Copy number variants and fetal structural abnormalities in stillborn fetuses: A secondary analysis of the Stillbirth Collaborative Research Network study.

OBJECTIVE: To examine the association of placental and fetal DNA copy number variants (CNVs) with fetal structural malformations (FSMs) in stillborn fetuses. DESIGN: A secondary analysis of stillbirth cases in the Stillbirth Collaborative Research Network (SCRN) study. SETTING: Multicenter, 59 hospitals in five geographic regions in the USA. POPULATION: 388 stillbirth cases of the SCRN study (2006-2008). METHODS: Fetal structural malformations were grouped by anatomic system and specific malformation type (e.g. central nervous system, thoracic, cardiac, gastrointestinal, skeletal, umbilical cord and craniofacial defects). Single-nucleotide polymorphism array detected CNVs of at least 500 kb. CNVs were classified into two groups: normal, defined as no CNVs >500 kb or benign CNVs, and abnormal, defined as pathogenic or variants of unknown clinical significance. MAIN OUTCOME MEASURES: The proportions of abnormal CNVs and normal CNVs were compared between stillbirth cases with and without FSMs using the Wald Chi-square test. RESULTS: The proportion of stillbirth cases with any FSMs was higher among those with abnormal CNVs than among those with normal CNVs (47.5 versus 19.1%; P-value <0.001). The most common organ system-specific FSMs associated with abnormal CNVs were cardiac defects, followed by hydrops, craniofacial defects and skeletal defects. A pathogenic deletion of 1q21.1 involving 46 genes (e.g. CHD1L) and a duplication of 21q22.13 involving four genes (SIM2, CLDN14, CHAF1B, HLCS) were associated with a skeletal and cardiac defect, respectively. CONCLUSION: Specific CNVs involving several genes were associated with FSMs in stillborn fetuses. The findings warrant further investigation and may inform counselling and care surrounding pregnancies affected by FSMs at risk for stillbirth.

Copy number variants and placental abnormalities in stillborn fetuses: A secondary analysis of the Stillbirth Collaborative Research Network study.

OBJECTIVE: To examine the association of fetal/placental DNA copy number variants (CNVs) with pathologic placental lesions (PPLs) in pregnancies complicated by stillbirth. DESIGN: A secondary analysis of stillbirth cases in the Stillbirth Collaborative Research Network case-control study. SETTING: Multicenter, 59 hospitals in five geographical regions in the USA. POPULATION: 387 stillbirth cases (2006-2008). METHODS: Using standard definitions, PPLs were categorised by type including maternal vascular, fetal vascular, inflammatory and immune/idiopathic lesions. Single-nucleotide polymorphism array detected CNVs of at least 500 kb. CNVs were classified into two groups: normal, defined as no CNV >500 kb or benign CNVs, and abnormal, defined as pathogenic or variants of unknown clinical significance. MAIN OUTCOME MEASURES: The proportions of abnormal CNVs and normal CNVs compared between stillbirth cases with and without PPLs using the Wald Chi-square test. RESULTS: Of 387 stillborn fetuses, 327 (84.5%) had maternal vascular PPLs and 60 (15.6%) had abnormal CNVs. Maternal vascular PPLs were more common in stillborn fetuses with abnormal CNVs than in those with normal CNVs (81.7% versus 64.2%; P = 0.008). The proportions of fetal vascular, maternal/fetal inflammatory and immune/idiopathic PPLs were similar among stillborn fetuses with abnormal CNVs and those with normal CNVs. Pathogenic CNVs in stillborn fetuses with maternal vascular PPLs spanned several known genes. CONCLUSIONS: Abnormal placental/fetal CNVs were associated with maternal vascular PPLs in stillbirth cases. The findings may provide insight into the mechanisms of specific genetic abnormalities associated with placental dysfunction and stillbirth.

Challenges in Interpreting Obstetrics and Gynecology Literature.

The field of obstetrics and gynecology is constantly replenished with the newest research findings. In an era of rapidly available study publications, there are a number of challenges to interpreting the obstetrics and gynecology literature. Common pitfalls include the over reliance on the dichotomized P-value, lack of transparency, bias in study reporting, limitations of resources, absence of standardized practices and outcomes in study design, and the rare concerns for data integrity. We review these predominant challenges and their potential solutions, in interpreting the obstetrics and gynecology literature.

Adjunct Therapy at Time of Examination-Indicated Cervical Cerclage in Singleton Pregnancies: A Systematic Review and Meta-analysis.

OBJECTIVE: Physical examination-indicated cerclage for cervical insufficiency prolongs gestation, but evidence on the addition of adjuncts to further prolong latency is limited. The aim of this systematic review and meta-analysis was to compare gestational latency between those who did and did not receive adjunct antibiotic or tocolytic therapy at the time of examination-indicated cerclage. STUDY DESIGN: Electronic databases (1966-2020) were searched for randomized controlled trials (RCTs) and cohort studies comparing adjunct antibiotic or tocolytic use versus nonuse at time of examination-indicated cerclage, defined as placement for cervical dilation ≥1 cm, in a current singleton pregnancy. Studies including individuals with intra-amniotic infection, cerclage in place, nonviable gestation, or ruptured membranes were excluded. The primary outcome was latency from cerclage placement to delivery. Secondary outcomes included preterm birth, preterm premature rupture of membranes, birth weight, and neonatal survival. Risk of bias was assessed using standardized tools. Heterogeneity was assessed using χ 2 and I 2 tests. Results were pooled and analyzed using a random-effects model. This study is registered with The International Prospective Register of Systematic Reviews (PROSPERO) with registration no.: CRD42021216370. RESULTS: Of 923 unique records, 163 were reviewed in full. Three met inclusion criteria: one RCT and two retrospective cohorts. The included RCT (n = 50) and one cohort (n = 142) compared outcomes with and without adjunct use of antibiotic and tocolytic, while the second cohort (n = 150) compared outcomes with and without adjunct tocolytic, with a subpopulation also receiving antibiotics. The RCT was nested within one of the cohorts, and therefore only one of these two studies was utilized for any given outcome to eliminate counting individuals twice. Risk of bias was "critical" for one cohort study, "moderate" for the other cohort study, and "some concerns" for the RCT. Gestational latency could not be pooled and meta-analyzed. Adjunct tocolytic-antibiotic therapy was not associated with a decrease in risk of preterm delivery <28 weeks (relative risk [RR] = 0.90, 95% confidence interval [CI]: 0.65-1.26; χ 2 = 0.0, I 2 = 0.0%) or neonatal survival to discharge (RR = 1.11, 95% CI: 0.91-1.35; χ 2 = 0.05, I 2 = 0.0%). CONCLUSION: There is not enough evidence to robustly evaluate the use of adjunct tocolytics or antibiotics at time of examination-indicated cerclage to prolong latency. KEY POINTS: · Limited data on adjunct antibiotic tocolytics at cerclage.. · Widely variable practices at time of cerclage identified.. · Role of adjunct therapies at time of examination-indicated cerclage remains unclear..

Association of Prostaglandin Use for Cervical Ripening with Mode of Delivery in Small for Gestational Age versus Non-Small for Gestational Age Neonates.

OBJECTIVE: Prostaglandins (PGs) use for cervical ripening with small for gestational age (SGA) fetuses is controversial since it remains uncertain if use increases the chance of cesarean delivery (CD). We aimed to assess the association between PG use for cervical ripening and mode of delivery between SGA and appropriate for gestational age (AGA) neonates. STUDY DESIGN: Secondary analysis of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b), a prospective observational cohort study of 10,038 nulliparas. We included women undergoing induction with nonanomalous fetuses in the cephalic presentation. Women with >2 cm cervical dilation or prior uterine scar were excluded. We assessed the association of PG use with CD among women with SGA and AGA neonates. SGA was defined as birth weight <10th percentile for gestational age and sex. Multivariable logistic regression was used to adjust for potential confounders and test for interaction. Secondary outcomes included adverse neonatal outcomes, indication for CD, maternal hemorrhage, and chorioamnionitis. RESULTS: Among 2,353 women eligible, PGs were used in 54.8%, SGA occurred in 15.1%, and 35.0% had CD. The association between PG use and CD differed significantly (interaction p = 0.018) for SGA versus AGA neonates; CD occurred more often in SGA neonates exposed to PGs than not (35 vs. 22%, p = 0.009). PG use was not associated with CD among AGA neonates (36 vs. 36%, p = 0.8). This effect remained significant when adjusting for body mass index, race/ethnicity, and cervical dilation. Among SGA neonates, CD for "nonreassuring fetal status" was similar between PG groups. Among SGA neonates, PG use was not associated with adverse neonatal outcomes or postpartum hemorrhage but had a higher rate of chorioamnionitis (7.0 vs. 2.1%, p = 0.048). CONCLUSION: PG use was associated with a higher rate of CD in SGA but not AGA neonates; however, further studies are needed before PG use is discouraged with SGA neonates. KEY POINTS: · PGs are commonly used for cervical ripening.. · PG use was associated with increased risk of cesarean delivery in SGA neonates.. · PG use was not associated with adverse neonatal outcomes..

Impact of the p-Value Threshold on Interpretation of Trial Outcomes in Obstetrics and Gynecology.

OBJECTIVE: Randomized controlled trials (RCTs) are considered the highest level of evidence to inform clinical practice. However, the reproducibility crisis has raised concerns about the scientific rigor of published RCT findings. Some advocate for a lower p-value threshold. We aimed to review published OB/Gyn topical RCTs in three representative OB/Gyn journals and three high impact non-OB/Gyn journals to determine if their interpretations would change with adoption of a p-value threshold for significance of 0.005. Secondarily, we evaluated if there were differences in methodologic characteristics between those that did and did not lose significance. STUDY DESIGN: A manual search was performed to identify all OB/Gyn RCTs published in the selected journals between July 2017 and June 2019. Data were collected on primary outcome(s), methodology, and p-values. We determined the proportion of primary outcomes that would remain statistically significant with adoption of a p-value significance threshold of 0.005 versus be reinterpreted as "suggestive" (defined as p-value between 0.005 and 0.05). Chi-square or Fisher's exact test were used to compare study characteristics. RESULTS: Overall, 202 RCTs met inclusion criteria; 52% in obstetrics and 48% in gynecology. Of 90 studies considered significant with p <0.05 at the time of publication, 54.4% (n = 49) would maintain significant (p < 0.005), while 45.6% (n = 41) would become suggestive using the lower threshold. Most RCTs utilized a single (90.1%) versus composite (8.9%) primary outcome type, used an intent-to-treat analysis (73.3%), and studied a drug intervention (46.5%). Methodologically, 23.7% did not prespecify analysis type, 28.2% did not meet the pre-determined sample size, and 9.4% did not report an a priori sample size calculation. Studies maintaining significance were more likely to be international and report a funding source. CONCLUSION: Adopting a p-value significance threshold of 0.005 would require reinterpretation of almost half of RCT results in the OB/Gyn literature. Highly variable methodological quality was identified. KEY POINTS: · New p-value threshold results in reinterpretation of nearly half of RCT results in OB/Gyn literature.. · Highly variable methodological quality was identified.. · Reduced use of binary interpretations of significance is necessary..

Antenatal Fetal Adrenal Measurements at 22 to 30 Weeks' Gestation, Fetal Growth Restriction, and Perinatal Morbidity.

OBJECTIVE: Our objective was to test the association of fetal adrenal size with perinatal morbidity among fetuses with fetal growth restriction (FGR; estimated fetal weight [EFW] < 10th percentile). STUDY DESIGN: This was a secondary analysis of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be (nuMoM2b) adrenal study, which measured fetal adrenal gland size at 22 to 30 weeks' gestation. We analyzed the transverse adrenal area (TAA) and fetal zone area (absolute measurements and corrected for fetal size) and the ratio of the fetal zone area to the total transverse area using a composite perinatal outcome of stillbirth, neonatal intensive care unit admission, respiratory distress syndrome, necrotizing enterocolitis, retinopathy of prematurity, sepsis, mechanical ventilation, seizure, or death. Among fetuses with FGR, adrenal measurements were compared between those that did and did not experience the composite perinatal outcome. RESULTS: There were 1,709 eligible neonates. Seven percent (n = 120) were diagnosed with FGR at the time of adrenal measurement, and 14.7% (n = 251) experienced perinatal morbidity. EFW-corrected and absolute adrenal measurements were similar among fetuses with and without FGR as well as among those who did and did not experience morbidity. The area under the curve for corrected TAA was 0.52 (95% confidence interval 0.38-0.67). CONCLUSION: In our cohort, adrenal size was not associated with risk of morbidity among fetuses with FGR.

Customized versus Population Growth Standards for Morbidity and Mortality Risk Stratification Using Ultrasonographic Fetal Growth Assessment at 22 to 29 Weeks' Gestation.

OBJECTIVE: The aim of study is to compare the performance of ultrasonographic customized and population fetal growth standards for prediction adverse perinatal outcomes. STUDY DESIGN: This was a secondary analysis of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be, in which l data were collected at visits throughout pregnancy and after delivery. Percentiles were assigned to estimated fetal weights (EFWs) measured at 22 to 29 weeks using the Hadlock population standard and a customized standard (www.gestation.net). Areas under the curve were compared for the prediction of composite and severe composite perinatal morbidity using EFW percentile. RESULTS: Among 8,701 eligible study participants, the population standard diagnosed more fetuses with fetal growth restriction (FGR) than the customized standard (5.5 vs. 3.5%, p < 0.001). Neither standard performed better than chance to predict composite perinatal morbidity. Although the customized performed better than the population standard to predict severe perinatal morbidity (areas under the curve: 0.56 vs. 0.54, p = 0.003), both were poor. Fetuses considered FGR by the population standard but normal by the customized standard had morbidity rates similar to fetuses considered normally grown by both standards.The population standard diagnosed FGR among black women and Hispanic women at nearly double the rate it did among white women (p < 0.001 for both comparisons), even though morbidity was not different across racial/ethnic groups. The customized standard diagnosed FGR at similar rates across groups. Using the population standard, 77% of FGR cases were diagnosed among female fetuses even though morbidity among females was lower (p < 0.001). The customized model diagnosed FGR at similar rates in male and female fetuses. CONCLUSION: At 22 to 29 weeks' gestation, EFW percentile alone poorly predicts perinatal morbidity whether using customized or population fetal growth standards. The population standard diagnoses FGR at increased rates in subgroups not at increased risk of morbidity and at lower rates in subgroups at increased risk of morbidity, whereas the customized standard does not.

The Hadlock Method Is Superior to Newer Methods for the Prediction of the Birth Weight Percentile.

OBJECTIVES: To compare a traditional ultrasound (US) method for estimated fetal weight (EFW) calculation and fetal growth restriction diagnosis with 2 newer methods for the prediction of small for gestational age (SGA) at birth. METHODS: We reviewed deliveries at our institution from January 1, 2013, to March 31, 2017. Singleton, nonanomalous, well-dated fetuses with a US examination within 2 weeks of delivery were included. Estimated fetal weights and percentiles were calculated by a traditional method (Hadlock et al; Radiology 1991; 181:129-133) and 2 newer methods: Intergrowth-21st (INTG; Ultrasound Obstet Gynecol 2017; 49:478-486) and Salomon et al (Ultrasound Obstet Gynecol 2007; 29:550-555). We calculated each method's test characteristics to predict SGA (birth weight < 10th percentile) using both traditional (EFW < 10th percentile) and receiver operating characteristic (ROC)-derived fetal growth restriction cutoffs. Mean percentile discrepancies between EFW and birth weight measurements were calculated to compare method accuracy. We hypothesized that the INTG and Salomon methods would have superior SGA prediction compared with the Hadlock method. RESULTS: Of 831 pregnancies with a US examination within 2 weeks of delivery, 138 (16.7%) were SGA at birth. Hadlock had the smallest US-birth weight percentile discrepancy (P < .001 versus both INTG and Salomon). When comparing ROC curves, the Hadlock and INTG methods performed comparably, with areas under the curve of 0.91 and 0.90 (P = .08) and optimal EFW cutoffs of the 15th and 22nd percentiles, respectively. The Salomon method performed less well, with an area under the curve of 0.82 (P < .001 versus both Hadlock and INTG methods). CONCLUSIONS: In our study cohort, the Hadlock method predicted the birth weight percentile more accurately than the INTG or Salomon methods and performed comparably with INTG to predict SGA when ROC-derived cutoffs were used.

Comparing the Hadlock fetal growth standard to the Eunice Kennedy Shriver National Institute of Child Health and Human Development racial/ethnic standard for the prediction of neonatal morbidity and small for gestational age.

BACKGROUND: The fetal growth standard in widest use was published by Hadlock >25 years ago and was derived from a small, homogeneous cohort. In 2015, The Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Study published updated standards that are specific to race/ethnicity. These do not allow for precise estimated fetal weight percentile calculation, however, and their effectiveness to predict neonatal morbidity and small for gestational age has not yet been compared to the long-standing Hadlock standard. OBJECTIVE: We compared the ability of the Hadlock standard to predict neonatal morbidity and small for gestational age at birth with that of The Eunice Kennedy Shriver National Institute of Child Health and Human Development race-/ethnicity-specific standard. Our secondary objective was to compare their performance among our Native American population, which is not accounted for in the Eunice Kennedy Shriver National Institute of Child Health and Human Development standard. STUDY DESIGN: For this retrospective study of diagnostic accuracy, we reviewed deliveries at the University of New Mexico Hospital from Jan. 1, 2013, through March 31, 2017. We included mothers with singleton, well-dated pregnancies and nonanomalous fetuses with an estimated fetal weight within 30 days of delivery. Cubic spline interpolation was performed on the Eunice Kennedy Shriver National Institute of Child Health and Human Development estimated fetal weight-percentile tables to calculate percentiles specific to the gestational day. Estimated fetal weight percentiles were then calculated using both the Hadlock and Eunice Kennedy Shriver National Institute of Child Health and Human Development race-/ethnicity-specific standards according to maternal self-identified race/ethnicity. We calculated the receiver operator area under the curve of each method to predict composite and severe composite neonatal morbidity and small for gestational age at birth (birthweight <10th percentile). As an additional measure of method accuracy, we calculated the mean ultrasound-birthweight percentile discrepancy. For Native Americans, percentiles were calculated using the Hadlock and Eunice Kennedy Shriver National Institute of Child Health and Human Development race/ethnicity standards (white, black, Hispanic, Asian), and test characteristics were calculated for each to predict neonatal morbidity and small for gestational age. RESULTS: We included 1514 women, with a mean ultrasonography-to-delivery interval of 14.4 days (±8.8) and a small for gestational age rate of 13.6% (n = 206). For the prediction of both composite and severe composite neonatal morbidity, the Hadlock method had superior performance, with higher areas under the curve than the Eunice Kennedy Shriver National Institute of Child Health and Human Development method (P < .001 for both), though neither had good discriminatory value (all areas under the curve <0.8). For the prediction of small for gestational age at birth, the Hadlock standard had higher sensitivity (61.1%) than the Eunice Kennedy Shriver National Institute of Child Health and Human Development standard, both when using the interpolated Eunice Kennedy Shriver National Institute of Child Health and Human Development method (36.2%, P < .01) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development whole-week 10th percentile cutoff (46.7%, P < .01). The Hadlock method also had a higher area under the curve than the Eunice Kennedy Shriver National Institute of Child Health and Human Development interpolated method to predict small for gestational age (0.89 vs 0.88, P < .01). The Hadlock method had a lower ultrasound-birthweight percentile discrepancy than the Eunice Kennedy Shriver National Institute of Child Health and Human Development method (6.1 vs 16.5 percentile points, P < .01). Fetuses classified as growth restricted by Hadlock but not Eunice Kennedy Shriver National Institute of Child Health and Human Development had significantly higher composite morbidity than normally grown fetuses. Among Native American women, the Hadlock method had the highest area under the curve to predict composite and severe composite morbidity, while the Hadlock and all Eunice Kennedy Shriver National Institute of Child Health and Human Development race-/ethnicity-specific methods performed comparably to predict small for gestational age. CONCLUSION: Despite its publication >25 years ago, the Hadlock standard is superior to the Eunice Kennedy Shriver National Institute of Child Health and Human Development race-/ethnicity-specific standard for the prediction of both neonatal morbidity and small for gestational age.

Effect of ibuprofen vs acetaminophen on postpartum hypertension in preeclampsia with severe features: a double-masked, randomized controlled trial.

BACKGROUND: Nonsteroidal antiinflammatory drug use has been shown to increase blood pressure in nonpregnant adults. Because of this, the American College of Obstetricians and Gynecologists suggests avoiding their use in women with postpartum hypertension; however, evidence to support this recommendation is lacking. OBJECTIVE: Our goal was to test the hypothesis that nonsteroidal antiinflammatory drugs, such as ibuprofen, adversely affect postpartum blood pressure control in women with preeclampsia with severe features. STUDY DESIGN: At delivery, we randomized women with preeclampsia with severe features to receive around-the-clock oral dosing with either 600 mg of ibuprofen or 650 mg of acetaminophen every 6 hours. Dosing began within 6 hours after delivery and continued until discharge, with opioid analgesics available as needed for breakthrough pain. Study drugs were encapsulated in identical capsules such that patients, nurses, and physicians were masked to study allocation. Exclusion criteria were serum aspartate aminotransferase or alanine aminotransferase >200 mg/dL, serum creatinine >1.0 mg/dL, infectious hepatitis, gastroesophageal reflux disease, age <18 years, or current incarceration. Our primary outcome was the duration of severe-range hypertension, defined as the time (in hours) from delivery to the last blood pressure ≥160/110 mm Hg. Secondary outcomes were time from delivery to last blood pressure ≥150/100 mm Hg, mean arterial pressure, need for antihypertensive medication at discharge, prolongation of hospital stay for blood pressure control, postpartum use of short-acting antihypertensives for acute blood pressure control, and opioid use for breakthrough pain. We analyzed all outcome data according to intention-to-treat principles. RESULTS: We assessed 154 women for eligibility, of whom 100 met entry criteria, agreed to participate, and were randomized to receive postpartum ibuprofen or acetaminophen for first-line pain control. Seven patients crossed over or did not receive their allocated study drug, and 93 completed the study protocol in their assigned groups. We found no differences in baseline characteristics between groups, including mode of delivery, body mass index, parity, race, chronic hypertension, and maximum blood pressure prior to delivery. We did not find a difference in the duration of severe-range hypertension in the ibuprofen vs acetaminophen groups (35.3 vs 38.0 hours, P = .30). There were no differences between groups in the secondary outcome measures of time from delivery to last blood pressure ≥150/100 mm Hg, postpartum mean arterial pressure, maximum postpartum systolic or diastolic blood pressures, any postpartum blood pressure ≥160/110 mm Hg, short-acting antihypertensive use for acute blood pressure control, length of postpartum stay, need to extend postpartum stay for blood pressure control, antihypertensive use at discharge, or opioid use for inadequate pain control. In a subgroup analysis of patients who experienced severe-range hypertension, the mean time to blood pressure control in the acetaminophen group was 68.4 hours and ibuprofen group was 56.7 hours (P = .26). At 6 weeks postpartum, there were no differences between groups in the rates of obstetric triage visits, hospital readmissions, continued opioid use, or continued antihypertensive use. CONCLUSION: The first-line use of ibuprofen rather than acetaminophen for postpartum pain did not lengthen the duration of severe-range hypertension in women with preeclampsia with severe features.

Neonatal Outcomes by Mode of Delivery in Preterm Birth.

OBJECTIVE: We set out to test the hypothesis that infants born vaginally at ≤ 30 weeks gestation have less respiratory distress syndrome (RDS) than those born by cesarean delivery. STUDY DESIGN: We conducted a retrospective cohort study of 652 infants born between 24 and 30 (6/7) weeks gestation from March 31, 1996 to May 31, 2014. Comparisons of neonatal outcomes by intended and actual mode of delivery were made using chi-square and t-tests (α = 0.05). Multiple logistic regression was performed to control for confounding variables. RESULTS: Neonates born by cesarean delivery were more likely to have RDS (odds ratio [OR], 1.79; 95% confidence interval [CI], 1.10-2.90), require intubation (OR, 1.80; 95% CI, 1.12-2.88), and have longer neonatal intensive care unit stay (70.0 ± 37.1 vs. 57.3 ± 40.1 days, p = 0.02). CONCLUSION: Compared with cesarean delivery, vaginal delivery is associated with a significant reduction in RDS among infants born at ≤ 30 weeks gestation.

Placental somatic mutation in human stillbirth and live birth: A pilot case-control study of paired placental, fetal, and maternal whole genomes.

INTRODUCTION: A high frequency of single nucleotide somatic mutations in the placenta has been recently described, but its relationship to placental dysfunction is unknown. METHODS: We performed a pilot case-control study using paired fetal, maternal, and placental samples collected from healthy live birth controls (n = 10), live births with fetal growth restriction (FGR) due to placental insufficiency (n = 7), and stillbirths with FGR and placental insufficiency (n = 11). We quantified single nucleotide and structural somatic variants using bulk whole genome sequencing (30-60X coverage) in four biopsies from each placenta. We also assessed their association with clinical and histological evidence of placental dysfunction. RESULTS: Seventeen pregnancies had sufficiently high-quality placental, fetal, and maternal DNA for analysis. Each placenta had a median of 473 variants (range 111-870), with 95 % arising in just one biopsy within each placenta. In controls, live births with FGR, and stillbirths, the median variant counts per placenta were 514 (IQR 381-779), 582 (450-735), and 338 (245-441), respectively. After adjusting for depth of sequencing coverage and gestational age at birth, the somatic mutation burden was similar between groups (FGR live births vs. controls, adjusted diff. 59, 95 % CI -218 to +336; stillbirths vs controls, adjusted diff. -34, -351 to +419), and with no association with placental dysfunction (p = 0.7). DISCUSSION: We confirmed the high prevalence of somatic mutation in the human placenta and conclude that the placenta is highly clonal. We were not able to identify any relationship between somatic mutation burden and clinical or histologic placental insufficiency.

Genome Sequencing is Critical for Forecasting Outcomes following Congenital Cardiac Surgery.

While genome sequencing has transformed medicine by elucidating the genetic underpinnings of both rare and common complex disorders, its utility to predict clinical outcomes remains understudied. Here, we used artificial intelligence (AI) technologies to explore the predictive value of genome sequencing in forecasting clinical outcomes following surgery for congenital heart defects (CHD). We report results for a cohort of 2,253 CHD patients from the Pediatric Cardiac Genomics Consortium with a broad range of complex heart defects, pre- and post-operative clinical variables and exome sequencing. Damaging genotypes in chromatin-modifying and cilia-related genes were associated with an elevated risk of adverse post-operative outcomes, including mortality, cardiac arrest and prolonged mechanical ventilation. The impact of damaging genotypes was further amplified in the context of specific CHD phenotypes, surgical complexity and extra-cardiac anomalies. The absence of a damaging genotype in chromatin-modifying and cilia-related genes was also informative, reducing the risk for adverse postoperative outcomes. Thus, genome sequencing enriches the ability to forecast outcomes following congenital cardiac surgery.

Whole-genome sequencing analysis in families with recurrent pregnancy loss: A pilot study.

One to two percent of couples suffer recurrent pregnancy loss and over 50% of the cases are unexplained. Whole genome sequencing (WGS) analysis has the potential to identify previously unrecognized causes of pregnancy loss, but few studies have been performed, and none have included DNA from families including parents, losses, and live births. We conducted a pilot WGS study in three families with unexplained recurrent pregnancy loss, including parents, healthy live births, and losses, which included an embryonic loss (<10 weeks' gestation), fetal deaths (10-20 weeks' gestation) and stillbirths (≥ 20 weeks' gestation). We used the Illumina platform for WGS and state-of-the-art protocols to identify single nucleotide variants (SNVs) following various modes of inheritance. We identified 87 SNVs involving 75 genes in embryonic loss (n = 1), 370 SNVs involving 228 genes in fetal death (n = 3), and 122 SNVs involving 122 genes in stillbirth (n = 2). Of these, 22 de novo, 6 inherited autosomal dominant and an X-linked recessive SNVs were pathogenic (probability of being loss-of-function intolerant >0.9), impacting known genes (e.g., DICER1, FBN2, FLT4, HERC1, and TAOK1) involved in embryonic/fetal development and congenital abnormalities. Further, we identified inherited missense compound heterozygous SNVs impacting genes (e.g., VWA5B2) in two fetal death samples. The variants were not identified as compound heterozygous SNVs in live births and population controls, providing evidence for haplosufficient genes relevant to pregnancy loss. In this pilot study, we provide evidence for de novo and inherited SNVs relevant to pregnancy loss. Our findings provide justification for conducting WGS using larger numbers of families and warrant validation by targeted sequencing to ascertain causal variants. Elucidating genes causing pregnancy loss may facilitate the development of risk stratification strategies and novel therapeutics.

Genetic Associations with Dynamic Placental Proteins Identify Causal Biomarkers for Hypertension in Pregnancy.

Preeclampsia (PE), a gestational hypertensive disorder, ranks as the second leading cause of maternal mortality worldwide. While PE is considered a multifactorial disease, placental insufficiency is believed to drive its progression. To noninvasively study placental physiology related to adverse pregnancy outcomes (APOs) and predict these outcomes before symptom onset, we measured nine placental protein levels in first- and second-trimester serum samples from 2,352 nulliparous pregnant women in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers- to-Be (nuMoM2b) study. The proteins analyzed include VEGF, PlGF, ENG, sFlt-1, ADAM-12, PAPP-A, fßHCG, INHA, and AFP. Currently, little is known about the genetic variants contributing to the heritability of these proteins during pregnancy, and no studies have explored the causal relationships between early pregnancy proteins and gestational hypertensive disorders. Our study has three objectives. First, we conducted genome-wide association study (GWAS) of nine placental proteins in maternal serum during the first and second trimesters and the difference between time points to understand how genetics may influence placental proteins in early pregnancy. Second, we examined whether early pregnancy placental proteins are causal factors for PE and gestational hypertension (gHTN). Lastly, we investigated the causal relationship between PE/gHTN and long-term HTN. In conclusion, our study discovered significant genetic associations with placental proteins ADAM-12, VEGF, and sFlt-1, offering insights into their regulation during pregnancy. Mendelian randomization (MR) analyses demonstrated evidence of causal relationships between placental proteins, particularly ADAM-12, and gHTN, potentially informing prevention and treatment strategies. Our findings suggest that placental proteins like ADAM-12 could serve as biomarkers for postpartum HTN risk.

Searching and visualizing genetic associations of pregnancy traits by using GnuMoM2b.

Adverse pregnancy outcomes (APOs) are major risk factors for women's health during pregnancy and even in the years after pregnancy. Due to the heterogeneity of APOs, only few genetic associations have been identified. In this report, we conducted genome-wide association studies (GWAS) of 479 traits that are possibly related to APOs using a large and racially diverse study, Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b). To display the extensive results, we developed a web-based tool GnuMoM2b ( https://gnumom2b.cumcobgyn.org/ ) for searching, visualizing, and sharing results from GWAS of 479 pregnancy traits as well as phenome-wide association studies (PheWAS) of more than 17 million single nucleotide polymorphisms (SNPs). The genetic results from three ancestries (Europeans, Africans, and Admixed Americans) and meta-analyses are populated in GnuMoM2b. In conclusion, GnuMoM2b is a valuable resource for extraction of pregnancy-related genetic results and shows the potential to facilitate meaningful discoveries.

Searching and visualizing genetic associations of pregnancy traits by using GnuMoM2b.

Adverse pregnancy outcomes (APOs) are major risk factors for women's health during pregnancy and even in the years after pregnancy. Due to the heterogeneity of APOs, only few genetic associations have been identified. In this report, we conducted genome-wide association studies (GWASs) of 479 traits that are possibly related to APOs using a large and racially diverse study, Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b). To display extensive results, we developed a web-based tool GnuMoM2b (https://gnumom2b.cumcobgyn.org/) for searching, visualizing, and sharing results from a GWAS of 479 pregnancy traits as well as phenome-wide association studies of more than 17 million single nucleotide polymorphisms. The genetic results from 3 ancestries (Europeans, Africans, and Admixed Americans) and meta-analyses are populated in GnuMoM2b. In conclusion, GnuMoM2b is a valuable resource for extraction of pregnancy-related genetic results and shows the potential to facilitate meaningful discoveries.