Hemolytic disease of fetus and newborn course, management and outcomes - an analysis based on the Israeli Maccabi database

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The main objective of this study is to understand the clinical impact of HDFN on pregnant women and newborns. Study Design : A retrospective cohort study was performed on de-identified data extracted from a large nationwide health organization. The cohort included women and newborns diagnosed with HDFN between 1998-2021. Cohort characteristics and outcomes are described. Result : Over the 24-year study period, incidence rate of HDFN among pregnant women was stable while incidence rate among newborns declined. Severe HDFN was diagnosed in 28.8% of 73 HDFN affected pregnancies. One third of 450 HDFN newborns were diagnosed with anemia or jaundice; 5 cases of kernicterus were observed. Conclusion : Severe prenatal and postnatal outcomes following HDFN were observed. Further studies are needed to evaluate treatment regimens and assess the association between treatment management and short- and long-term outcomes. Figures Figure 1 Figure 2 Introduction Hemolytic disease of the fetus and newborn (HDFN) occurs during pregnancy when the maternal alloantibodies of the IgG class cross the placenta and bind to fetal red blood cells (RBC) possessing the corresponding antigen, thereby causing RBC destruction and anemia in the fetus or newborn 1 . The clinical presentation of HDFN ranges from mild anemia to severe cases of anemia leading to fetal demise, hydrops, pre-term labor induction or the need for intrauterine transfusion (IUT) 1 , 2 . The epidemiology of HDFN is poorly characterized in medical literature. The global HDFN incidence has been estimated as 27.6 per 10,000 live births; in developed nations, this reduces to 2.5 per 10,000 live births attributed to higher quality perinatal-neonatal care 3 . Similarly, in the United States, there are an estimated 0.3-8 HDFN cases per 10,000 live births per year 4 . There is no approved drug therapy for the treatment of HDFN. The standard of care for pregnancies at risk of severe fetal anemia includes monitoring of middle cerebral artery peak systolic velocity (MCA-PSV) by Doppler ultrasound to detect fetal anemia followed by IUTs once fetal anemia is confirmed by cordocentesis. Intravenous immunoglobulin G (IVIg) or plasmapheresis can be administered in selected pregnancies to delay the onset of fetal anemia and the need for IUT. 5 Neonatal complications of HDFN include severe hyperbilirubinemia, neonatal jaundice, kernicterus, thrombocytopenia, iron overload and cholestasis 6 , 7 . Close monitoring for abnormal laboratory results in neonates is recommended in order to diagnose late anemia and other complications. 8 Long-term consequences of kernicterus may lead to further disorders such as auditory dysfunction and development disorders 9 . The main objective of this study is to better understand the clinical impact of non-ABO HDFN on pregnant women, fetuses and newborns. Secondary objectives include the evaluation of incidence and trends of HDFN in Israel, the frequency and outcomes of severe HDFN, as well as treatment patterns and complications of HDFN among pregnant women, fetuses and newborns. Methods Data sources and extraction De-identified data captured between January 1998 and December 2021 were extracted from the Maccabi Healthcare Services (MHS) database. MHS is a nationwide health plan (payer-provider) representing over a quarter of the population in Israel. The MHS database contains longitudinal data on a stable population of > 2.6 million people since 1993 (with < 1%/year disengagement rate). Data are automatically collected and include comprehensive laboratory data from a single central lab, full pharmacy prescription and purchase data, and extensive demographic data on each patient. MHS uses the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) coding systems as well as MHS-developed coding systems to provide more granular diagnostic information beyond the ICD codes. Medications are coded according to the Israeli coding system with translations to ATC coding system wherever available. Procedures are coded using Current Procedural Terminology (CPT) codes. Socioeconomic status (SES) is described by a 1–10 scale (higher rank represents higher socioeconomic status) based on residence place (at the neighborhood level) 10 , 11 . It was originally derived by the Israel Central Bureau of Statistics using the national census and augmented by POINTS location profiling Ltd using aggregated data. Details on delivery/birth were extracted from hospitalization discharge letters. Treatments exclusively given in the hospital setting were not fully captured in the MHS database. Descriptions of HDFN complications diagnosis codes are detailed in Supplementary Table 1. Study population HDFN is diagnosed by identifying the presence of maternal RBC antibodies. However, since alloantibody data was available in the MHS database only from 2005, any subject with an HDFN diagnosis recorded in the MHS database was included in the study, independent of an alloantibody test result. The main study cohorts included subjects identified through an antenatal or postnatal non-ABO HDFN diagnosis code within the study period 1998–2021. ICD-9 diagnoses codes are described in Supplementary Table 2. The alloantibody-confirmed cohorts included subgroups of subjects from the main cohorts for whom the HDFN diagnosis was confirmed with a maternal positive alloantibody test result. Main study cohorts Women with a HDFN diagnosis during pregnancy were included in the pregnancy cohort. Women with multiple pregnancies could repeatedly be included in this cohort, once for each HDFN pregnancy. The newborn cohort included offspring from these respective pregnancies as well as children with an HDFN diagnosis during their first year of life. Severe HDFN was defined as the occurrence of at least one of the following during pregnancy: IUT, fetal hydrops, pre-term labor induction or intrauterine death 1 . HDFN diagnosis at 24 weeks of gestation or later was defined as late onset HDFN. Alloantibody-confirmed cohort Sensitivity analyses were conducted on subgroups of the pregnancy and newborn cohorts for whom the HDFN diagnosis was confirmed with a maternal positive alloantibody test result. Women with an HDFN diagnosis during pregnancy and an antibody titter ≥ 1:8, during or before the current pregnancy, were included in the alloantibody-confirmed pregnancy cohort. Children born from those respective pregnancies were included in the alloantibody-confirmed newborn cohort, as were children with an HDFN diagnosis during their first year of life whose mothers had an antibody titter ≥ 1:8 before or up to 1 month after the respective child's birth. Statistical analysis HDFN incidence rates were calculated from the total number of diagnosed MHS members, divided by the corresponding total number of MHS members (pregnant women or newborns). Poisson regressions were used to assess incidence trends over time. Descriptive statistics are presented as mean and standard deviation (SD) for continuous variables and as frequencies and percentage for categorical variables. Statistical analyses were performed using SAS version 9.4. A p-value of < 0.05 was considered statistically significant (two-sided hypotheses). Results Incidence of HDFN during pregnancy was stable in Israel at an incidence rate ranging between 0.4-1 per 10,000 pregnancies during most of the study period. The incidence of HDFN diagnosed in newborns is higher compared to the incidence of HDFN diagnosed during pregnancy and has declined from 1.8 (95% CI 0.9–3.4) in 1998 to 1.1 (95% CI 0.4–2.5) in 2021 per 10,000 newborns (p < 0.001, Fig. 1 ). A total of 76 pregnancies with an HDFN diagnosis were identified in 70 women, 73 (96%) of them with medical information regarding their pregnancy course and outcome. Alloantibodies were confirmed in 27 women during or before 28 pregnancies, representing 38.4% of all HDFN pregnancies (Fig. 2 ). During the same 24-year study period, 395 additional newborns, who had not been identified during pregnancy because their mothers were not diagnosed during pregnancy (72%) or because their mothers were not included in the MHS database, were diagnosed postnatally with HDFN. Out of the 57 newborns born to HDFN diagnosed mothers, 55 were found in the MHS database and added to the HDFN newborn cohort. Therefore, in total, 450 HDFN newborns were identified and confirmed to have HDFN during their first year of life. Of the 450 HDFN newborns, 66 (14.7%) were confirmed to have HDFN during their first year of life based om maternal alloimmunization (Fig. 2 ). Pregnancy and prenatal outcomes of HDFN The average maternal age of 73 women diagnosed with HDFN at the time of diagnosis was 31.4+-5.8 years old. Frequency of comorbidities were low and included diabetes (2.7%), cardiovascular disease (4.1%) and hypertension (6.8%). The majority (54.8%) of women had never smoked. (Supplementary Table 3). The average gravidity at which HDFN was diagnosed among the 73 pregnancies was 3.4 +- 1.8, diagnosis tended to occur during the fourth pregnancy (41.1%). HDFN was diagnosed at an average of 23.4 +- 9.3 weeks of gestation. Late onset (diagnosed after 24 weeks of gestation) HDFN was diagnosed in 38 (52.1%) pregnancies. Three pregnancies were treated with IVIg; two required at least one IUT following IVIg. Twelve additional pregnancies not treated with IVIg required at least one IUT. Hydrops was diagnosed in 8 pregnancies (Table 1 ). Of the 73 pregnancies with a diagnosis of HDFN, 22 were severe i.e., 14 were treated by intrauterine transfusion, 8 were diagnosed with fetal hydrops, 6 were induced pre-term and 1 resulted in an intrauterine death. The average gestational age (GA) of severe HDFN diagnosis was 24.5 +- 8.0 weeks (Table 1 ). The majority of cases of severe HDFN in pregnancy required at least one IUT (14, 63.6%). Table 1 Pregnancy characteristics and outcomes of prenatal diagnosed HDFN Mean +- SD/ N (%) Pregnancy cohort Alloantibody confirmed pregnancy cohort Parameter Procedure/ Total N=73 Severe N=22 Total N=28 Severe N=11 Category Pregnancy Characteristics GA at HDFN diagnosis 23.4 +- 9.3 24.5 +-8.0 23.9 +-9.5 24.5 +-6.6 Gravidity 3.4 +-1.8 4.1 +-1.9 4.1 +-1.5 4.7 +-1.6 Pregnancy number category at diagnosis 1 12 (16.4) 2 (9.1) 1 (3.6) 0 2 9 (12.3) 2 (9.1) 1 (3.6) 0 3 12 (16.4) 2 (9.1) 8 (28.6) 2 (18.2) 4+ 30 (41.1) 12 (54.5) 17 (60.7) 9 (81.8) Unknown 10 (13.7) 4 (18.2) 1 (9.1) 0 Twins 2 (2.7) 0 0 0 Late onset HDFN at 24 GA or later 38 (52.1) 12 (54.5) 17 (60.7) 6 (54.5) Any IVIg 3 (4.1) 2 (9.1) 2 (7.1) 2 (18.2) Any Intrauterine transfusion 14 (19.2) 14 (63.6) 9 (32.1) 9 (81.8) Hydrops 8 (11.0) 8 (36.4) 2 (7.1) 2 (18.2) Pregnancy Outcomes Outcome Live Birth 57 (78.1) 16 (72.7) 24 (85.7) 9 (81.8) Miscarriage 9 (12.3) 6 (27.3) 3 (10.7) 2 (18.2) Unknown 7 (9.6) 0 1 (3.6) 0 GA at delivery 37.6 +-3.1 34.9 +- 3.2 36.2 +-2.8 34.9 +-2.9 GA at miscarriage 18.2 +- 7.0 19.9 +- 6.9 13.9 +-9.6 20.7* Birthweight (g) 2964.2 +- 710.9 2464.8 +- 560.5 2750.9 +-687.5 2702.3 +-747.8 Type of miscarriage IUFD 1 (11.1) 1 (16.7) 0 0 Spontaneous 2 (22.2) 0 1 (33.3) 0 Induced 6 (66.7) 5 (83.3) 2 (66.7) 2 (100.0) Induced preterm labor 6 (31.6) 6 (46.2) 5 (33.3) 5 (71.4) Preterm labor 19 (33.3) 13 (81.3) 15 (62.5) 7 (77.8) Preterm Category Extreme preterm (<28 GA) 0 0 0 0 Very preterm (28-31+6 GA) 3 (15.8) 3 (23.1) 2 (13.3) 2 (28.6) Moderate preterm (32-33+6 GA) 3 (15.8) 1 (7.7) 2 (13.3) 0 Late preterm (34-36+6 GA) 13 (68.4) 9 (69.2) 11 (73.3) 5 (71.4) GA - gestational age; late onset defined as onset after 24 weeks of gestation Among the subgroup of 28 pregnancies in the alloantibody confirmed cohort (N = 28), the average gravidity at which a woman was diagnosed with HDFN was 4.1+-1.5 and the majority (60.7%) were late onset HDFN. Eleven of these pregnancies were severe. A total of 9 pregnancies (32.1%) required at least one IUT. Two of the pregnancies were administered IVIg and both did require at least one IUT. Hydrops was diagnosed in two pregnancies. No cases of intrauterine death were reported. Among the 73 pregnancies with HDFN, 57 (78.1%) resulted in live births, 9 in miscarriages and 7 had unknown outcomes. Of the 57 live births, 19 (33%) were preterm of which 6 were induced. The majority of these were late preterm (68.4%). Overall, the average birthweight was 2964.2+-710.9 grams (Table 1 ). Miscarriages included 1 intrauterine death at 28 gestational age (GA), 6 induced terminations of pregnancy at 15.8 GA (± 7.2) on average and 2 spontaneous miscarriages at 19.4 GA (± 3.7). Pregnancy outcomes in 22 severe HDFN pregnancies included 16 (72.7%) live births; 13 (81.3%) of these were preterm. Of the preterm births, 3 were very preterm between 28–32 weeks of gestation, 1 moderate preterm between 32–34 weeks of gestation and 9 late preterm between 34–37 weeks of gestation. Of the remaining six cases of severe HDFN, there were 5 induced miscarriages and 1 intrauterine fetal death (IUFD). Out of the 7 preterm deliveries among the severe HDFN alloantibody confirmed pregnancies, 5 were induced labors. Characteristics and outcomes of early and late onset HDFN pregnancies are presented in Supplementary Tables 4 and 5. Among the subgroup of 28 alloantibody confirmed pregnancies, 24 (85.7%) resulted in live births, 2 induced abortions (1 at 20.7 GA and 1 at unknown GA), 1 spontaneous miscarriage at 7.1 GA and 1 unknown outcome. Of the 24 live births, 15 (62.5%) occurred preterm, most of which were late preterm (73.3%), and average birthweight was 2750.9 +-687.5 grams (Table 1 ). The pregnancy cohort included 3 women each with 2 HDFN pregnancies in the study period. Pregnancy characteristics and outcomes for both pregnancies are presented in Supplementary Table 6. One woman delivered in both pregnancies, one woman delivered in the first pregnancy and had an induced miscarriage in the second pregnancy and one woman spontaneously miscarried in the first pregnancy and delivered very preterm in the second. There were no cases of hydrops or IUFD. Postnatal outcomes of HDFN newborns The median age at diagnosis of the 395 newborns diagnosed only postnatally was 2.7 weeks (IQR 0.7–5.7). The majority (58.2%) of all 450 HDFN newborns, including 55 born from HDFN pregnancies, were male. Anemia and jaundice were the most common complications of HDFN during the first year of life. Both complications were diagnosed in over 30% of the full newborn cohort. Twelve percent of the newborn cohort (n = 54) had developmental disorders. Other complications included edema (5.1%), auditory dysfunction (3.3%), blood disorders (2.7%) and kernicterus (1.1%) as depicted in Table 2 . Anemia was diagnosed in 63.6% and jaundice in 19.7% of the subgroup of the alloantibody confirmed newborn cohort; kernicterus was observed in 4 newborns (6.1%), edema in 4.5% and development disorders in 3.0%. Almost one third of alloantibody confirmed newborns underwent blood transfusions (31.8%) and 10.6% underwent phototherapy. Table 2 Complications reported in newborns diagnosed postnatally with HDFN Complication Newborn cohort N = 450 Alloantibody confirmed newborn cohort N = 66 N (%) Age at diagnosis (months)/ Mean +- SD N (%) Age at diagnosis (months)/ Mean +- SD Anemia 158 (35.1) 1.9 +-2.4 42 (63.6) 1.6 +-2.2 Auditory Dysfunction/Deafness 15 (3.3) 3.8 +-3.5 0 NA Development Disorder 54 (12.0) 6.5 +-3.3 2 (3.0) 3.6+-0.9 Edema 23 (5.1) 6.8 +-2.9 3 (4.5) 9.1 +-0.9 Jaundice 154 (34.2) 0.8 +-1.4 18 (27.3) 0.6 +-0.5 Kernicterus 5 (1.1) 0.2 +-0.1 4 (6.1) 0.3 +-0.1 Movement Disorder 1 (0.2) 7.3 0 NA Oculomotor Impairments 4 (0.9) 5.9 +-4.1 0 NA Blood Disorder (acidosis, calcemia) 12 (2.7) 1.9 +-2.0 0 NA Other Blood Disorder (transient neonatal neutropenia) 13 (2.9) 3.4 +-3.8 1 0.2 Of the 450 newborns, 29% and 37% of newborns had complete blood count (CBC) results between 2–3 months of age and 10–12 months of age, respectively. Among the alloantibody confirmed newborns, CBC results were available for 40% of newborns up to 1 month old as well as in 10–12 month olds. Laboratory test results were comparable between the full newborn cohort and the alloantibody confirmed cohort (Supplementary tables 7,8). Mean hemoglobin and hematocrit values were low during the first 3 months of life; however, the mean values rose to normal levels by the age of one year (Supplementary Fig. 1). Discussion This is the largest study to investigate the epidemiology and outcomes of HDFN in Israel. Based on MHS data, prenatal HDFN diagnosis is stable in Israel while postnatal HDFN diagnosis has declined from 1.8 per 10,000 to 1.1 per 10,000 newborns since 1998, respectively. These results present lower incidence compared to a Canadian single center study 12 from 2010–2017, that showed an incidence rate of 6 per 10,000 newborns diagnosed with HDFN and a national US study 13 from 1996–2010 that found an incidence rate of 4 to 10 per 10,000 newborns. The US study also reported a decline in HDFN incidence due to reduced alloimmunization rates over time. HDFN pregnancies During the study period, 76 women were diagnosed with HDFN during pregnancy, compared to 395 newborns diagnosed during their first year of life. This result may indicate the lack of screening and surveillance in pregnancies at risk. Timely perinatal diagnosis of HDFN is important to initiate optimal management and thus prevent hydrops fetalis or fetal death 14 . The ‘Postponing Early intrauterine Transfusion with Intravenous immunoglobulin Treatment’ (PETIT) study showed that if IVIg was initiated before 13 weeks of gestation, fetal anemia was delayed and anemia prior to 20 weeks gestation occurred less often 15 . The lower rate of prenatal compared to postnatal diagnosis of HDFN may explain the rates of severe cases found in this study. More than one quarter (28.8%) of all HDFN pregnancies and nearly 40% of alloantibody confirmed pregnancies were severe cases. Hydrops occurred in 7.1% of alloantibody confirmed cases, comparable to 7.3% reported in a recent systematic review 16 . IVIg was administered to 7.1% of alloantibody confirmed cases, both of whom required at least one IUT. Very preterm delivery, between 28–32 GA, occurred only in severe HDFN pregnancies, increasing the risk of neonatal complications 17 . Most miscarriages were induced during the first trimester which may indicate that the fetuses were in grave condition. A 10 year observational study from Finland 18 found 3.8% IUFD and 82% live births among women treated with IUTs for HDFN, comparable to the findings in this study. HDFN newborns One third of all newborns were diagnosed with anemia and/or jaundice at a mean age of less than 2 months and less than 1 month, respectively. The requirement for transfusion was much greater than that previously reported by Yu and colleagues 13 . This finding may indicate a more severe disease phenotype in this Israeli database, though the higher transfusion rate found may be associated with other factors such as differences in healthcare and reimbursement structures. While abnormally low values of hemoglobin and hematocrit were observed in the first months of HDFN newborns' lives, laboratory test results normalized for most newborns within one year. This observation was expected, as any residual maternal alloantibodies or residual effects of IUTs dissipate by the age of 1 year old. Kernicterus, a severe complication of hyperbilirubinemia, causing chronic neurologic impairments including hearing loss, visual abnormalities, abnormalities in dentition and involuntary movements, was reported in 5 (over 1%) newborns, 4 of whom were alloantibody confirmed HDFN cases. These complications occurred at rates higher than previously reported and similarly, indicating a more severe cohort of patients in this database 14 , 19 . Over 10% of newborns were reported as having a developmental disorder, however among the alloantibody confirmed HDFN cases the rate was reduced to 3%. Lindenburg and colleagues 19 previously reported moderate and severe developmental delay in 14.4% and 3.1% of a severe population of patients exposed to IUT, respectively. Given the lack of pre-natal data available for this newborn cohort (severity in pregnancy, incidence of hydrops etc.) it is difficult to decipher obvious factors for the high incidence observed in this study. However, the data do reiterate the importance of continued exploration of risk factors for developmental disorders to ensure early identification and implementation of prenatal interventions, which may improve short- and long-term outcomes. Measures that allow early detection of severe fetal anemia prior to development of fetal hydrops as well as medical interventions, that can postpone onset of severe fetal anemia, may prove to be beneficial in improving both neonatal and longer-term developmental outcomes. The main strength of this study is the longitudinal follow-up over a large database including a quarter of Israel's population for more than 20 years. This database includes extensive medical information recorded continually, including treatments, diagnoses, laboratory results and procedures for all members. In addition, Israel has a high birth rate 20 with a stable total fertility rate of 3 children per woman during the study period 21 . As risk of HDFN rises with each pregnancy 4 , the high birth rate allowed us to capture more HDFN cases as well as more severe cases than expected in countries with lower birth rates. Last, in this study we were able to conduct sensitivity analyses on alloantibody confirmed cases which validated the study findings. There are several limitations in this study. First, as this was a retrospective observational study, not all clinical and demographic information was fully captured in the database. Missing data included information needed to match pregnant women and child of the same pregnancy thus the study cohorts did not include all HDFN cases, and the approach included two initial sets of cohorts. Second, alloantibody test results were not included in the MHS database until 2005, therefore the inclusion of HDFN cases in the main cohort of this study was based on diagnoses captured in the database alone. Third, HDFN management and treatment given in an inpatient setting is not always reported back to MHS (a community-based organization), and therefore not captured in this database, therefore treatment may be underestimated in this report. Therefore, this study cannot show evidence of associations between HDFN management during pregnancy with perinatal outcomes. Further studies including larger cohorts of HDFN pregnancies are needed to assess fetal and newborn outcomes following specific treatment of HDFN. Conclusion Although diagnoses of HDFN cases in Israel have declined between 1998–2021, we observed severe outcomes with a diagnosis of HDFN including pregnancy termination, hydrops, pre-term labor, anemia, jaundice, and kernicterus. Routine maternal blood testing for alloantibodies at early gestation can enable early diagnosis and management of HDFN pregnancies which are at risk for the development of fetal anemia. Further studies are needed to understand and evaluate current treatment regimens for HDFN and assess the association between perinatal management and short- to long-term outcomes. Declarations Conflict of Interest Statement This study was funded by Janssen Pharmaceuticals. M.F., W.K., N.B., S.I., A.B. and W.M. are employees of Janssen Pharmaceuticals. The remaining authors declare no conflict of interest. The study was conducted according to the guidelines of the Declaration of Helsinki and approved by Maccabi’s Ethics Committee (approval #0021-22-MHS). As this non-interventional administrative study involves de-identified structured data, which according to applicable legal requirements does not contain data subject to privacy laws, obtaining informed consent from patients was waived by MHS IRB, as in accordance with the Declaration of Helsinki. Availability of Data and Materials The data that support the findings of this study are available from Kahn-Sagol-Maccabi Research and Innovation Institute but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of Kahn-Sagol-Maccabi Research and Innovation Institute. Please apply to Dr. Moshe Hoshen for further information. Upon request, and subject to review, the study Sponsor, Kahn-Sagol-Maccabi Research and Innovation Institute, will provide data that support the findings of this study. Subject to certain criteria, conditions and exceptions, Kahn-Sagol-Maccabi Research and Innovation Institute may also provide access to the related individual de-identified participant data. Contact Kahn-Sagol-Maccabi Research and Innovation Institute for more information. Funding: This study was sponsored by Kahn-Sagol-Maccabi Research and Innovation Institute and funded by Janssen Pharmaceuticals. Author Contributions: N.F., M.F., W.K., N.B., S.I., S.G., A.B. and W.M. have made substantial contributions to the conception and design of the work. M.H., Y.S., D.M. and Y.Y. contributed to the discussion and critical revision of the manuscript. All authors made substantial contributions in the acquisition, analysis, and interpretation of data, have drafted the work, and substantively revised it. References De Haas M, Thurik F, Koelewijn J, van der Schoot CE. Haemolytic disease of the fetus and newborn. Vox sanguinis . 2015;109(2):99-113. Bennardello F, Coluzzi S, Curciarello G, Todros T, Villa S. Recommendations for the prevention and treatment of haemolytic disease of the foetus and newborn. Blood Transfusion . 2015;13(1):109. Costumbrado J, Mansour T, Ghassemzadeh S. Rh incompatibility. StatPearls [Internet] . StatPearls Publishing; 2022. 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American journal of obstetrics and gynecology . 2012;206(2):141. e1-141. e8. Weinreb A, Chernichovsky D, Brill A. Israel’s exceptional fertility. Retrieved April . 2018;19:2020. statistics ICBo. Fertility of Jewish and Other Women in Israel, by Level of Religiosity 1979–2020. https://www.cbs.gov.il/en/publications/Pages/2022/Fertility-of-Jewish-and-Other-Women-in-Israel-by-Level-of-Religiosity-1979-2020.aspx Additional Declarations No competing interests reported. Supplementary Files Supplementary.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Fallach","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAuklEQVRIie2QsQrCMBCG06mLD9MpIoT0QVyuBNJFwQfoUKcsvoqr80FBl2AcC12aN3DsaCLuOTfBfMPdDf/HT8JYJvObFAhCxH1EsoOgdVT6LxSmh89BYV2aB87g5NkMoaUT26SyOdkDAkzqYpugXPW+TynVuANslklxDErRD0QF4K6482SlxaCg5CO5xdrwyaCAj6EFSG+5Ge8XkDV3rZ+fnUgrjK2qOJt3EtLxSDnHWdPCmUwm85e8ABIVUCKmtp1RAAAAAElFTkSuQmCC","orcid":"","institution":"Kahn-Sagol-Maccabi Research and Innovation Institute","correspondingAuthor":true,"prefix":"","firstName":"Noga","middleName":"","lastName":"Fallach","suffix":""},{"id":326607994,"identity":"42068f4b-7f4a-4d79-8c4e-cd362851efa0","order_by":1,"name":"Moshe Hoshen","email":"","orcid":"","institution":"Kahn-Sagol-Maccabi Research and Innovation Institute","correspondingAuthor":false,"prefix":"","firstName":"Moshe","middleName":"","lastName":"Hoshen","suffix":""},{"id":326607996,"identity":"ecbbca56-d999-44b3-8e80-874d7d40013b","order_by":2,"name":"Sivan Gazit","email":"","orcid":"","institution":"Kahn-Sagol-Maccabi Research and Innovation Institute","correspondingAuthor":false,"prefix":"","firstName":"Sivan","middleName":"","lastName":"Gazit","suffix":""},{"id":326607998,"identity":"ec4c4cbd-1e29-42a2-b3b5-b9242df10947","order_by":3,"name":"Yaakov Segal","email":"","orcid":"","institution":"Kahn-Sagol-Maccabi Research and Innovation Institute","correspondingAuthor":false,"prefix":"","firstName":"Yaakov","middleName":"","lastName":"Segal","suffix":""},{"id":326608001,"identity":"25d8e1bd-f5d7-4109-b9a9-9320a89b5463","order_by":4,"name":"Marie Fitzgibbon","email":"","orcid":"","institution":"Janssen Pharmaceuticals NV","correspondingAuthor":false,"prefix":"","firstName":"Marie","middleName":"","lastName":"Fitzgibbon","suffix":""},{"id":326608002,"identity":"172dedcd-19a1-451e-8992-0ad9780845dc","order_by":5,"name":"Wisam Karmous","email":"","orcid":"","institution":"Janssen Pharmaceuticals NV","correspondingAuthor":false,"prefix":"","firstName":"Wisam","middleName":"","lastName":"Karmous","suffix":""},{"id":326608003,"identity":"665c4aed-c420-49b1-80df-b3e4138c62c6","order_by":6,"name":"Norma Barthelmes","email":"","orcid":"","institution":"Janssen Pharmaceuticals NV","correspondingAuthor":false,"prefix":"","firstName":"Norma","middleName":"","lastName":"Barthelmes","suffix":""},{"id":326608007,"identity":"74c47a92-c198-4b8f-9b55-fb377a8c5539","order_by":7,"name":"Sofia Iqbal","email":"","orcid":"","institution":"Janssen Pharmaceuticals NV","correspondingAuthor":false,"prefix":"","firstName":"Sofia","middleName":"","lastName":"Iqbal","suffix":""},{"id":326608010,"identity":"b5d1c38e-d9bc-4779-b043-c23abb1e6ae4","order_by":8,"name":"Andras Borsi","email":"","orcid":"","institution":"Janssen Pharmaceuticals NV","correspondingAuthor":false,"prefix":"","firstName":"Andras","middleName":"","lastName":"Borsi","suffix":""},{"id":326608013,"identity":"78618d7f-1eb1-449f-b871-1cf2f4bda069","order_by":9,"name":"Wim Noel","email":"","orcid":"","institution":"Janssen Pharmaceuticals NV","correspondingAuthor":false,"prefix":"","firstName":"Wim","middleName":"","lastName":"Noel","suffix":""},{"id":326608019,"identity":"64ba944d-9f26-42de-8826-9f389a218746","order_by":10,"name":"Dror Mandel","email":"","orcid":"","institution":"Dana Dwek Children's Hospital, Neonatal Intensive Care Unit, Neonatalogy, Tel Aviv University","correspondingAuthor":false,"prefix":"","firstName":"Dror","middleName":"","lastName":"Mandel","suffix":""},{"id":326608022,"identity":"0723a8c8-cae8-40ab-9732-e367747407f6","order_by":11,"name":"Yoav Yinon","email":"","orcid":"","institution":"Sheba Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Yoav","middleName":"","lastName":"Yinon","suffix":""}],"badges":[],"createdAt":"2024-06-26 06:30:31","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4640361/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4640361/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":60711638,"identity":"7b4cdc33-1d2f-4feb-9c10-a63e60bc2da6","added_by":"auto","created_at":"2024-07-19 20:19:51","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":146704,"visible":true,"origin":"","legend":"\u003cp\u003eIncidence rate of HDFN diagnosis during pregnancy and in newborns\u003c/p\u003e\n\u003cp\u003eP-value of Poisson regression for trend over time\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4640361/v1/fd0ebc91a18b7d493ca8d216.png"},{"id":60712872,"identity":"bbabc41e-6508-4da4-af19-bfeca0291855","added_by":"auto","created_at":"2024-07-19 20:27:51","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":145982,"visible":true,"origin":"","legend":"\u003cp\u003eCohort description\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4640361/v1/04d988f437adc42bd635811f.png"},{"id":71310961,"identity":"ad3ca6b0-d503-4083-9ca4-bfada6f968dc","added_by":"auto","created_at":"2024-12-13 07:23:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":848978,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4640361/v1/1b91cd2a-7c09-4a5d-bcc0-9c83854fa34a.pdf"},{"id":60711640,"identity":"70fc4756-eafc-422e-8d06-94f4a8944679","added_by":"auto","created_at":"2024-07-19 20:19:51","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":116186,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary.docx","url":"https://assets-eu.researchsquare.com/files/rs-4640361/v1/cd1f865c86ddf754e1389bb2.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Hemolytic disease of fetus and newborn course, management and outcomes - an analysis based on the Israeli Maccabi database","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHemolytic disease of the fetus and newborn (HDFN) occurs during pregnancy when the maternal alloantibodies of the IgG class cross the placenta and bind to fetal red blood cells (RBC) possessing the corresponding antigen, thereby causing RBC destruction and anemia in the fetus or newborn\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. The clinical presentation of HDFN ranges from mild anemia to severe cases of anemia leading to fetal demise, hydrops, pre-term labor induction or the need for intrauterine transfusion (IUT)\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe epidemiology of HDFN is poorly characterized in medical literature. The global HDFN incidence has been estimated as 27.6 per 10,000 live births; in developed nations, this reduces to 2.5 per 10,000 live births attributed to higher quality perinatal-neonatal care\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Similarly, in the United States, there are an estimated 0.3-8 HDFN cases per 10,000 live births per year\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThere is no approved drug therapy for the treatment of HDFN. The standard of care for pregnancies at risk of severe fetal anemia includes monitoring of middle cerebral artery peak systolic velocity (MCA-PSV) by Doppler ultrasound to detect fetal anemia followed by IUTs once fetal anemia is confirmed by cordocentesis. Intravenous immunoglobulin G (IVIg) or plasmapheresis can be administered in selected pregnancies to delay the onset of fetal anemia and the need for IUT.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eNeonatal complications of HDFN include severe hyperbilirubinemia, neonatal jaundice, kernicterus, thrombocytopenia, iron overload and cholestasis\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Close monitoring for abnormal laboratory results in neonates is recommended in order to diagnose late anemia and other complications. \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Long-term consequences of kernicterus may lead to further disorders such as auditory dysfunction and development disorders\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe main objective of this study is to better understand the clinical impact of non-ABO HDFN on pregnant women, fetuses and newborns. Secondary objectives include the evaluation of incidence and trends of HDFN in Israel, the frequency and outcomes of severe HDFN, as well as treatment patterns and complications of HDFN among pregnant women, fetuses and newborns.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData sources and extraction\u003c/h2\u003e \u003cp\u003eDe-identified data captured between January 1998 and December 2021 were extracted from the Maccabi Healthcare Services (MHS) database. MHS is a nationwide health plan (payer-provider) representing over a quarter of the population in Israel. The MHS database contains longitudinal data on a stable population of \u0026gt;\u0026thinsp;2.6\u0026nbsp;million people since 1993 (with \u0026lt;\u0026thinsp;1%/year disengagement rate). Data are automatically collected and include comprehensive laboratory data from a single central lab, full pharmacy prescription and purchase data, and extensive demographic data on each patient. MHS uses the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) coding systems as well as MHS-developed coding systems to provide more granular diagnostic information beyond the ICD codes. Medications are coded according to the Israeli coding system with translations to ATC coding system wherever available. Procedures are coded using Current Procedural Terminology (CPT) codes. Socioeconomic status (SES) is described by a 1\u0026ndash;10 scale (higher rank represents higher socioeconomic status) based on residence place (at the neighborhood level)\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. It was originally derived by the Israel Central Bureau of Statistics using the national census and augmented by POINTS location profiling Ltd using aggregated data. Details on delivery/birth were extracted from hospitalization discharge letters. Treatments exclusively given in the hospital setting were not fully captured in the MHS database. Descriptions of HDFN complications diagnosis codes are detailed in Supplementary Table\u0026nbsp;1.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eHDFN is diagnosed by identifying the presence of maternal RBC antibodies. However, since alloantibody data was available in the MHS database only from 2005, any subject with an HDFN diagnosis recorded in the MHS database was included in the study, independent of an alloantibody test result. The main study cohorts included subjects identified through an antenatal or postnatal non-ABO HDFN diagnosis code within the study period 1998\u0026ndash;2021. ICD-9 diagnoses codes are described in Supplementary Table\u0026nbsp;2. The alloantibody-confirmed cohorts included subgroups of subjects from the main cohorts for whom the HDFN diagnosis was confirmed with a maternal positive alloantibody test result.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eMain study cohorts\u003c/h2\u003e \u003cp\u003eWomen with a HDFN diagnosis during pregnancy were included in the pregnancy cohort. Women with multiple pregnancies could repeatedly be included in this cohort, once for each HDFN pregnancy. The newborn cohort included offspring from these respective pregnancies as well as children with an HDFN diagnosis during their first year of life.\u003c/p\u003e \u003cp\u003eSevere HDFN was defined as the occurrence of at least one of the following during pregnancy: IUT, fetal hydrops, pre-term labor induction or intrauterine death\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. HDFN diagnosis at 24 weeks of gestation or later was defined as late onset HDFN.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eAlloantibody-confirmed cohort\u003c/h2\u003e \u003cp\u003eSensitivity analyses were conducted on subgroups of the pregnancy and newborn cohorts for whom the HDFN diagnosis was confirmed with a maternal positive alloantibody test result. Women with an HDFN diagnosis during pregnancy and an antibody titter\u0026thinsp;\u0026ge;\u0026thinsp;1:8, during or before the current pregnancy, were included in the alloantibody-confirmed pregnancy cohort.\u003c/p\u003e \u003cp\u003eChildren born from those respective pregnancies were included in the alloantibody-confirmed newborn cohort, as were children with an HDFN diagnosis during their first year of life whose mothers had an antibody titter\u0026thinsp;\u0026ge;\u0026thinsp;1:8 before or up to 1 month after the respective child's birth.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eHDFN incidence rates were calculated from the total number of diagnosed MHS members, divided by the corresponding total number of MHS members (pregnant women or newborns). Poisson regressions were used to assess incidence trends over time. Descriptive statistics are presented as mean and standard deviation (SD) for continuous variables and as frequencies and percentage for categorical variables. Statistical analyses were performed using SAS version 9.4. A p-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant (two-sided hypotheses).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eIncidence of HDFN during pregnancy was stable in Israel at an incidence rate ranging between 0.4-1 per 10,000 pregnancies during most of the study period. The incidence of HDFN diagnosed in newborns is higher compared to the incidence of HDFN diagnosed during pregnancy and has declined from 1.8 (95% CI 0.9\u0026ndash;3.4) in 1998 to 1.1 (95% CI 0.4\u0026ndash;2.5) in 2021 per 10,000 newborns (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Fig. \u003cspan\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eA total of 76 pregnancies with an HDFN diagnosis were identified in 70 women, 73 (96%) of them with medical information regarding their pregnancy course and outcome. Alloantibodies were confirmed in 27 women during or before 28 pregnancies, representing 38.4% of all HDFN pregnancies (Fig. \u003cspan\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eDuring the same 24-year study period, 395 additional newborns, who had not been identified during pregnancy because their mothers were not diagnosed during pregnancy (72%) or because their mothers were not included in the MHS database, were diagnosed postnatally with HDFN. Out of the 57 newborns born to HDFN diagnosed mothers, 55 were found in the MHS database and added to the HDFN newborn cohort. Therefore, in total, 450 HDFN newborns were identified and confirmed to have HDFN during their first year of life. Of the 450 HDFN newborns, 66 (14.7%) were confirmed to have HDFN during their first year of life based om maternal alloimmunization (Fig. \u003cspan\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv id=\"Sec9\"\u003e\n \u003ch2\u003ePregnancy and prenatal outcomes of HDFN\u003c/h2\u003e\n \u003cp\u003eThe average maternal age of 73 women diagnosed with HDFN at the time of diagnosis was 31.4+-5.8 years old. Frequency of comorbidities were low and included diabetes (2.7%), cardiovascular disease (4.1%) and hypertension (6.8%). The majority (54.8%) of women had never smoked. (Supplementary Table\u0026nbsp;3).\u003c/p\u003e\n \u003cp\u003eThe average gravidity at which HDFN was diagnosed among the 73 pregnancies was 3.4 +- 1.8, diagnosis tended to occur during the fourth pregnancy (41.1%). HDFN was diagnosed at an average of 23.4 +- 9.3 weeks of gestation. Late onset (diagnosed after 24 weeks of gestation) HDFN was diagnosed in 38 (52.1%) pregnancies. Three pregnancies were treated with IVIg; two required at least one IUT following IVIg. Twelve additional pregnancies not treated with IVIg required at least one IUT. Hydrops was diagnosed in 8 pregnancies (Table \u003cspan\u003e1\u003c/span\u003e). Of the 73 pregnancies with a diagnosis of HDFN, 22 were severe i.e., 14 were treated by intrauterine transfusion, 8 were diagnosed with fetal hydrops, 6 were induced pre-term and 1 resulted in an intrauterine death. The average gestational age (GA) of severe HDFN diagnosis was 24.5 +- 8.0 weeks (Table \u003cspan\u003e1\u003c/span\u003e). The majority of cases of severe HDFN in pregnancy required at least one IUT (14, 63.6%).\u003c/p\u003e\n \u003cp\u003eTable 1 Pregnancy characteristics and outcomes of prenatal diagnosed HDFN\u0026nbsp;\u003c/p\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" rowspan=\"2\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean +- SD/ N (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003ePregnancy cohort\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eAlloantibody confirmed pregnancy cohort\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eParameter\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eProcedure/\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal N=73\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eSevere N=22\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal N=28\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eSevere N=11\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eCategory\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"12\"\u003e\n \u003cp\u003ePregnancy Characteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eGA at HDFN diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e23.4 +- 9.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e24.5 +-8.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e23.9 +-9.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e24.5 +-6.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eGravidity\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3.4 +-1.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4.1 +-1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4.1 +-1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4.7 +-1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"5\"\u003e\n \u003cp\u003ePregnancy number category at diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12 (16.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9 (12.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12 (16.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e4+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30 (41.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12 (54.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e17 (60.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9 (81.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10 (13.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eTwins\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (2.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eLate onset HDFN at 24 GA or later\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e38 (52.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12 (54.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e17 (60.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6 (54.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAny IVIg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3 (4.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAny Intrauterine transfusion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14 (19.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14 (63.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9 (32.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9 (81.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eHydrops\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8 (11.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8 (36.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"15\"\u003e\n \u003cp\u003ePregnancy Outcomes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\"\u003e\n \u003cp\u003eOutcome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eLive Birth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e57 (78.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e16 (72.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e24 (85.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9 (81.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eMiscarriage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9 (12.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6 (27.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3 (10.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7 (9.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cspan dir=\"RTL\"\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cspan dir=\"RTL\"\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eGA at delivery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e37.6 +-3.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e34.9 +- 3.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e36.2 +-2.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e34.9 +-2.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eGA at miscarriage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e18.2 +- 7.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19.9 +- 6.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13.9 +-9.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20.7*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eBirthweight (g)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2964.2 +- 710.9\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2464.8 +- 560.5\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2750.9 +-687.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2702.3 +-747.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\"\u003e\n \u003cp\u003eType of miscarriage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIUFD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSpontaneous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cspan dir=\"RTL\"\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cspan dir=\"RTL\"\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eInduced\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5 (83.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (100.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eInduced preterm labor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6 (31.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6 (46.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5 (71.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePreterm labor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13 (81.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15 (62.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7 (77.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\"\u003e\n \u003cp\u003ePreterm Category\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eExtreme preterm (\u0026lt;28 GA)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cspan dir=\"RTL\"\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cspan dir=\"RTL\"\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cspan dir=\"RTL\"\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cspan dir=\"RTL\"\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eVery preterm (28-31+6 GA)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3 (15.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3 (23.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (13.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eModerate preterm (32-33+6 GA)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3 (15.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (13.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eLate preterm (34-36+6 GA)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13 (68.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9 (69.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e11 (73.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5 (71.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u0026nbsp;GA - gestational age; late onset defined as onset after 24 weeks of gestation\u003c/p\u003e\n \u003cp\u003eAmong the subgroup of 28 pregnancies in the alloantibody confirmed cohort (N\u0026thinsp;=\u0026thinsp;28), the average gravidity at which a woman was diagnosed with HDFN was 4.1+-1.5 and the majority (60.7%) were late onset HDFN. Eleven of these pregnancies were severe. A total of 9 pregnancies (32.1%) required at least one IUT. Two of the pregnancies were administered IVIg and both did require at least one IUT. Hydrops was diagnosed in two pregnancies. No cases of intrauterine death were reported.\u003c/p\u003e\n \u003cp\u003eAmong the 73 pregnancies with HDFN, 57 (78.1%) resulted in live births, 9 in miscarriages and 7 had unknown outcomes. Of the 57 live births, 19 (33%) were preterm of which 6 were induced. The majority of these were late preterm (68.4%). Overall, the average birthweight was 2964.2+-710.9 grams (Table \u003cspan\u003e1\u003c/span\u003e). Miscarriages included 1 intrauterine death at 28 gestational age (GA), 6 induced terminations of pregnancy at 15.8 GA (\u0026plusmn;\u0026thinsp;7.2) on average and 2 spontaneous miscarriages at 19.4 GA (\u0026plusmn;\u0026thinsp;3.7).\u003c/p\u003e\n \u003cp\u003ePregnancy outcomes in 22 severe HDFN pregnancies included 16 (72.7%) live births; 13 (81.3%) of these were preterm. Of the preterm births, 3 were very preterm between 28\u0026ndash;32 weeks of gestation, 1 moderate preterm between 32\u0026ndash;34 weeks of gestation and 9 late preterm between 34\u0026ndash;37 weeks of gestation. Of the remaining six cases of severe HDFN, there were 5 induced miscarriages and 1 intrauterine fetal death (IUFD). Out of the 7 preterm deliveries among the severe HDFN alloantibody confirmed pregnancies, 5 were induced labors. Characteristics and outcomes of early and late onset HDFN pregnancies are presented in Supplementary Tables\u0026nbsp;4 and 5.\u003c/p\u003e\n \u003cp\u003eAmong the subgroup of 28 alloantibody confirmed pregnancies, 24 (85.7%) resulted in live births, 2 induced abortions (1 at 20.7 GA and 1 at unknown GA), 1 spontaneous miscarriage at 7.1 GA and 1 unknown outcome. Of the 24 live births, 15 (62.5%) occurred preterm, most of which were late preterm (73.3%), and average birthweight was 2750.9 +-687.5 grams (Table \u003cspan\u003e1\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eThe pregnancy cohort included 3 women each with 2 HDFN pregnancies in the study period. Pregnancy characteristics and outcomes for both pregnancies are presented in Supplementary Table\u0026nbsp;6. One woman delivered in both pregnancies, one woman delivered in the first pregnancy and had an induced miscarriage in the second pregnancy and one woman spontaneously miscarried in the first pregnancy and delivered very preterm in the second. There were no cases of hydrops or IUFD.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\"\u003e\n \u003ch2\u003ePostnatal outcomes of HDFN newborns\u003c/h2\u003e\n \u003cp\u003eThe median age at diagnosis of the 395 newborns diagnosed only postnatally was 2.7 weeks (IQR 0.7\u0026ndash;5.7). The majority (58.2%) of all 450 HDFN newborns, including 55 born from HDFN pregnancies, were male.\u003c/p\u003e\n \u003cp\u003eAnemia and jaundice were the most common complications of HDFN during the first year of life. Both complications were diagnosed in over 30% of the full newborn cohort. Twelve percent of the newborn cohort (n\u0026thinsp;=\u0026thinsp;54) had developmental disorders. Other complications included edema (5.1%), auditory dysfunction (3.3%), blood disorders (2.7%) and kernicterus (1.1%) as depicted in Table \u003cspan\u003e2\u003c/span\u003e. Anemia was diagnosed in 63.6% and jaundice in 19.7% of the subgroup of the alloantibody confirmed newborn cohort; kernicterus was observed in 4 newborns (6.1%), edema in 4.5% and development disorders in 3.0%. Almost one third of alloantibody confirmed newborns underwent blood transfusions (31.8%) and 10.6% underwent phototherapy.\u003c/p\u003e\n \u003cdiv\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 2\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eComplications reported in newborns diagnosed postnatally with HDFN\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eComplication\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eNewborn cohort N\u0026thinsp;=\u0026thinsp;450\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eAlloantibody confirmed newborn cohort N\u0026thinsp;=\u0026thinsp;66\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eN (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAge at diagnosis (months)/\u003c/p\u003e\n \u003cp\u003eMean +- SD\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eN (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAge at diagnosis (months)/\u003c/p\u003e\n \u003cp\u003eMean +- SD\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e158 (35.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.9 +-2.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e42 (63.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.6 +-2.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAuditory Dysfunction/Deafness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15 (3.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.8 +-3.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDevelopment Disorder\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e54 (12.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.5 +-3.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.6+-0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEdema\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e23 (5.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.8 +-2.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (4.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.1 +-0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJaundice\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e154 (34.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.8 +-1.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18 (27.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.6 +-0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKernicterus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5 (1.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.2 +-0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.3 +-0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMovement Disorder\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1 (0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOculomotor Impairments\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.9 +-4.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBlood Disorder (acidosis, calcemia)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12 (2.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.9 +-2.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOther Blood Disorder (transient neonatal neutropenia)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.4 +-3.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eOf the 450 newborns, 29% and 37% of newborns had complete blood count (CBC) results between 2\u0026ndash;3 months of age and 10\u0026ndash;12 months of age, respectively. Among the alloantibody confirmed newborns, CBC results were available for 40% of newborns up to 1 month old as well as in 10\u0026ndash;12 month olds. Laboratory test results were comparable between the full newborn cohort and the alloantibody confirmed cohort (Supplementary tables 7,8). Mean hemoglobin and hematocrit values were low during the first 3 months of life; however, the mean values rose to normal levels by the age of one year (Supplementary Fig.\u0026nbsp;1).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis is the largest study to investigate the epidemiology and outcomes of HDFN in Israel. Based on MHS data, prenatal HDFN diagnosis is stable in Israel while postnatal HDFN diagnosis has declined from 1.8 per 10,000 to 1.1 per 10,000 newborns since 1998, respectively. These results present lower incidence compared to a Canadian single center study\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e from 2010\u0026ndash;2017, that showed an incidence rate of 6 per 10,000 newborns diagnosed with HDFN and a national US study\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e from 1996\u0026ndash;2010 that found an incidence rate of 4 to 10 per 10,000 newborns. The US study also reported a decline in HDFN incidence due to reduced alloimmunization rates over time.\u003c/p\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eHDFN pregnancies\u003c/h2\u003e \u003cp\u003eDuring the study period, 76 women were diagnosed with HDFN during pregnancy, compared to 395 newborns diagnosed during their first year of life. This result may indicate the lack of screening and surveillance in pregnancies at risk. Timely perinatal diagnosis of HDFN is important to initiate optimal management and thus prevent hydrops fetalis or fetal death\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. The \u0026lsquo;Postponing Early intrauterine Transfusion with Intravenous immunoglobulin Treatment\u0026rsquo; (PETIT) study showed that if IVIg was initiated before 13 weeks of gestation, fetal anemia was delayed and anemia prior to 20 weeks gestation occurred less often\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. The lower rate of prenatal compared to postnatal diagnosis of HDFN may explain the rates of severe cases found in this study.\u003c/p\u003e \u003cp\u003eMore than one quarter (28.8%) of all HDFN pregnancies and nearly 40% of alloantibody confirmed pregnancies were severe cases. Hydrops occurred in 7.1% of alloantibody confirmed cases, comparable to 7.3% reported in a recent systematic review\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. IVIg was administered to 7.1% of alloantibody confirmed cases, both of whom required at least one IUT. Very preterm delivery, between 28\u0026ndash;32 GA, occurred only in severe HDFN pregnancies, increasing the risk of neonatal complications\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Most miscarriages were induced during the first trimester which may indicate that the fetuses were in grave condition. A 10 year observational study from Finland\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e found 3.8% IUFD and 82% live births among women treated with IUTs for HDFN, comparable to the findings in this study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eHDFN newborns\u003c/h2\u003e \u003cp\u003eOne third of all newborns were diagnosed with anemia and/or jaundice at a mean age of less than 2 months and less than 1 month, respectively. The requirement for transfusion was much greater than that previously reported by Yu and colleagues\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. This finding may indicate a more severe disease phenotype in this Israeli database, though the higher transfusion rate found may be associated with other factors such as differences in healthcare and reimbursement structures. While abnormally low values of hemoglobin and hematocrit were observed in the first months of HDFN newborns' lives, laboratory test results normalized for most newborns within one year. This observation was expected, as any residual maternal alloantibodies or residual effects of IUTs dissipate by the age of 1 year old.\u003c/p\u003e \u003cp\u003eKernicterus, a severe complication of hyperbilirubinemia, causing chronic neurologic impairments including hearing loss, visual abnormalities, abnormalities in dentition and involuntary movements, was reported in 5 (over 1%) newborns, 4 of whom were alloantibody confirmed HDFN cases. These complications occurred at rates higher than previously reported and similarly, indicating a more severe cohort of patients in this database\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOver 10% of newborns were reported as having a developmental disorder, however among the alloantibody confirmed HDFN cases the rate was reduced to 3%. Lindenburg and colleagues\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e previously reported moderate and severe developmental delay in 14.4% and 3.1% of a severe population of patients exposed to IUT, respectively. Given the lack of pre-natal data available for this newborn cohort (severity in pregnancy, incidence of hydrops etc.) it is difficult to decipher obvious factors for the high incidence observed in this study. However, the data do reiterate the importance of continued exploration of risk factors for developmental disorders to ensure early identification and implementation of prenatal interventions, which may improve short- and long-term outcomes. Measures that allow early detection of severe fetal anemia prior to development of fetal hydrops as well as medical interventions, that can postpone onset of severe fetal anemia, may prove to be beneficial in improving both neonatal and longer-term developmental outcomes.\u003c/p\u003e \u003cp\u003eThe main strength of this study is the longitudinal follow-up over a large database including a quarter of Israel's population for more than 20 years. This database includes extensive medical information recorded continually, including treatments, diagnoses, laboratory results and procedures for all members. In addition, Israel has a high birth rate\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e with a stable total fertility rate of 3 children per woman during the study period\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. As risk of HDFN rises with each pregnancy\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e, the high birth rate allowed us to capture more HDFN cases as well as more severe cases than expected in countries with lower birth rates. Last, in this study we were able to conduct sensitivity analyses on alloantibody confirmed cases which validated the study findings.\u003c/p\u003e \u003cp\u003eThere are several limitations in this study. First, as this was a retrospective observational study, not all clinical and demographic information was fully captured in the database. Missing data included information needed to match pregnant women and child of the same pregnancy thus the study cohorts did not include all HDFN cases, and the approach included two initial sets of cohorts. Second, alloantibody test results were not included in the MHS database until 2005, therefore the inclusion of HDFN cases in the main cohort of this study was based on diagnoses captured in the database alone. Third, HDFN management and treatment given in an inpatient setting is not always reported back to MHS (a community-based organization), and therefore not captured in this database, therefore treatment may be underestimated in this report. Therefore, this study cannot show evidence of associations between HDFN management during pregnancy with perinatal outcomes. Further studies including larger cohorts of HDFN pregnancies are needed to assess fetal and newborn outcomes following specific treatment of HDFN.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAlthough diagnoses of HDFN cases in Israel have declined between 1998\u0026ndash;2021, we observed severe outcomes with a diagnosis of HDFN including pregnancy termination, hydrops, pre-term labor, anemia, jaundice, and kernicterus. Routine maternal blood testing for alloantibodies at early gestation can enable early diagnosis and management of HDFN pregnancies which are at risk for the development of fetal anemia. Further studies are needed to understand and evaluate current treatment regimens for HDFN and assess the association between perinatal management and short- to long-term outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of Interest Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by Janssen Pharmaceuticals. M.F., W.K., N.B., S.I., A.B. and W.M. are employees of Janssen Pharmaceuticals. The remaining authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003eThe study was conducted according to the guidelines of the Declaration of Helsinki and approved by Maccabi\u0026rsquo;s Ethics Committee (approval #0021-22-MHS). As this non-interventional administrative study involves de-identified structured data, which according to applicable legal requirements does not contain data subject to privacy laws, obtaining informed consent from patients was waived by MHS IRB, as in accordance with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAvailability of Data and Materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from Kahn-Sagol-Maccabi Research and Innovation Institute but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of Kahn-Sagol-Maccabi Research and Innovation Institute. Please apply to Dr. Moshe Hoshen for further information.\u003c/p\u003e\n\u003cp\u003eUpon request, and subject to review, the study Sponsor, Kahn-Sagol-Maccabi Research and Innovation Institute, will provide data that support the findings of this study. Subject to certain criteria, conditions and exceptions, Kahn-Sagol-Maccabi Research and Innovation Institute may also provide access to the related individual de-identified participant data. Contact Kahn-Sagol-Maccabi Research and Innovation Institute for more information.\u003c/p\u003e\n\u003cp\u003eFunding:\u003c/p\u003e\n\u003cp\u003eThis study was sponsored by Kahn-Sagol-Maccabi Research and Innovation Institute and funded by Janssen Pharmaceuticals.\u003c/p\u003e\n\u003cp\u003eAuthor Contributions:\u003c/p\u003e\n\u003cp\u003eN.F., M.F., W.K., N.B., S.I., S.G., A.B. and W.M. have made substantial contributions to the conception and design of the work. M.H., Y.S., D.M. and Y.Y. contributed to the discussion and critical revision of the manuscript. All authors made substantial contributions in the acquisition, analysis, and interpretation of data, have drafted the work, and substantively revised it.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDe Haas M, Thurik F, Koelewijn J, van der Schoot CE. Haemolytic disease of the fetus and newborn. \u003cem\u003eVox sanguinis\u003c/em\u003e. 2015;109(2):99-113.\u003c/li\u003e\n\u003cli\u003eBennardello F, Coluzzi S, Curciarello G, Todros T, Villa S. Recommendations for the prevention and treatment of haemolytic disease of the foetus and newborn. \u003cem\u003eBlood Transfusion\u003c/em\u003e. 2015;13(1):109.\u003c/li\u003e\n\u003cli\u003eCostumbrado J, Mansour T, Ghassemzadeh S. Rh incompatibility. \u003cem\u003eStatPearls [Internet]\u003c/em\u003e. StatPearls Publishing; 2022.\u003c/li\u003e\n\u003cli\u003eDelaney M, Matthews DC. Hemolytic disease of the fetus and newborn: managing the mother, fetus, and newborn. \u003cem\u003eHematology 2014, the American Society of Hematology Education Program Book\u003c/em\u003e. 2015;2015(1):146-151.\u003c/li\u003e\n\u003cli\u003eZwiers C, van Kamp I, Oepkes D, Lopriore E. Intrauterine transfusion and non-invasive treatment options for hemolytic disease of the fetus and newborn\u0026ndash;review on current management and outcome. \u003cem\u003eExpert review of hematology\u003c/em\u003e. 2017;10(4):337-344.\u003c/li\u003e\n\u003cli\u003eSmits-Wintjens VE, Walther FJ, Lopriore E. Rhesus haemolytic disease of the newborn: Postnatal management, associated morbidity and long-term outcome. Elsevier; 2008:265-271.\u003c/li\u003e\n\u003cli\u003eRee IM, Smits-Wintjens VE, van der Bom JG, van Klink JM, Oepkes D, Lopriore E. Neonatal management and outcome in alloimmune hemolytic disease. \u003cem\u003eExpert review of hematology\u003c/em\u003e. 2017;10(7):607-616.\u003c/li\u003e\n\u003cli\u003eDe Winter DP, Hulzebos C, Van \u0026lsquo;t Oever RM, De Haas M, Verweij E, Lopriore E. History and current standard of postnatal management in hemolytic disease of the fetus and newborn. \u003cem\u003eEuropean Journal of Pediatrics\u003c/em\u003e. 2023;182(2):489-500.\u003c/li\u003e\n\u003cli\u003eHall V, Avulakunta ID. Hemolytic diseases of the newborn. \u003cem\u003eStatPearls [Internet]\u003c/em\u003e. StatPearls Publishing; 2021.\u003c/li\u003e\n\u003cli\u003eRossman H, Shilo S, Meir T, Gorfine M, Shalit U, Segal E. COVID-19 dynamics after a national immunization program in Israel. \u003cem\u003eNature medicine\u003c/em\u003e. 2021;27(6):1055-1061.\u003c/li\u003e\n\u003cli\u003ehttps://points.co.il/database/demography/\u003c/li\u003e\n\u003cli\u003eLieberman L, Callum J, Cohen R, et al. Impact of red blood cell alloimmunization on fetal and neonatal outcomes: A single center cohort study. \u003cem\u003eTransfusion\u003c/em\u003e. 2020;60(11):2537-2546.\u003c/li\u003e\n\u003cli\u003eYu D, Ling LE, Krumme AA, Tjoa ML, Moise Jr KJ. Live birth prevalence of hemolytic disease of the fetus and newborn in the United States from 1996 to 2010. \u003cem\u003eAJOG Global Reports\u003c/em\u003e. 2023;3(2):100203.\u003c/li\u003e\n\u003cli\u003evan\u0026rsquo;t Oever RM, Zwiers C, de Winter D, et al. Identification and management of fetal anemia due to hemolytic disease. \u003cem\u003eExpert Review of Hematology\u003c/em\u003e. 2022;15(11):987-998.\u003c/li\u003e\n\u003cli\u003eZwiers C, van der Bom JG, van Kamp IL, et al. Postponing early intrauterine transfusion with intravenous immunoglobulin treatment; the PETIT study on severe hemolytic disease of the fetus and newborn. \u003cem\u003eAmerican journal of obstetrics and gynecology\u003c/em\u003e. 2018;219(3):291. e1-291. e9.\u003c/li\u003e\n\u003cli\u003ede Winter DP, Kaminski A, Tjoa ML, Oepkes D. Hemolytic disease of the fetus and newborn: systematic literature review of the antenatal landscape. \u003cem\u003eBMC Pregnancy and Childbirth\u003c/em\u003e. 2023;23(1):1-10.\u003c/li\u003e\n\u003cli\u003eBaron IS, Rey-Casserly C. Extremely preterm birth outcome: a review of four decades of cognitive research. \u003cem\u003eNeuropsychology review\u003c/em\u003e. 2010;20:430-452.\u003c/li\u003e\n\u003cli\u003eSainio S, Nupponen I, Kuosmanen M, et al. Diagnosis and treatment of severe hemolytic disease of the fetus and newborn: a 10‐year nationwide retrospective study. \u003cem\u003eActa Obstetricia et Gynecologica Scandinavica\u003c/em\u003e. 2015;94(4):383-390.\u003c/li\u003e\n\u003cli\u003eLindenburg IT, Smits-Wintjens VE, van Klink JM, et al. Long-term neurodevelopmental outcome after intrauterine transfusion for hemolytic disease of the fetus/newborn: the LOTUS study. \u003cem\u003eAmerican journal of obstetrics and gynecology\u003c/em\u003e. 2012;206(2):141. e1-141. e8.\u003c/li\u003e\n\u003cli\u003eWeinreb A, Chernichovsky D, Brill A. Israel\u0026rsquo;s exceptional fertility. \u003cem\u003eRetrieved April\u003c/em\u003e. 2018;19:2020.\u003c/li\u003e\n\u003cli\u003estatistics ICBo. Fertility of Jewish and Other Women in Israel, by Level of Religiosity 1979\u0026ndash;2020. https://www.cbs.gov.il/en/publications/Pages/2022/Fertility-of-Jewish-and-Other-Women-in-Israel-by-Level-of-Religiosity-1979-2020.aspx\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4640361/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4640361/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e: Hemolytic disease of the fetus and newborn (HDFN) can cause severe prenatal and postnatal outcomes. The main objective of this study is to understand the clinical impact of HDFN on pregnant women and newborns.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Design\u003c/strong\u003e: A retrospective cohort study was performed on de-identified data extracted from a large nationwide health organization. The cohort included women and newborns diagnosed with HDFN between 1998-2021. Cohort characteristics and outcomes are described.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResult\u003c/strong\u003e: Over the 24-year study period, incidence rate of HDFN among pregnant women was stable while incidence rate among newborns declined. Severe HDFN was diagnosed in 28.8% of 73 HDFN affected pregnancies. One third of 450 HDFN newborns were diagnosed with anemia or jaundice; 5 cases of kernicterus were observed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: Severe prenatal and postnatal outcomes following HDFN were observed. Further studies are needed to evaluate treatment regimens and assess the association between treatment management and short- and long-term outcomes.\u003c/p\u003e","manuscriptTitle":"Hemolytic disease of fetus and newborn course, management and outcomes - an analysis based on the Israeli Maccabi database","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-19 20:19:47","doi":"10.21203/rs.3.rs-4640361/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a3a0217f-b9e7-4bdf-9f5e-3538d5882600","owner":[],"postedDate":"July 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-12-13T07:23:40+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-19 20:19:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4640361","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4640361","identity":"rs-4640361","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}