Unexplained Stillbirth Research Articles

COMPARISON OF MISOPROSTOLAND DINOPROSTONE FOR ELECTIVE INDUCTION OF LABOUR IN NULLIPAROUS WOMEN AT FULL TERM: A RANDOMIZED PROSPECTIVE STUDY

Background: The objective of this randomized prospective study was to compare the efcacy of 50 mcg vaginal misoprostol and 3 mg dinoprostone, administered every nine hours for a maximum of three doses, for elective induction of labor in nulliparous women with an unfavorable cervix and more than 40 weeks of gestation. Material And Methods: One hundred and sixty-three pregnant women with more than 285 days of gestation were recruited and analyzed. The main outcome measures were time from induction to delivery and incidence of vaginal delivery within 12 and 24 hours. Admission rate to the neonatal intensive care unit within 24 hours post delivery was a secondary outcome. Results: The induction-delivery interval was signicantly lower in the misoprostol group than in the dinoprostone group (11.9 h vs. 15.5 h, p < 0.001). With misoprostol, more women delivered within 12 hours (57.5% vs. 32.5%, p < 0.01) and 24 hours (98.7% vs. 91.4%, p < 0.05), spontaneous rupture of the membranes occurred more frequently (38.8% vs. 20.5%, p < 0.05), there was less need for oxytocin augmentation (65.8% vs. 81.5%, p < 0.05) and fewer additional doses were required (7.5% vs. 22%, p < 0.05). Although not statistically signicant, a lower Caesarean section (CS) rate was observed with misoprostol (7.5% vs. 13.3%, p > 0.05) but with the disadvantage of higher abnormal fetal heart rate (FHR) tracings (22.5% vs. 12%, p > 0.05). From the misoprostol group more neonates were admitted to the intensive neonatal unit, than from the dinoprostone group (13.5% vs. 4.8%, p > 0.05). One woman had an unexplained stillbirth following the administration of one dose of dinoprostone. Conclusions: Vaginal misoprostol, compared with dinoprostone in the regimens used, is more effective in elective inductions of labor beyond 40 weeks of gestation. Nevertheless, this is at the expense of more abnormal FHR tracings and more admissions to the neonatal unit, indicating that the faster approach is not necessarily the better approach to childbirth

Molecular Pathways of Cellular Senescence and Placental Aging in Late Fetal Growth Restriction and Stillbirth.

Abnormally accelerated, premature placental senescence plays a crucial role in the genesis of pregnancy pathologies. Abnormal growth in the third trimester can present as small for gestational age fetuses or fetal growth restriction. One differs from the other by the presence of signs of placental insufficiency and the risk of stillbirth. The majority of stillbirths occur in normally grown fetuses and are classified as “unexplained”, which often leads to conclusions that they were unpreventable. The main characteristic of aging is a gradual decline in the function of cells, tissues, and organs. These changes result in the accumulation of senescent cells in mitotic tissues. These cells begin the aging process that disrupts tissues’ normal functions by affecting neighboring cells, degrading the extracellular matrix, and reducing tissues’ regeneration capacity. Different degrees of abnormal placentation result in the severity of fetal growth restriction and its sequelae, including fetal death. This review aims to present the current knowledge and identify future research directions to understand better placental aging in late fetal growth restriction and unexplained stillbirth. We hypothesized that the final diagnosis of placental insufficiency can be made only using markers of placental senescence.

Abnormal placental perfusion and the risk of stillbirth: a hospital-based retrospective cohort study

BackgroundA lack of information on specific and interventional factors for stillbirth has made designing preventive strategies difficult, and the stillbirth rate has declined more slowly than the neonatal death rate. We compared the prevalence of stillbirth among the offspring of women with or without abnormal placental perfusion (APP).MethodsWe conducted a hospital-based retrospective cohort study involving women with a singleton pregnancy between 2012 and 2016 (N = 41,632). Multivariate analysis was performed to compare the prevalence of stillbirth in infants exposed to APP (defined as any abnormality in right or left uterine artery pulsatility index or resistance index [UtA-PI, −RI] [e.g., > 95th percentile] or presence of early diastolic notching) with that in those not exposed to APP.ResultsStillbirths were more common among women with APP than among those with normal placental perfusion (stillbirth rate, 4.3 ‰ vs 0.9 ‰; odds ratio (OR), 4.2; 95% confidence interval (CI), 2.2 to 8.0). The association strengths were consistent across groups of infants exposed to APP that separately defined by abnormality in right or left UtA-PI or -RI (OR ranged from 3.2 to 5.3; all P ≤ 0.008). The associations were slightly stronger for the unexplained stillbirths. Most of the unexplained stillbirth risk was attributed to APP (59.0%), while a foetal sex disparity existed (94.5% for males and 58.0% for females). Women with normal placental perfusion and a male foetus had higher credibility (e.g., higher specificities) in excluding stillbirths than those with APP and a female foetus at any given false negative rate from 1 to 10% (93.4% ~ 94.1% vs. 12.3% ~ 14.0%).ConclusionsAPP is associated with and accounts for most of the unexplained stillbirth risk. Different mechanisms exist between the sexes. The performance of screening for stillbirth may be improved by stratification according to sex and placental perfusion.

Cardio-pathogenic variants in unexplained intrauterine fetal death: a retrospective pilot study

To describe the prevalence and spectrum of cardio-pathogenic variants in singleton fetuses after unexplained intrauterine fetal death (IUFD). DNA from post-mortem fibroblastic tissue samples of 16 fetuses after unexplained IUFD was retrieved at two tertiary university hospitals for clinical exome sequencing with subsequent filtering of 122 cardio-specific genes to elucidate underlying cardio-pathogenic variants. In total, we included 12 (75%) male and four (25%) female fetuses who were stillborn at a median gestational age of 34+6 (23+2–40+5) weeks. In two (12.5%) fetuses no cardio-pathogenic variants were found. In 14 (87.5%) fetuses, overall 33 variants were detected in 22 cardio-specific genes, involving 14 (63.63%) genes associated with cardiomyopathy, six (27.27%) arrhythmogenic susceptibility genes and two (9.09%) arrhythmia and cardiomyopathy associated genes. Among the 33 variants, five (15.2%) were classified as likely benign according to the American College of Medical Genetics and Genomics; 28 (84.8%) variants were considered as variants of uncertain significance. Compared to a cohort of explained IUFDs, the cases with and without fetal variants in cardiac genes differed not significantly regarding maternal age, previous history of stillbirth, time of stillbirth or fetal sex. Unexplained stillbirth may be caused by cardio-genetic pathologies, yet a high number of variants of uncertain significance merit a more detailed post-mortem examination including family segregation analysis.

Genomic Insights Into Stillbirth

(N Engl J Med. 2020;383;1182–1183) The majority of stillbirths in the United States are unexplained. Over the past few years, technology for sequencing and interpreting genomic data have improved, but it’s unclear if techniques will be useful in addressing unexplained stillbirth.

Sleep your baby supine, but mums-to-be should sleep on their side.

Sleep your baby supine, but mums-to-be should sleep on their side.

Silver nanoparticles in the fetal brain: new perspectives in understanding the pathogenesis of unexplained stillbirths.

We report, for the first time, the surprising presence of toxic nanoparticles, especially silver, in the brain of a fetus, who died unexpectedly at the end of a regular pregnancy. After an accurate autopsy, including the examination of the fetal annexes, an in-depth anatomopathological study of the nervous system and a search by scanning electron microscopy of nanoparticles in the brain, we highlighted the sequence of events that may have led to this fetal death, triggered primarily by the transition of nanosized xenobiotics from the mother to the fetal bloodstream. From this report emerges the importance of considering the search of nanosubstances in the brain during routine investigations following unexpected and unexplained fetal and infant deaths.

Understanding the complexities of unexplained stillbirth in sub-Saharan Africa: a mixed-methods study.

ObjectiveTo understand the complexities surrounding unexplained stillbirth for the development and implementation of culturally acceptable interventions to underpin care in Tanzania and Zambia.DesignMixed‐methods study.SettingTertiary, secondary and primary care facilities in Mansa, Zambia, and Mwanza, Tanzania.SampleQuantitative: 1997 women giving birth at two tertiary care facilities (one in each country). Qualitative: 48 women and 19 partners from tertiary, secondary and primary care facilities.MethodsCase review using data from a target of 2000 consecutive case records. Qualitative interviews with a purposive sample of women and partners, using a grounded theory approach.ResultsA total of 261 stillbirths were recorded, with a rate of 16% in Tanzania and 10% in Zambia, which is higher than the previous estimates of 2.24 and 2.09%, respectively, for those countries. Women in both countries who reported a previous stillbirth were more likely to have stillbirth (RR 1.86, 95% CI 1.23–2.81). The cause of death was unexplained in 28% of cases. Qualitative findings indicated that not knowing what caused the baby to be stillborn prevented women from grieving. This was compounded by the poor communication skills of health professionals, who displayed little empathy and skill when counselling bereaved families.ConclusionsThe stillbirth risk in both facilities was far higher than the risk recorded from national data, with women reporting a previous stillbirth being at higher risk. Women want to know the cause of stillbirth and an exploration of appropriate investigations in this setting is required. Providing health professionals with support and continuing training is key to improving the experiences of women and future care.Tweetable abstractStillbirths receive little investigation and are often unexplained. Communication with women about the death of their baby is limited.

Healthcare costs of investigations for stillbirth from a population-based study in Australia.

Objective Stillbirth investigations incur healthcare costs, but these investigations are necessary to provide information that will help reduce the risk of a recurrent stillbirth, as well as advice regarding family planning and future pregnancies. The aims of this study were to determine the healthcare costs of investigations for stillbirths, identify drivers and assess cost differences between explained and unexplained stillbirths. Methods Data from 697 stillbirths were extracted from the Stillbirth Causes Study covering the period 2013-18. The dataset comprised all investigations related to stillbirth on the mother, baby and placenta. Unit costs applied were sourced from the Australian Medicare Benefits Schedule, local hospital estimates and published literature. Multivariable regression analyses were used to assess key factors in cost estimates. Results In all, 200 (28.7%) stillbirths were unexplained and 76.8% of these had between five and eight core investigations. Unexplained stillbirths were twice as likely to have eight core investigations as explained stillbirths (16.5% vs 7.7%). The estimated aggregated cost of stillbirth investigations for 697 stillbirths was A$2.13 million (mean A$3060, median A$4246). The main cost drivers were autopsies or cytogenetic screening. Mean costs were similar when stillbirths had known or unknown causes and by reason for stillbirth among cases with definable causes. Conclusion Investigations for stillbirth in Australia cost approximately A$4200 per stillbirth on average and are critical for managing future pregnancies and preventing more stillbirths. These findings improve our understanding of the costs that may be averted if stillbirths can be prevented through primary prevention initiatives. What is known about the topic? Approximately 2000 stillbirths occur each year in Australia, and this trend has not changed for several decades. Stillbirth investigations incur healthcare costs, but these investigations are necessary to provide information to help reduce the risk of a recurrent stillbirth and advice regarding family planning and future pregnancies. Recommendations for the core set of stillbirth investigations have recently been agreed upon by consensus. What does this paper add? The costs of stillbirth investigations are unknown in Australia. The assessment of these costs is challenging because not all investigations involved in stillbirths are recorded within formal administrative systems because a stillborn baby is not formally recognised as a patient. The present population-based analysis of 697 stillbirths in Australia estimated that, on average, A$4200 was spent on investigations for each stillbirth, with key drivers being autopsies and cytogenetic screening. These costs are typical, with most cases having between five and eight of the core eight recommended investigations. What are the implications for practitioners? There are cost implications for stillbirth investigations, and this analysis gives a true account of current practice in Australia. Together with the high downstream economic costs of stillbirths, the cost burden of stillbirth investigations is high but ultimately avoidable when practitioners adhere to the core investigations, build knowledge around preventable risk factors and use this information to reduce the number of stillbirths.

Pregnancy outcome among gestational diabetes mellitus patients

Background and Aim: Though not all babies have birth defects there is still a high probability ofcongenital defects if the glucose level is not under control during pregnancy and also increasedmorbidity in terms of hypoglycemia, hyperbilirubinemia, and respiratory distress syndromewarranting NICU admissions. The objective of this study was to find out the maternal and perinataloutcome in patients with gestational diabetes mellitus. Material and Methods: An observationalstudy was conducted among 400 pregnant women who came for antenatal checkups attending theOPD of the department of obstetrics and gynecology, the tertiary care institute of Gujarat, from June2012 to November 2013. A detailed history including maternal age, parity, BMI, and clinicalexamination along with antenatal checkup was done. Results: Out of 400 antenatal women testedfor OGTT using 75 grams of glucose, about 12.75% (51) of antenatal women developed GDM. Out of51 GDM mothers, about 10% ie.,5 antenatal women had pregnancy-induced hypertension and only2 developed polyhydramnios and preterm delivery in 11.76% of antenatal women with GDM Out of51 babies, 19.6% of them had respiratory distress syndrome, 7.8% of the babies requiring NICUadmissions because of hypoglycemia, hyperbilirubinemia, and hypocalcemia. Conclusion:Gestational diabetes mellitus was once thought to be a mild condition but now it carries significantshort-term and long-term implications for the women and their offspring. Screening for diabetes ismandatory in preventing complications as strict glycemic control is necessary for preventingmacrosomia and unexplained stillbirths.

A comparison of three classification systems for stillbirth

Background Understanding the causes of perinatal death can provide relevant information to couples, caregivers, and society. Classification systems play a crucial role in identifying the most relevant conditions suggesting preventive measures for decreasing stillbirth (SB). In 2016 the International Classification of Disease to Deaths during the Perinatal Period (ICD-PM) was released with the aim to suggest a universally accepted classification. Methods This is a prospective cohort study that enrolled all SBs occurred in Emilia–Romagna, from 2014 to 2017. We prospectively applied ReCoDe classification and retrospectively used Simplified CODAC classification and ICD-PM. The aim of this study is to compare different classification systems on a cohort of SBs, undergoing a comprehensive workup, to establish what classification minimizes rates of unexplained SB. Results We registered 443 SBs. According to ReCoDe the largest category of SB was “placental insufficiency/infarction” (16.9%), followed by “abruptio placentae” (14.2%). Unexplained cases are 16.7%. Gestational age <37 weeks is less frequent in the group of women with unclassified SB (OR 0.50, OR95%CI [0.3–0.8]) against women with classified SB. Considering CODAC the two largest categories are “infarctions or thrombi” (16.3%) and “abruption or retro-placental haematoma” (15.1%), instead only 17.2% of cases remained unexplained. Conclusions Comparing ReCoDe and CODAC we found no real difference in any category. ReCoDe and CODAC better underlines the primary cause of death. ICD-PM reveals to be easily applicable to clinical practice. ICD-PM has the lowest rate of unexplained SBs (9.3%) due to the structure itself and not to a deeper comprehension of death.

Evaluation and Management of Women who Have Experienced Stillbirth in Their Previous Pregnancies

Objective: To evaluate the subsequent pregnancy outcomes of women who have experienced unexplained stillbirth in their previous gestations.Study Design: This retrospective cohort consisted of 14 pregnancies who had stillbirth (without known risk factors) in their previous pregnancies. These patients had been included in a special preconceptional care program to be evaluated in terms of etiological risk factors for stillbirth. At least one of the risk factors, such as methylenetetrahydrofolate reductase (MTHFR) polymorphisms, hereditary thrombophilias and autoimmune problems, were defined in this study population. After detection of pregnancy, the patients were administered low-dose low-molecular-weight heparin (LMWH) (enoxaparin, 1×2000 Anti-XA IU/0.2 mL/day), low-dose salicylic acid (100 mg/day) and low-dose corticosteroid (methylprednisolone, 1×4 mg/day orally) in necessary cases.Results: Out of 14 pregnancies, 4 (28.5%) ended up with miscarriages at 9, 11, 11 and 15 gestational weeks, respectively. The remaining 10 pregnancies ended up with alive deliveries. The mean gestational week at birth was 36.4±0.51, while the mean birthweight was 2882±381.01 g. Out of 10 pregnancies, only one was diagnosed as IUGR. Only two newborn necessitated hospitalization in the neonatal intensive care unit (NICU) due to respiratory problems. Both newborns were discharged from the NICU without any further complication at the post-partum 5th day. Conclusion: Patients with a prior stillbirth should be screened for MTHFR polymorphisms, autoimmune problems and hereditary thrombophilias, especially in case of absence of any etiological factor. Management of these patients with low-dose aspirin, low-dose low molecular weight heparin and corticosteroids seemed to be beneficial for increasing live birth rates and avoiding obstetric complications.

Value of Placental Examination in the Diagnostic Evaluation of Stillbirth

Objective The aim was to assess the contribution of placental examination in the etiologic investigation of stillbirth. Materials and Methods: A retrospective review of stillbirths that occurred after 14 weeks gestation was conducted for a one-year period. Twin pregnancies and fetuses without placentas were excluded. According to the fetoplacental examination, stillbirths were classified into etiologic groups. Results: A total of 147 stillbirths were selected. They were associated with placental, materno-fetal, fetal and multiple causes in 89 cases (61%), 23 cases (16%), 14 cases (9%) and 13 cases (9%), respectively. Unexplained stillbirths were observed in 8 cases (5%). Placental abnormalities were identified in 132/147 cases (90%). They were consistent with vascular, inflammatory and developmental lesions in 82/132 cases (61%), 28/132 cases (21%) and 18/132 cases (13%), respectively. Conclusion: Placental lesions were the main causes of stillbirth and were predominantly of vascular type including chronic villous hypoxia-ischemia and funicular anomalies.

Challenges in developing prediction models for stillbirth.

Stillbirth is a major global public health problem, but in the absence of a robust method to predict a woman's individualized risk of stillbirth, identifying women at increased risk remains a challenge. Awareness of factors that increase risk is a necessary step in improving care through better communication and shared decision-making, with the goal of reducing stillbirths. Despite a high proportion of unexplained stillbirths, many women have one or more risk factors that are often unrecognized (Flenady, V. et al Lancet 2011, 377, 1331-40).

The etiology of stillbirth over 30 years: A cross-sectional study in a tertiary referral unit.

Stillbirth remains an often unpredictable and devastating pregnancy outcome, and despite thorough investigation, the number of stillbirths attributable to unexplained causes remains high. Placental examination has become increasingly important where access to perinatal autopsy is limited. We aimed to examine the causes of stillbirth in normally formed infants over 30years and whether a declining autopsy rate has affected our ability to determine a cause for stillbirths. All cases of normally formed singleton infants weighing ≥500g that died prior to the onset of labor from 1989 to 2018 were examined. Trends for specific causes and uptake of perinatal autopsy were analyzed individually. In all, 229641 infants were delivered, with 840 stillbirths giving a rate of 3.66/1000. The rate of stillbirth declined from 4.84/1000 in 1989 to 2.51 in 2018 (P<.001). There was no difference in the rate of stillbirth between nulliparous and multiparous women (4.25 vs 3.66 per 1000, P=.026). Deaths from placental abruption fell (1.13/1000 in 1989 to 0 in 2018, P<.001) and the relative contribution of placental abruption to the incidence of stillbirth also fell, from 23.3% (7/30) in 1989 to 0.0% (0/19) in 2018 (P<.001). Stillbirth attributed to infection remained static (0.31/1000 in 1989 to 0.13 in 2018, P=.131), while a specific causal organism was found in 79.2% (42/53) of cases. Unexplained stillbirths decreased from 2.58/1000 (16/6200) in 1989 to 0.13 (1/7581) in 2018 (P<.001) despite a fall in the uptake of perinatal autopsy (96.7% [29/30] in 1989 to 36.8% (7/19) in 2018; P<.001). Placental disease emerged as a significant cause of stillbirth from 2004 onwards (89.5% [17/19] in 2018). The present analysis is one of the largest single-center studies on stillbirth published to date. Stillbirth rates have fallen across the study period across parity. A decrease in deaths secondary to placental abruption contributed largely to this. Infection-related deaths are static; however, in one-fifth of cases a causative organism was not found. Despite a decreasing autopsy rate, the number of unexplained stillbirths continues to fall as the importance of placental pathology is increasingly recognized.

Perceptions of the healthcare providers regarding acceptability and conduct of minimal invasive tissue sampling (MITS) to identify the cause of death in under-five deaths and stillbirths in North India: a qualitative study

BackgroundIndia contributes the highest share of under-five and neonatal deaths and stillbirths globally. Diagnostic autopsy, although useful for cause of death identification, have limited acceptance. Minimally invasive tissue sampling (MITS) is an alternative to autopsy for identification of the cause of death (CoD). A formative research linked to pilot MITS implementation was conducted to document the perceptions and attitudes of the healthcare professionals and the barriers for implementation.MethodsThis exploratory qualitative study conducted at a tertiary care hospital in New Delhi, India included the hospital staffs. In-depth interviews were conducted with the doctors, nurses and support staffs from pediatrics, neonatology, obstetrics and forensic medicine departments. Inductive data analysis was done to identify the emerging themes and codes.ResultsA total of 26 interviews (doctors, n = 10; nurses, n = 9 and support staffs, n = 7) were conducted. Almost all professional and support staffs were positive about the MITS and its advantage for CoD identification including co-existing and underlying illnesses. Some opined conduct of MITS for the cases without clear diagnosis. All participants perceived that MITS would be acceptable for parents due to the non-disfigurement and preferred by those who had unexplained child deaths or stillbirths in past. The key factors for MITS acceptance were appropriate communication, trust building, involvement of senior doctors, and engagement of the counselor prior to deaths and training of the personnel. For implementation and sustenance of MITS, involvement of the institute authority and government stakeholders would be essential.ConclusionsMITS was acceptable for the doctors, nurses and support staffs and critical for better identification of the causes of death and stillbirths. The key facilitating factors and challenges for implementing MITS at the hospital in Indian context were identified. It emphasized on appropriate skill building, counseling, system organization and buy-in from institution and health authorities for sustenance of MITS.

Identification of the optimal growth chart and threshold for the prediction of antepartum stillbirth.

To evaluate the effect of the choice growth chart and threshold used to define small for gestational age (SGA) on the predictive value of SGA for placenta-related or unexplained antepartum stillbirth. A retrospective cohort study of all women with a singleton pregnancy who gave birth > 24week gestation in a single center (2000-2016). The exposure of interest was SGA, defined as birth weight < 10th or < 25th centile according to three fetal growth charts (Hadlock et al., Radiology 181:129-133, 1991; intergrowth-21st (IG21), WHO 2017, and a Canadian birthweight-based reference-Kramer et al., Pediatrics 108:E35, 2001). The outcome of interest was antepartum stillbirth due to placental dysfunction or unknown etiology. Cases of stillbirth attributed to other specific etiologies were excluded. A total of 49,458 women were included in the cohort. There were 103 (0.21%) cases of stillbirth due to placental dysfunction or unknown etiology. For cases in the early stillbirth cluster (≤ 30weeks), the detection rate was high and was similar for the three ultrasound-based fetal growth charts of Hadlock, IG21, and WHO (range 83.3-87.0%). In contrast, the detection rate of SGA for cases in the late stillbirth cluster (> 30weeks) was low, being highest for WHO and Hadlock (36.7% and 34.7%, respectively), and lowest for IG21 (18.4%). Using a threshold of the 25th centile increased the detection rate for stillbirth by approximately 15-20% compared with that achieved by the 10th centile cutoff. At > 30week gestation, the Hadlock or WHO fetal growth charts provided the best balance between detection rate and false positive rate for stillbirth.

A missense mutation of ErbB2 produces a novel mouse model of stillbirth associated with a cardiac abnormality but lacking abnormalities of placental structure.

BackgroundIn humans, stillbirth describes the death of a fetus before birth after 28 weeks gestation, and accounts for approximately 2.6 million deaths worldwide annually. In high-income countries, up to half of stillbirths have an unknown cause and are described as “unexplained stillbirths”; this lack of understanding impairs efforts to prevent stillbirth. There are also few animal models of stillbirth, but those that have been described usually have significant placental abnormalities. This study describes a novel mutant murine model of fetal death with atrial conduction block due to an ErbB2 missense mutation which is not associated with abnormal placental morphology.MethodsPhenotypic characterisation and histological analysis of the mutant mouse model was conducted. The mRNA distribution of the early cardiomyocyte marker Nkx2-5 was assessed via in situ hybridisation. Cardiac structure was quantified and cellular morphology evaluated by electron microscopy. Immunostaining was employed to quantify placental structure and cell characteristics on matched heterozygous and homozygous mutant placental samples.ResultsThere were no structural abnormalities observed in hearts of mutant embryos. Comparable Nkx2-5 expression was observed in hearts of mutants and controls, suggesting normal cardiac specification. Additionally, there was no significant difference in the weight, placenta dimensions, giant cell characteristics, labyrinth tissue composition, levels of apoptosis, proliferation or vascularisation between placentas of homozygous mutant mice and controls.ConclusionEmbryonic lethality in the ErbB2 homozygous mutant mouse cannot be attributed to placental pathology. As such, we conclude the ErbB2M802R mutant is a model of stillbirth with a non-placental cause of death. The mechanism of the atrial block resulting from ErbB2 mutation and its role in embryonic death is still unclear. Studying this mutant mouse model could identify candidate genes involved in stillbirth associated with structural or functional cardiac defects.

Complex and Novel Arrhythmias Precede Stillbirth in Fetuses With De Novo Long QT Syndrome.

Long QT syndrome (LQTS) is a leading cause of sudden cardiac death in early life and has been implicated in ≈10% of sudden infant deaths and unexplained stillbirths. The purpose of our study was to use fetal magnetocardiography to characterize the electrophysiology and rhythm phenotypes of fetuses with de novo and inherited LQTS variants and identify risk factors for sudden death before birth. We reviewed the fetal magnetocardiography database from the University of Wisconsin Biomagnetism Laboratory for fetuses with confirmed LQTS. We assessed waveform intervals, heart rate, and rhythm, including the signature LQTS rhythms: functional 2° atrioventricular block, T-wave alternans, and torsade de pointes (TdP). Thirty-nine fetuses had pathogenic variants in LQTS genes: 27 carried the family variant, 11 had de novo variants, and 1 was indeterminate. De novo variants, especially de novo SCN5A variants, were strongly associated with a severe rhythm phenotype and perinatal death: 9 (82%) showed signature LQTS rhythms, 6 (55%) showed TdP, 5 (45%) were stillborn, and 1 (9%) died in infancy. Those that died exhibited novel fetal rhythms, including atrioventricular block with 3:1 conduction ratio, QRS alternans in 2:1 atrioventricular block, long-cycle length TdP, and slow monomorphic ventricular tachycardia. Premature ventricular contractions were also strongly associated with TdP and perinatal death. Fetuses with familial variants showed a lower incidence of signature LQTS rhythm (6/27=22%), including TdP (3/27=11%). All were live born. The malignancy of de novo LQTS variants was remarkably high and demonstrate that these mutations are a significant cause of stillbirth. Their ability to manifest rhythms not known to be associated with LQTS increases the difficulty of echocardiographic diagnosis and decreases the likelihood that a resultant fetal loss is attributed to LQTS. Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03047161.

Classifying stillbirths in a tertiary care hospital of India: International Classification of Disease-perinatal Mortality (ICD-PM) versus cause of death-associated condition (CODAC) system

A number of classification system are available to classify stillbirths, but there remains a lack of a uniform global system of classification. This study evaluated the feasibility of the ICD-PM classification system and COD-AC to classify the stillbirths and to discuss the interpretation of “the newer” classification system (ICD-PM) over the COD-AC system. Over a period of one year, out of 5776 total births 314 were stillborns with a stillbirth rate of 54 per 1000 total births. As per ICD PM Classification System, 69.1% of stillbirths were ante partum and rest intrapartum. The associated maternal conditions at the time of foetal death were also classified into five groups and maximum mothers (44.3%) were grouped under M4-medical/surgical disorders. According to COD-AC system of classification 90% of cases were assigned the cause of death, rest 10% remained unexplained. The ICD-PM and CODAC classification both seem to be feasible but ICD-PM clearly defines the time of foetal death and correlates feto-maternal dyad together. IMPACT STATEMENT What is already known on this subject? Classifying stillbirths is crucial to recognise the actual cause of foetal death and to gather the relevant information for planning the preventive strategies especially in low middle-income countries (LMICs) which contribute to 98% of total global burden of 2.6 million stillbirths annually. In literature CODAC system was found most suitable for low middle-income countries. In 2016, WHO proposed a newer system, i.e., ICD-PM: WHO application of ICD-10 to deaths during the perinatal period. What do the results of this study add? With ICD-PM classification stillbirths were categorised more clearly in different groups and feto-maternal condition were linked together along with both intrapartum and ante partum stillbirth which can help to set the priorities and future planning for prevention. The proportion of unexplained stillbirth has also reduced significantly compared to CODAC system. What are the implications of these findings for clinical practice and/or further research? CD-PM system of classification seems feasible and would facilitate the uniform and consistent stillbirth data even from LMICs for global comparison although more number of studies are needed for conclusion. The system has been changed to ICD-PM in our institute.