Objective: To determine whether certain medication use during pregnancy is associated with restless legs syndrome (RLS). Design, Setting, Participants: A secondary analysis of a cohort study of first-time pregnant individuals enrolled at 8 U.S. sites between 10/1/2010 and 9/30/2013. Main Outcome Measures: RLS symptoms were ascertained in early (6 0-13 6) and mid (22 0-29 6) pregnancy based on the International RLS Study Group diagnostic criteria. Methods: Throughout their pregnancy, participants reported all medications taken. In early and mid-pregnancy, we created a set of dichotomous variables to indicate whether participants took any ‘at-risk’ medication from the 5 pre-specified categories, including first-generation antihistamines, serotonergic antidepressants, dopamine antagonists, tricyclic antidepressants, and mirtazapine. We estimated the relative risks of RLS symptoms by each category of medication use using Poisson regression, adjusting for age, race and ethnicity, and tobacco use. Results: Of 8,390 participants (27.2±5.6 years), 11.9% and 8.6% took ‘at-risk’ medications in early and mid-pregnancy, respectively. The most frequent medications were first-generation antihistamines and serotonergic antidepressants. The prevalence of RLS symptoms was 17.8% in early pregnancy and 30.0% in mid-pregnancy. Participants taking first-generation antihistamines (aRR [95% CI], 1.28 [1.08-1.53]) or serotonergic antidepressants (aRR [95% CI], 1.81 [1.53-2.14]) were more likely to experience concurrent RLS symptoms in early pregnancy. These associations were weaker in mid-pregnancy. Conclusions: The use of first-generation antihistamines and serotonergic antidepressants is prevalent in pregnancy and is associated with a higher prevalence of RLS symptoms. Awareness of this association may help both pregnant people and their clinicians make individualized decisions regarding medication use.

Objective. The purpose of this study was to explore individuals’ beliefs, values, and experiences surrounding stillbirth evaluation decisions. Design. Qualitative research Setting. University of Utah Health Population. Parents who experienced a stillbirth in the past 5 years (n=19) were interviewed about their experiences and decision to consent or decline postmortem evaluations Methods. Qualitative content analysis Main outcome measures. Barriers and facilitators to parents’stillbirth postmortem decision-making. Results. Participants communicated several facilitators and barriers that contributed to their stillbirth evaluation decision. Reasons for consenting to evaluations were belief in science, background in medicine, altruism, to inform future pregnancies, thinking about preventing another stillbirth, and how patients viewed the care of their stillborn by the medical team. Reasons for declining evaluations were receiving a diagnosis prior to being offered a postmortem evaluation, intent to avoid causing further harm to the baby, interest to spend more time with their baby, and cost of the evaluation. Conclusion. Participants identified stillbirth as one of their most difficult experiences as a parent. Diagnostic and emotional barriers create further challenges to decision-making for stillbirth postmortem evaluations. Parents often rely on inadequate information and personal values and beliefs during this time-sensitive decision process. Decision support for stillbirth evaluations and training for medical providers could benefit parents, may increase stillbirth evaluation uptake, and potentially prevent decisional regret.

Objective: To derive and test the implications of a sex-specific fetal growth standard. Design: Secondary analysis of a prospective observational cohort. Setting: Eight U.S. centers. Population or Sample: Nulliparas followed longitudinally through pregnancy. A lower-risk subgroup (exclusions: chronic hypertension, pre-gestational diabetes, suspected aneuploidy, preterm delivery) was selected for fetal growth equation derivation. Methods: Fetal weights at 14-20 weeks, 22-29 weeks, and birth were used to derive a sex-specific fetal growth equation. We compared rates of SGA and LGA by sex using the sex-specific and sex-neutral (Hadlock) standards. Using the full unselected cohort, we assessed outcomes and clinical management according to SGA and LGA status. Main outcome measures: Proportion considered SGA and LGA; obstetric interventions relevant to SGA and LGA. Results: We derived a sex-specific equation using 7,280 infants. The sex-neutral standard diagnosed SGA more often in female and LGA more often in male newborns. The sex-specific standard resolved these disparities. Using the full unselected cohort (N=8,339), newborns reclassified from SGA to AGA by the sex-specific standard were more likely to be delivered for growth restriction with comparable risk of morbidity compared to newborns considered AGA by both methods. Newborns reclassified from AGA to LGA by the sex-specific standard had higher rates of cesarean for arrest of descent, cesarean for arrest of dilation, and shoulder dystocia than newborns considered AGA by both methods. Conclusions: The sex-neutral standard generates sex disparities in SGA and LGA at birth. A sex-specific standard resolves these disparities and may improve growth pathology risk stratification.

Objective: This study aims to estimate the familial risk of placental abruption using a large population database. Design: Retrospective familial aggregation study of placental abruption utilizing a case-control design. Population: The Utah Population Database is a genealogic database of over 11 million individuals, which contains medical and demographic information linked to official records dating back to the 1900s. Methods: Cases of placental abruption and controls were ascertained from birth certificates, death certificates, and inpatient medical records. Controls were matched 3:1 to cases based on age, parity, and number of relatives in the database. Familial risk of placental abruption was estimated using generalized linear mixed-effect regression and conditional logistic regression. Main outcome measures: Unadjusted and adjusted odds of placental abruption between first-, second-, and third-degree relatives. Results: Of 1,168,378 pregnancies analyzed in the Utah Population Database, 32,823 cases (2.8%) of placental abruption were identified. First-degree relatives inherit an adjusted odds of placental abruption estimated at 1.18 (95% CI: 1.12 – 1.23) when a family member has had at least one placental abruption, and 1.38 (95% CI: 1.17 – 1.63) with two or more placental abruptions. The estimated effect is lower for second- and third-degree relatives. After controlling for clinical risk factors, individuals inherit an adjusted odds of placental abruption estimated at 1.16 (95% CI: 1.03 – 1.31, p=0.014) with a first-degree family history of placental abruption. The estimates for second- and third-degree relatives using this method are not statistically significant. Conclusion: These findings represent an argument for the inheritance of genetic factors which predispose the occurrence of placental abruption.

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 5 geographic regions in the USA. Population 384 stillbirth cases of the SCRN study (2006-2008). Methods FSMs 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 500kb. CNVs were classified into two groups: normal, defined as no CNVs>500kb 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-squared test. Results The proportion of stillbirth cases with any FSMs was higher among those with abnormal CNVs compared with those with normal CNVs (46.7% vs. 19.6%; p-value<0.001). The most common organ system-specific FSMs associated with abnormal CNVs were cardiac defects, followed by craniofacial and skeletal defects. A pathogenic deletion of 1q21.1 involving 46 genes (e.g., CHD1L) and a duplication of 21q22.13 involving 4 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 counseling and care surrounding pregnancies affected by FSMs at risk for stillbirth.

OBJECTIVE To assess the relationship between allostatic load in early pregnancy and CVD, 2 to 7 years postpartum, and potential pathways contributing to racial disparities in CVDs. DESIGN Secondary analysis of an observational cohort study. SETTING nuMom2b Heart Health Study. POPULATION Pregnant individuals. METHODS Our primary exposure was dichotomous high allostatic load in the first trimester, defined as four or more out of 12 biomarkers in the “worst” quartile. The primary outcome was new diagnosis of composite CVD, consisting of HTN and or MD (fasting glucose greater than 100 mg/dL or medication for diabetes). Each outcome and allostatic load component was analyzed secondarily. Multivariable logistic regression was used to test the association between high allostatic load and CVD adjusted for potential confounders. Mediation and moderation analyses assessed the role of high allostatic load in racial disparities of CVD. MAIN OUTCOME MEASURE Composite CVD. RESULTS Among 4,022 individuals, CVD was identified in 1,462 (36.4%); 26.6% had HTN, and had 15.4% MD. High allostatic load was present in 33.0%. After adjustment for covariates, high allostatic load was associated with CVD (aOR 2.0, 1.8-2.3), HTN (2.1, 1.8-2.4), and MD (1.7, 1.5-2.1). There was a reduction in the magnitude of the relationship between race and CVD with the addition of allostatic load. Self-reported race did not significantly moderate the relationship between allostatic load and CVD. CONCLUSION High allostatic load is associated with CVD. Allostatic load was a partial mediator between race and CVD. Race did not moderate the relationship between allostatic load and CVD.

Objective To conduct a feasibility whole-genome sequencing (WGS) study in families to identify genetic variants relevant to unexplained pregnancy loss. Methods We conducted a pilot WGS study of four families with 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. Results 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 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 missense compound heterozygous SNVs impacting genes (e.g., VWA5B2) in two fetal death samples that were absent from live births and population controls, providing evidence for haplosufficient genes relevant to pregnancy loss. Conclusions 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.

Objective To determine if stillbirth aggregates in families and quantify its familial risk using extended pedigrees. Design State-wide matched case-control study. Setting Utah, United States. Population Stillbirth cases (n=9 404) and live-birth controls (18 808) between 1978 and 2019. Methods Using the Utah Population Database, a population‐based genealogical resource linked with state fetal death and birth records, we identified high-risk pedigrees with excess familial aggregation of stillbirth using the Familial Standardized Incidence Ratio (FSIR). Stillbirth odds ratio (OR) for first-degree relatives (FDR), second-degree relatives (SDR), and third-degree relatives (TDR) of parents with a stillbirth and live-birth were estimated using logistic regression models. Results We identified 390 high-risk pedigrees with evidence for excess familial aggregation (FSIR≥2.00 and P-value<0.05). FDRs, SDRs and TDRs of affected parents had 1.14-fold (95% confidence interval [CI]: 1.04-1.26), 1.22-fold (95% CI: 1.11-1.33), and 1.15-fold (95% CI: 1.08-1.21) higher stillbirth odds compared to FDRs, SDRs and TDRs of unaffected parents, respectively. Parental sex-specific analyses showed male FDRs, SDRs and TDRs of affected fathers had 1.22-fold (95% CI: 1.02-1.47), 1.38-fold (95% CI: 1.17-1.62), 1.17-fold (95% CI: 1.05-1.30) higher stillbirth odds compared to those of unaffected fathers, respectively. FDRs, SDRs and TDRs of affected mothers had 1.12-fold (95% CI: 0.98-1.28), 1.09-fold (95% CI: 0.96-1.24), and 1.15-fold (95% CI: 1.06-1.24) higher stillbirth odds compared with those of unaffected mothers, respectively. Conclusions We provide evidence for familial aggregation of stillbirth. Our findings warrant investigation into genes associated with stillbirth and underscore the need to design large-scale studies to determine its genetic architecture.

Objective To examine the association of DNA copy number variants (CNVs) with pathologic placental lesions (PPLs) in stillborn fetuses. Design A secondary analysis of stillbirth cases in the Stillbirth Collaborative Research Network case-control study. Setting Multicenter, 59 hospitals in 5 geographic regions in the USA. Population 387 stillbirth cases (2006-2008). Methods Using standard definitions, PPLs were categorized by type including maternal and fetal vascular, inflammatory and immune/idiopathic lesions. Using single-nucleotide polymorphism array, CNVs of at least 500 kb were detected. 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 PPLs using the Wald Chi-squared 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 compared with those with normal CNVs (81.7% vs. 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 compared to those with normal CNVs. Pathogenic CNVs in stillborn fetuses with maternal vascular PPLs spanned several genes with known relevant mechanisms. Conclusions Abnormal placental/fetal CNVs were associated with maternal vascular PPLs in stillborn fetuses. Findings may provide insight on the mechanisms of specific genetic abnormalities associated with placental dysfunction and stillbirth.

Placenta accreta spectrum: Welcome progress and a call for standardization.Mini-commentary for BJOG on Kayem et al 2021 BJOG-20-1462R3Placenta accreta spectrum (PAS) is among the most feared causes of maternal morbidity worldwide, and yet few prospective data are available to inform best practice. PAS is rare enough that rigorous study in a single center is difficult, but common enough that most obstetric hospitals now encounter PAS. Management and outcomes vary strikingly between hospitals and best practice, regrettably, is guided more by expert consensus than by level I evidence. In fact, most clinical questions regarding management of PAS are informed by essentially no prospective data (Collins et al. Am J Obstet Gynecol. 2019;220:511-526).Into this data void has come the PACCRETA cohort (Kayem et al. Act Obstet Gynecol Scand 2013;92:476-482) and some of its first results, published in this issue of BJOG (Kayem et al. BJOG 2021). PACCRETA is a prospective population-based study from 176 hospitals in France, capturing 30% of all French deliveries, from from 2013 to 2015. The study investigators identified 249, or 4.8 per 10,000, cases of PAS.Of all PAS patients, Kayem and colleagues found that a full half did not have the classic combination of risk factors for PAS (previa with history of cesarean). This group had lower morbidity and milder disease than those with the classic combination. Only 17% of those without classic risk factors were diagnosed antenatally. The message here is mixed: those without classic PAS risk factors are less likely to be diagnosed antenatally (bad) but appear to suffer less morbidity overall (good).But did these patients actually have PAS? Only 21% of those without prior cesarean and previa had a hysterectomy. Although this could be due to a regional preference for conservative treatments, the presence of false positives seems likely. Without a hysterectomy specimen, the diagnosis of PAS is difficult, controversial, and (in our opinion) highly susceptible to overdiagnosis. The authors define “strict” criteria for true cases of PAS, but several criteria depended entirely on the subjective assessment of a clinician faced with a difficult placental removal and the flawed principle of PAS as diagnosis of exclusion . Difficulty in manual placental removal or massive bleeding from an implantation site does not always indicate that microscopic PAS was present. Similarly, areas of prior cesarean section scar dehiscence (windows) where the placenta can be seen through the serosa are often diagnosed as percreta (Figure) without any histological evidence of the villous tissue having invaded through the serosa or beyond (Hecht et al. Modern Pathol 2020;33:2382-2396).We congratulate Kayem and colleagues for the current study and all of their important contributions to our understanding of PAS. However, these data illustrate the need for standardization of the definition of PAS, especially in conservatively managed cases with considerable potential for misdiagnosis. There is a desperate need for controlled studies of patients with antenatally suspected PAS with detailed and objective documentation of imaging, intra-operative findings, and when available, histopathological examination. In absence of such studies, the void of definitive data to guide treatment options will remain wide open.