the local population is needed to identify possible etiologic and Gynecology, and Section of Neonatology, factors. This is particularly significant in countries like the Department of Pediatrics. Medical charts of delivered cases Philippines where prenatal diagnosis is practiced in a at the PGH from January 1, 2010 to December 31, 2014 were limited way and termination of is not allowed by retrieved from the Medical Records Section, Philippine law.17 A review of previous cases of NIHF would aid in General Hospital. appropriate management and treatment planning. The Maternal demographic data recorded were: initials, age, results can also be utilized in genetic counseling of families obstetric score, gestational age at time of diagnosis, number regarding management options available and risk of having of prenatal visits, co-morbid conditions, previous history of further affected children. For ethnicities with increased risk hydrops fetalis and obstetric complications. Pertinent for certain conditions such as alpha-thalassemia in Filipinos, obstetric history and work-ups done during the course of the the results can be used to strengthen and create policies pregnancy were obtained. regarding prenatal detection and patient education. Fetal data recorded were: dates of antenatal ultrasound, This retrospective study aimed to identify the etiologic gestational aging at birth, pediatric aging, mode of delivery, profile of HF in the local population. The specific objectives birth weight, APGAR scores, fetal outcome and laboratory of this study were: to identify delivered cases of HF at the tests done. PGH from 2010 to 2014; and to review the epidemiologic profile (maternal demographic characteristics, identification Data Analysis of possible maternal risk factors, antenatal diagnostic work- Clinical data collected were transferred to a password- ups done, and birth outcomes) of hydrops fetalis cases. protected Microsoft Excel (Microsoft Corporation, Redmond, WA, USA) spreadsheet file. Patients were assigned case Methods codes that were used in recording data. Data were recorded and screened. The number of deliveries during the five-year Description of the Study Setting study period was obtained from the records of the Section of The PGH is the largest tertiary hospital and referral Neonatology, Department of Pediatrics. The sample size for center in the Philippines with a 1500-bed capacity. It has 14 this study is 73, using the formula n=Z2 x [p(1-p)]/e2, where clinical departments, namely: Anesthesiology, Emergency Z=1.96, p=0.05 and e=0.05. Medicine, Family Medicine, Internal Medicine, Neurosciences, Obstetrics and Gynecology, Ophthalmology, Results Orthopedics, Otorhinolaryngology, , Pediatrics, Table 1 shows the identified cases of hydrops fetalis Psychiatry, Radiology and Surgery. The hospital also has the from the Section of Perinatology, Department of Obstetrics most number of subspecialty services. This includes the and Gynecology. While the identified cases of hydrops Section of Perinatology under the Department of Obstetrics fetalis met the computed sample size for the study (n=75),

Table 1. Total number of deliveries and occurrence of patients with hydrops fetalis per 1,000 deliveries, 2010-2014

Total number Total number of patients Cases reviewed Occurrence of patients with Year of deliveries with hydrops fetalis n (%) hydrops fetalis per 1,000 deliveries 2010 5852 18 6 (33.33) 3.08 2011 5710 16 16 (100) 2.80 2012 5120 12 7 (58.33) 2.34 2013 4692 11 11 (100) 2.13 2014 5340 18 18 (100) 3.37 TOTAL 26,714 75 58 (77.33)

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the frequently encountered congenital anomalies detected by and Gynecology; and Section of Neonatology under the only 58 (77.33%) have medical records available for review. section. Indications for cesarean section include prenatal ultrasound. However, most of the hydropic fetuses Department of Pediatrics. As a tertiary referral center, it During the study period, there were 26,714 live births giving deteriorating fetal status, multiple gestation, maternal did not have a complete work-up as to the possible receives patient referrals needing specialized medical and an incidence for HF of 2.77/1000 live births. Mirror Syndrome and identified fetal multiple anomalies on etiology.14 Recent advances in prenatal ultrasound made it surgical care from other institutions all over the country. Mean maternal age is 28 years, and median age of congenital anomaly scan (CAS). The male-to-female ratio is possible to identify hydrops fetalis early in gestation. gestation is 31. Majority of those in the study were 1:1.3. The median APGAR score at one minute is 2; while the However, despite this, fetuses with hydrops fetalis die Study Design and Population multigravid (91.53%); four (4) had a previous history of median APGAR score at five minutes is 4. While 32 (54.24%) antepartum or intrapartum with a mortality rate of 20- For the purpose of this study, hydrops fetalis is defined hydrops fetalis delivery. The gestational age when hydrops neonates were delivered alive, majority (93.75%) died in the 90%.14,15 According to the 2012 health statistics of the as excessive fluid accumulation within at least 2 fetalis was first detected was not indicated in most cases. One immediate neonatal period. Two of the deliveries born alive Department of Health (DOH), conditions originating in the extravascular compartments of the body. The study was of the women who had a previous hydrops fetalis delivery had documented advanced directives of do not intubate perinatal period (P00-P99) ranked tenth in the 10 leading reviewed and approved by the University of the Philippines had her deliveries in this institution. For the two women (DNI) and do not resuscitate (DNR). No documentation was causes of overall mortality.16 Hydrops fetalis is included in Manila Research Ethics Board (UPMREB). Names and who had twin , both delivered neonates who done on the resuscitation and management after delivery. this cluster. personal information were anonymized and kept underwent twin-to-twin transfusion syndrome (Table 2). There were no fetal autopsies documented. Hydrops fetalis is a diagnosis with significant morbidity confidential. The lists of hydrops fetalis deliveries were and mortality. An epidemiologic profile of hydrops fetalis in obtained from the Section of Perinatology, Department of Table 2. Maternal demographics and risk factors for Table 3. Neonatal demographics the local population is needed to identify possible etiologic Obstetrics and Gynecology, and Section of Neonatology, hydrops fetalis pregnancy n (%) factors. This is particularly significant in countries like the Department of Pediatrics. Medical charts of delivered cases VARIABLE n (%) Pediatric aging 30 (23-40)* Philippines where prenatal diagnosis is practiced in a at the PGH from January 1, 2010 to December 31, 2014 were Maternal age (years) 28.5+ 6.08 Mode of delivery Normal vaginal delivery 10 (17.24) limited way and termination of pregnancy is not allowed by retrieved from the Medical Records Section, Philippine Age of gestation on delivery 31* Gravidity Assisted vaginal delivery 5 (8.62) 17 law. A review of previous cases of NIHF would aid in General Hospital. Primigravid 7 (12.07) Cesarean section 39 (67.24) appropriate management and treatment planning. The Maternal demographic data recorded were: initials, age, Multigravid 51 (87.93) Unspecified 4 (6.90) Median birth weight 2,300 (500-4,300)* results can also be utilized in genetic counseling of families obstetric score, gestational age at time of diagnosis, number Number of pregnancy Singleton pregnancy 56 (96.55) Sex regarding management options available and risk of having of prenatal visits, co-morbid conditions, previous history of Twin pregnancy 2 (3.45) Male 23 (36.66) further affected children. For ethnicities with increased risk hydrops fetalis and obstetric complications. Pertinent Maternal risk factors for hydrops fetalis Female 29 (50.00) for certain conditions such as alpha-thalassemia in Filipinos, obstetric history and work-ups done during the course of the Previous hydrops fetalis pregnancy 4 (6.90) Ambiguous 1 (1.72) Unspecified 5 (8.62) the results can be used to strengthen and create policies pregnancy were obtained. Anemia 15 (25.96) Alpha thalassemia 2 APGAR score regarding prenatal detection and patient education. Fetal data recorded were: dates of antenatal ultrasound, Infection 3 (5.17) 1 minute 2 (0 -9)* This retrospective study aimed to identify the etiologic gestational aging at birth, pediatric aging, mode of delivery, Toxoplasmosis 1 5 minutes 4 (0-9)* Fetal outcome profile of HF in the local population. The specific objectives birth weight, APGAR scores, fetal outcome and laboratory Syphilis 2 Maternal complication secondary to HF Stillbirth 19 (32.76) of this study were: to identify delivered cases of HF at the tests done. Mirror syndrome 3 (5.17) Alive 32 (55.17) PGH from 2010 to 2014; and to review the epidemiologic *Data presented as median Died in the neonatal period 30 (93.75) Undetermined 7 (12.07) profile (maternal demographic characteristics, identification Data Analysis *Data presented as range of possible maternal risk factors, antenatal diagnostic work- Clinical data collected were transferred to a password- All mothers had complete blood count (CBC) done prior ups done, and birth outcomes) of hydrops fetalis cases. protected Microsoft Excel (Microsoft Corporation, Redmond, to delivery. Of the 58 charts reviewed, 15 mothers presented Coombs test was done for 16 (27%) cases. For the 16 WA, USA) spreadsheet file. Patients were assigned case with microcytic, hypochromic anemia. For this study, cases, all had negative direct and indirect Coombs. Causes of Methods codes that were used in recording data. Data were recorded microcytic anemia was defined as having mean corpuscular hydrops fetalis were identified in 14 cases (Table 4). and screened. The number of deliveries during the five-year volume (MCV) of less than 83 and mean corpuscular Description of the Study Setting study period was obtained from the records of the Section of hemoglobin (MCH) of less than 27. Of the 15 women, one Table 4. Determined causes of Hydrops Fetalis The PGH is the largest tertiary hospital and referral Neonatology, Department of Pediatrics. The sample size for was identified to have alpha thalassemia trait. Another n (%) center in the Philippines with a 1500-bed capacity. It has 14 this study is 73, using the formula n=Z2 x [p(1-p)]/e2, where woman was confirmed to have alpha thalassemia. For the Congenital anomaly 4 (7) clinical departments, namely: Anesthesiology, Emergency Z=1.96, p=0.05 and e=0.05. rest of the women with microcytic, hypochromic anemia, no Skeletal dysplasia 2 (3) Medicine, Family Medicine, Internal Medicine, further investigations were done to probe on the possible Multiple congenital anomaly (hydrocephalus, cardiomegaly, pelvocaliectasia, distended bladder) 1 (2) Neurosciences, Obstetrics and Gynecology, Ophthalmology, Results etiology of the anemia. Paternal CBC results were not Chromosomal Anomaly (Trisomy 21) 1 (2) Orthopedics, Otorhinolaryngology, Pathology, Pediatrics, Table 1 shows the identified cases of hydrops fetalis documented in the newborn charts. Cardiac 3 (5) Psychiatry, Radiology and Surgery. The hospital also has the from the Section of Perinatology, Department of Obstetrics Infection is identified as an etiologic factor for hydrops Fetal heart block 1 (2) most number of subspecialty services. This includes the and Gynecology. While the identified cases of hydrops fetalis. Identified etiologic agents in the study include Fetal cardiomegaly 1 (2) Coarctation of aorta 1 (2) Section of Perinatology under the Department of Obstetrics fetalis met the computed sample size for the study (n=75), toxoplasmosis and syphilis. In this study, one woman had Infectious 3 (5) an active toxoplasma infection (IgM reactive); while two Toxoplasmosis 1 (2) Table 1. Total number of deliveries and occurrence of patients with hydrops fetalis per 1,000 deliveries, 2010-2014 Syphilis 2 (3) other women had syphilis infection. Total number Total number of patients Cases reviewed Occurrence of patients with Placental abnormality 2 (3) Year Mirror syndrome, or Ballantine syndrome, is the of deliveries with hydrops fetalis n (%) hydrops fetalis per 1,000 deliveries Twin-to-twin transfusion syndrome 2 (3) association of fetal and placental hydrops with maternal 2010 5852 18 6 (33.33) 3.08 Hematologic 2 (3) 2011 5710 16 16 (100) 2.80 preeclampsia. This was seen in three mothers in this study. α-thalassemia 2 (3) 2012 5120 12 7 (58.33) 2.34 Relevant neonatal demographics are presented in Table Congenital tumor 1 (2) Cervical teratoma 1 (2) 2013 4692 11 11 (100) 2.13 3. Most deliveries had Pediatric Aging (PA) of 30, with PA 2014 5340 18 18 (100) 3.37 Undetermined 43 (74) TOTAL 26,714 75 58 (77.33) range of 23 to 40. Majority were delivered by cesarean TOTAL 58

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For this study, the probable causes of HF were classified by fetal 2D-echocardiography. In a previous retrospective as infectious, hematologic, placental abnormality, cardiac, study, congenital heart disease and cardiac arrhythmias and congenital tumor. Cause of hydrops fetalis was were the most common causes of hydrops fetalis.6 Structural undetermined for majority of the cases. Only 14 (24%) cardiac anomalies lead to high right atrial pressure or women were screened for intrauterine infections. However, volume overload and right-sided heart congestion. This in most were only screened for syphilis and TORCH turn leads to increased central venous pressure and heart (Toxoplasma, Rubella, Cytomegalovirus, Herpes) infection. failure; or obstruction of venous and arterial blood flow Hemoglobin electrophoresis was only done in two of the 15 which would lead to edema.3,5 patients presenting with microcytic, hypochromic anemia on Complete blood count (CBC) is a basic laboratory work- CBC. Fetal cardiac anomalies were identified by fetal 2D- up noted in the cases reviewed. Microcytic, hypochromic echocardiography. The case of cervical teratoma was anemia is commonly seen in alpha-thalassemia. In our identified by fetal Congenital Anomaly Scan (CAS). study, 15 mothers presented with microcytic, hypochromic There were 4 cases of multiple congenital anomalies anemia. Alpha thalassemia is frequent in Mediterranean and (MCA) identified by CAS (Table 4). Two were cases of Southeast Asian countries, which includes the Philippines.10 skeletal dysplasias while one is a possible case of Trisomy It is important to also screen the partners of women 21. However, chromosomal analysis results and other suspected to have alpha thalassemia. In this study, paternal investigations were not documented for these cases. CBC was not documented in the charts reviewed. Deletion of the four alpha-globin chains would result Discussion into Hb Bart’s hydrops fetalis syndrome, the fatal form of Hydrops fetalis can be categorized as isoimmune and the alpha thalassemia syndromes.9-11 The deletion of all the non-isoimmune. Coombs test can be done to differentiate alpha-genes is inherited from both parents; with both between isoimmune and non-isoimmune HF.18 It is an parents having alpha thalassemia. The absence of the four- important initial tool in directing the work-up for HF. In this globin chains would result into anemia and hypoxia. There study, Coombs test was only done for 16 (27%) cases. For the would then be an increase in cardiac output which will 16 cases, the probable cause of HF is non-isoimmune since progress to cardiac failure. Increased central venous all were negative for both direct and indirect Coombs. pressure would result from cardiac failure; this would then Neonatal demographics of the study show that result to increase in interstitial fluid and decreased lymph neonates were delivered preterm (median PA 30) with a flow. The accumulation of interstitial fluid would explain median APGAR score at one minute of two (2) and four (4) the presence of edema in hydrops fetalis.3,5 at five minutes. In a previous study by Abrams et al.,6 Aside from microcytosis, carriers are detected on the infants who died were more likely to be premature and basis of normal serum ferritin. A clinical practice guidelines sicker (i.e. lower 5-minute APGAR scores). In the same in the management of non-immune hydrops fetalis study, patients discharged had a median PA of 34 and recommends a routine hemoglobin electrophoresis screening APGAR score of >3 in the 1st and 5th minute. In this study, in ethnicities with high frequencies of alpha thalassemia.19 In the relatively low pediatric aging and APGAR scores may a previous study done in another Southeast Asian country, be attributed to lack of prenatal work-ups done for both the Thailand, 36.58% of the cases of HF were due to Hb Bart’s mother and the fetus. There was no available data on the hydrops fetalis.20 In another study done in Singapore, HF number of prenatal consults that the mothers had. As a secondary to homozygous alpha-thalassemia is relatively tertiary referral center, PGH receives imminent deliveries low at 7% due to antenatal thalassemia screening.7 In the from other institutions. study by Fucharoen and Winichagon in 2007, wherein the Ideally, confirmatory tests are done upon the antenatal prevention and control of thalassemia were discussed, it was diagnosis of hydrops fetalis by ultrasound. This include identified that prenatal diagnosis and genetic counselling are congenital anomaly scan, fetal echocardiography and done ideally for high-risk couples.21 Doppler studies. Further investigation is done to the mother Hydrops fetalis secondary to intrauterine infections and fetus. Maternal diagnostic work-ups include CBC, blood (IUI) were also observed in the reviewed cases. Work-ups group and antibodies, hemoglobin electrophoresis, TORCH were done for the TORCHES (Toxoplasma, Rubella, screen, VDRL, autoantibody screen for cases of congenital Cytomegalovirus, Herpes, Syphilis) infection. Test for heart blocks and oral glucose test. Additional fetal work up Parvovirus B19 and varicella should also be included in the includes fetal blood sampling. Prenatally, amniotic fluid work-up for hydrops fetalis.19 Intrauterine infections affect sampling, fetal karyotyping and genetic microarray testing the fetal liver, which is the site of erythrocyte production are also done. Autopsy is recommended for all neonatal and during early development.19,22 This then leads to fetal fetal deaths.18,19 anemia, which would increase cardiac output. This results Five percent of the reviewed cases had cardiac into congestive heart failure and increased central venous anomalies. In this study, cardiac anomalies were identified pressure.5

184 ACTA MEDICA PHILIPPINA VOL. 51 NO. 3 2017 Etiology Hydrops Fetalis at the PGH Etiology Hydrops Fetalis at the PGH

For this study, the probable causes of HF were classified by fetal 2D-echocardiography. In a previous retrospective There were four identified cases of hydrops fetalis with complete search of its etiology. An ongoing study in PGH as infectious, hematologic, placental abnormality, cardiac, study, congenital heart disease and cardiac arrhythmias concomitant congenital anomalies. One is a suspected case of investigates the etiology of hydrops fetalis, prospectively. In and congenital tumor. Cause of hydrops fetalis was were the most common causes of hydrops fetalis.6 Structural Trisomy 21 while two were cases of skeletal dysplasias. the case of the Philippines where alpha-thalassemia is more undetermined for majority of the cases. Only 14 (24%) cardiac anomalies lead to high right atrial pressure or Skeletal dysplasias involve deformation of the thoracic frequent, prenatal screening and genetic counseling should women were screened for intrauterine infections. However, volume overload and right-sided heart congestion. This in skeleton; causing constriction of the thoracic viscera.3 In the be done. The results of this study, along with a more most were only screened for syphilis and TORCH turn leads to increased central venous pressure and heart study done by Abrams et al. in 2007, mortality rates for HF extensive prospective study, can be used to draft health (Toxoplasma, Rubella, Cytomegalovirus, Herpes) infection. failure; or obstruction of venous and arterial blood flow were highest among neonates with associated congenital policies regarding prenatal screening of genetic disorders. Hemoglobin electrophoresis was only done in two of the 15 which would lead to edema.3,5 anomalies.6 For the patient with multiple congenital ______patients presenting with microcytic, hypochromic anemia on Complete blood count (CBC) is a basic laboratory work- anomalies, hydrops fetalis may be secondary to a cardiac CBC. Fetal cardiac anomalies were identified by fetal 2D- up noted in the cases reviewed. Microcytic, hypochromic anomaly presenting as fetal cardiomegaly. Statement of Authorship echocardiography. The case of cervical teratoma was anemia is commonly seen in alpha-thalassemia. In our The results of this retrospective study show the All authors have approved the final version submitted. identified by fetal Congenital Anomaly Scan (CAS). study, 15 mothers presented with microcytic, hypochromic importance of knowing the etiology of hydrops fetalis. The ______There were 4 cases of multiple congenital anomalies anemia. Alpha thalassemia is frequent in Mediterranean and findings can be used to counsel pregnant women about the (MCA) identified by CAS (Table 4). Two were cases of Southeast Asian countries, which includes the Philippines.10 investigation, the prognosis of the disease, as well as the Author Disclosure skeletal dysplasias while one is a possible case of Trisomy It is important to also screen the partners of women optimal modalities for management.20 Genetic counseling is All the authors declared no conflicts of interest. 21. However, chromosomal analysis results and other suspected to have alpha thalassemia. In this study, paternal particularly important for cases of hydrops fetalis that are 21 ______investigations were not documented for these cases. CBC was not documented in the charts reviewed. hereditary; such as alpha thalassemia. If diagnosed Deletion of the four alpha-globin chains would result prenatally, in-utero interventional measures may be done Funding Source Discussion into Hb Bart’s hydrops fetalis syndrome, the fatal form of depending on the etiology of hydrops fetalis: fetal None. Hydrops fetalis can be categorized as isoimmune and the alpha thalassemia syndromes.9-11 The deletion of all the intravascular transfusion for fetal anemia, direct fetal drug non-isoimmune. Coombs test can be done to differentiate alpha-genes is inherited from both parents; with both therapy for fetal arrhythmia and pleuro-amniotic shunt for ______

18 18 between isoimmune and non-isoimmune HF. It is an parents having alpha thalassemia. The absence of the four- pleural effusion. References important initial tool in directing the work-up for HF. In this globin chains would result into anemia and hypoxia. There As a retrospective study, this paper has many 1. Maheshwari A,Carlo WA. Hemolytic Disease of the Newborn. In: study, Coombs test was only done for 16 (27%) cases. For the would then be an increase in cardiac output which will limitations. Data available in the charts may be incomplete. Kliegman RM, Stanton BF, St Geme III JW, et al., eds. Nelson Textbook 16 cases, the probable cause of HF is non-isoimmune since progress to cardiac failure. Increased central venous Not all charts were available for review. The Sections of of Pediatrics, 20th ed. Philadelphia: Elsevier Saunders; 2016. pp. 883-887. 2. Chen JY. Etiology and outcome of Hydrops Fetalis. Pediatr Neonatol. all were negative for both direct and indirect Coombs. pressure would result from cardiac failure; this would then Neonatology and Perinatology do not have duplicate copies 2014; 55(2):77. Neonatal demographics of the study show that result to increase in interstitial fluid and decreased lymph of the medical charts of HF cases. Currently, there is no 3. Bellini C, Hennekam RC, Fulcheri E, et al. Etiology of nonimmune neonates were delivered preterm (median PA 30) with a flow. The accumulation of interstitial fluid would explain available database for HF cases in PGH. Information on hydrops fetalis: A systematic review. Am J Med Genet A. 2009; median APGAR score at one minute of two (2) and four (4) the presence of edema in hydrops fetalis.3,5 severity of prenatal presentation and intervention were also 149A(5):844-51. 4. Yurdakok M. Non-immune hydrops fetalis. J Pediatr Neonat Individual 6 at five minutes. In a previous study by Abrams et al., Aside from microcytosis, carriers are detected on the not available. These would had been important in Med. 2014; 3(2): e030214. infants who died were more likely to be premature and basis of normal serum ferritin. A clinical practice guidelines determining the previous work-ups done for HF. 5. Bellini C, Hennekam RC. Non-immune Hydrops Fetalis: a short review sicker (i.e. lower 5-minute APGAR scores). In the same in the management of non-immune hydrops fetalis of etiology and pathophysiology. Am J Med Genet A. 2012; 158A(3):597- 605. study, patients discharged had a median PA of 34 and recommends a routine hemoglobin electrophoresis screening Conclusion 6. Abrams ME, Meredith KS, Kinnard P, Clark RH. Hydrops Fetalis: a APGAR score of >3 in the 1st and 5th minute. In this study, in ethnicities with high frequencies of alpha thalassemia.19 In It is important to determine the etiology of HF to retrospective review of cases to a large national database and the relatively low pediatric aging and APGAR scores may a previous study done in another Southeast Asian country, explain its overlying pathophysiology. In this study, identification of risk factors associated with death. Pediatrics. 2007; be attributed to lack of prenatal work-ups done for both the Thailand, 36.58% of the cases of HF were due to Hb Bart’s majority of the cause of HF is undetermined. Majority 120(1):84-9. 7. Ng ZM, Seet MJ, Erng MN, Buendia F, Chang AS, Sriram B. 20 mother and the fetus. There was no available data on the hydrops fetalis. In another study done in Singapore, HF (93.75%) of those born alive died in the immediate neonatal Nonimmune hydrops fetalis in a children’s hospital: a six-year series. number of prenatal consults that the mothers had. As a secondary to homozygous alpha-thalassemia is relatively period. Knowing the etiology of this condition would aid in Singapore Med J. 2013; 54(9):487-90. tertiary referral center, PGH receives imminent deliveries low at 7% due to antenatal thalassemia screening.7 In the treatment planning and appropriate parental genetic 8. Chui DH, Waye JS. Hydrops fetalis caused by α Thalassemia: an emerging health care problem. Blood. 1998; 91(7):2213-22. from other institutions. study by Fucharoen and Winichagon in 2007, wherein the counseling. Furthermore, knowing the common causes of 9. Lorey F, Charoenkwan P, Witkowska E, et al. Hb H hydrops foetalis Ideally, confirmatory tests are done upon the antenatal prevention and control of thalassemia were discussed, it was HF in our population would also aid in designing the syndrome: a case report and review of literature. Br J Haematol. 2001; diagnosis of hydrops fetalis by ultrasound. This include identified that prenatal diagnosis and genetic counselling are appropriate framework for the work-up of cases of hydrops 115(1):72-8. 10. Harteveld CL, Higgs DR. Alpha thalassemia. Orphanet J Rare Dis. 2010; congenital anomaly scan, fetal echocardiography and done ideally for high-risk couples.21 fetalis. For suspected hereditary causes of hydrops fetalis, 5:13. Doppler studies. Further investigation is done to the mother Hydrops fetalis secondary to intrauterine infections such as alpha thalassemia, paternal work-ups should also be 11. Singer ST. Variable clinical phenotypes of α-Thalassemia Syndromes. and fetus. Maternal diagnostic work-ups include CBC, blood (IUI) were also observed in the reviewed cases. Work-ups done to support the diagnosis. Scientific World Journal. 2009; 9:615-25. group and antibodies, hemoglobin electrophoresis, TORCH were done for the TORCHES (Toxoplasma, Rubella, 12. Gamutan KGC, F Lucero-Tan. Non-immune hydrops fetalis: A review of 5 years’ experience (Abstract). Philipp Scient J. 2003; 36(1):15-24. screen, VDRL, autoantibody screen for cases of congenital Cytomegalovirus, Herpes, Syphilis) infection. Test for Recommendations 13. Padilla CD, Cutiongco EM, Sia JM. Birth Defects ascertainment in the heart blocks and oral glucose test. Additional fetal work up Parvovirus B19 and varicella should also be included in the A local database of hydrops fetalis is recommended for Philippines. Southeast Asian J Trop Med Public Health. 2003; 34 Suppl includes fetal blood sampling. Prenatally, amniotic fluid work-up for hydrops fetalis.19 Intrauterine infections affect cases to be properly documented. Further studies are also 3:239-43. sampling, fetal karyotyping and genetic microarray testing the fetal liver, which is the site of erythrocyte production recommended to look into the etiologic factors of hydrops 14. Abarquez CG, Alcausin MMB, David-Padilla C, Cutiongco-Dela Paz EM. A five-year review of cases referred to the Genetics Clinic, PGH for 19,22 are also done. Autopsy is recommended for all neonatal and during early development. This then leads to fetal fetalis. In a low-resources setting, it is important for findings of congenital anomalies on prenatal ultrasound. Acta Med fetal deaths.18,19 anemia, which would increase cardiac output. This results laboratory work-ups to be directed, depending on the Philipp. 2009; 43(1):22-8. Five percent of the reviewed cases had cardiac into congestive heart failure and increased central venous etiology of hydrops fetalis. A local systematic guideline for 15. Liu CA, Huang HC, Chou YY. Retrospective analysis of 17 liveborn neonates with Hydrops Fetalis. Chang Gung Med J. 2002; 25(12):826-31. anomalies. In this study, cardiac anomalies were identified pressure.5 the work-up of hydrops fetalis is recommended to ensure a

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16. Department of Health. The 2012 Philippine Health Statistics [Online]. 20. Ratanasiri T, Komwilaisak R, Sittivech A, Kleebkeaw P, Seejorn K. 2012 [cited 2016 Sep]. Available from http://www.doh.gov.ph/sites/ Incidence, causes and pregnancy outcomes of Hydrops Fetalis at default/files/publications/PHS2012.pdf. Srinagarind Hospital, 1996-2005: A 10-year review. J Med Assoc Thai. 17. David-Padilla C, Dela Paz EMC. Genetic services and testing in the 2009; 92(5):594-9. Philippines. J Community Genet. 2013; 4(3):399-411. 21. Fucharoen S, Winichagoon P. Prevention and control of thalassemia in 18. Anandakumar C, Biswas A, Wong YC, et al. Management of non- Asia. Asian Biomedicine. 2007; 1 (1):1-6. immune hydrops: 8 years’ experience. Ultrasound Obstet Gynecol. 1996; 22. Figueiredo CA, de Oliveira MI, Afonso AMS, et al. Detection of human 8(3):196-200. Parvovirus B19 in cases of hydrops fetalis in Sao Paulo, Brazil. J Bras 19. Desilets V, Audibert F, Society of Obstetricians and Gynecologists of Patol Med Lab. 2008; 44(6):423-7. Canada. Investigation and Management of Non-immune Fetal Hydrops. J Obstet Gynaecol Can. 2013; 35(10):923-38.

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