Publications by authors named "Ronald Wapner"

438 Publications

Case Report: Prenatal Identification of a Mosaic Neocentric Marker Resulting in 13q31.1→qter Tetrasomy in a Mildly Affected Girl.

Front Genet 2022 19;13:906077. Epub 2022 Jul 19.

Department of Pathology & Cell Biology, Columbia University Vagelos College of Physicians and Surgeons and New York-Presbyterian Morgan Stanley Children's Hospital, New York, NY, United States.

Partial tetrasomy of distal 13q has a reported association with a variable phenotype including microphthalmia, ear abnormalities, hypotelorism, facial dysmorphisms, urogenital defects, pigmentation and skin defects, and severe learning difficulties. A wide range of mosaicism has been reported, which may, to some extent, account for the variable spectrum of observed phenotypes. We report here a pregnancy conceived using intrauterine insemination in a 32-year-old female with a history of infertility. Non-invasive prenatal screening (NIPS) was performed in the first trimester which reported an increased risk for trisomy 13. Follow-up cytogenetic workup using chorionic villus sampling (CVS) and amniotic fluid samples showed a mosaic karyotype with a small supernumerary marker chromosome (sSMC). Chromosomal microarray analysis (CMA) identified a mosaic 31.34 Mb terminal gain on chr13q31.1q34 showing the likely origin of the sSMC to distal chromosome 13q. Follow-up metaphase FISH testing suggested an inverted duplication rearrangement involving 13q31q34 in the marker chromosome and the presence of a neocentromere. At 21 months of age, the proband has a history of gross motor delay, hypotonia, left microphthalmia, strabismus, congenital anomaly of the right optic nerve, hemangiomas, and a tethered spinal cord. Postnatal chromosome analyses in buccal, peripheral blood, and spinal cord ligament tissues were consistent with the previous amniocentesis and CVS findings, and the degree of mosaicism varied from 25 to 80%. It is often challenging to pinpoint the chromosomal identity of sSMCs using banding cytogenetics. A combination of low-pass genome sequencing of cell-free DNA, chromosomal microarray, and FISH enabled the identification of the precise chromosomal rearrangement in this patient. This study adds to the growing list of clinically identified neocentric marker chromosomes and is the first described instance of partial tetrasomy 13q31q34 identified in a mosaic state prenatally. Since NIPS is now being routinely performed along with invasive testing for advanced maternal age, an increased prenatal detection rate for mosaic sSMCs in otherwise normal pregnancies is expected. Future studies investigating how neocentromeres mediate gene expression changes could help identify potential epigenetic targets as treatment options to rescue or reverse the phenotypes seen in patients with congenital neocentromeres.
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http://dx.doi.org/10.3389/fgene.2022.906077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9343796PMC
July 2022

Prenatal phenotyping: A community effort to enhance the Human Phenotype Ontology.

Am J Med Genet C Semin Med Genet 2022 Jul 24. Epub 2022 Jul 24.

Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.

Technological advances in both genome sequencing and prenatal imaging are increasing our ability to accurately recognize and diagnose Mendelian conditions prenatally. Phenotype-driven early genetic diagnosis of fetal genetic disease can help to strategize treatment options and clinical preventive measures during the perinatal period, to plan in utero therapies, and to inform parental decision-making. Fetal phenotypes of genetic diseases are often unique and at present are not well understood; more comprehensive knowledge about prenatal phenotypes and computational resources have an enormous potential to improve diagnostics and translational research. The Human Phenotype Ontology (HPO) has been widely used to support diagnostics and translational research in human genetics. To better support prenatal usage, the HPO consortium conducted a series of workshops with a group of domain experts in a variety of medical specialties, diagnostic techniques, as well as diseases and phenotypes related to prenatal medicine, including perinatal pathology, musculoskeletal anomalies, neurology, medical genetics, hydrops fetalis, craniofacial malformations, cardiology, neonatal-perinatal medicine, fetal medicine, placental pathology, prenatal imaging, and bioinformatics. We expanded the representation of prenatal phenotypes in HPO by adding 95 new phenotype terms under the Abnormality of prenatal development or birth (HP:0001197) grouping term, and revised definitions, synonyms, and disease annotations for most of the 152 terms that existed before the beginning of this effort. The expansion of prenatal phenotypes in HPO will support phenotype-driven prenatal exome and genome sequencing for precision genetic diagnostics of rare diseases to support prenatal care.
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http://dx.doi.org/10.1002/ajmg.c.31989DOI Listing
July 2022

The association of race and ethnicity with severe maternal morbidity among individuals diagnosed with hypertensive disorders of pregnancy.

Am J Perinatol 2022 Jun 28. Epub 2022 Jun 28.

Obstetrics & Gynecology, University of Texas Health Sciences Center at Houston, Houston, United States.

Objective: To examine racial disparities in severe maternal morbidity in patients with hypertensive disorder of pregnancy (HDP).

Study Design: Secondary analysis of an observational study of 115,502 patients who had a live birth at ≥ 20 weeks in 25 hospitals in the US, 2008-2011. Only patients with HDP were included in this analysis. Race and ethnicity were categorized as non-Hispanic White (NHW), non-Hispanic Black (NHB) and Hispanic. Associations were estimated between race and ethnicity and the primary outcome of severe maternal morbidity, defined as any of the following: blood transfusion ≥4 units, unexpected surgical procedure, need for a ventilator ≥ 12 hours, intensive care unit (ICU) admission, or failure of ≥ 1 organ system, were estimated by unadjusted logistic and multivariable backward logistic regressions. Multivariable models were run classifying HDP into 3 levels: 1) gestational hypertension; 2) preeclampsia (mild, severe or superimposed); and 3) eclampsia or HELLP.

Results: A total of 9,612 individuals with HDP were included. The frequency of the primary outcome, composite severe maternal morbidity, was higher in NHB patients compared with that in NHW or Hispanic patients (11.8% vs. 4.5% in NHW and 4.8% in Hispanic, p<0.001). This was driven by a higher frequency of blood transfusions and ICU admissions among NHB individuals. After adjusting for sociodemographic and clinical factors, hospital site, and the severity of HDP, the odds ratios of composite severe maternal morbidity did not differ between the groups (adjusted OR 1.26, 95% CI 0.95, 1.67 for NHB and adjusted OR 1.29, 95% CI 0.94, 1.77 for Hispanic, compared to NHW patients).

Conclusion: NHB patients with HDP had higher rates of the composite maternal morbidity compared with NHW, driven mainly by higher frequencies of blood transfusions and ICU admissions. However, once severity and other confounding factors were taken into account, the differences did not persist.
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http://dx.doi.org/10.1055/a-1886-5404DOI Listing
June 2022

ASSOCIATION OF MATERNAL BODY MASS INDEX AND MATERNAL MORBIDITY AND MORTALITY.

Am J Perinatol 2022 Jun 16. Epub 2022 Jun 16.

Oregon Health Sciences University, Portland, Portland, United States.

Objective: To assess the association of maternal BMI with a composite of severe maternal outcomes.

Study Design: Secondary analysis of a cohort of deliveries on randomly selected days at 25 hospitals from 2008-2011. Data on comorbid conditions, intrapartum events, and postpartum course were collected. The reference group (REF, BMI 18.5-29.9), obese (OB, BMI 30-39.9), morbidly obese (MO, BMI 40-49.9) and super morbidly obese (SMO, BMI  50) women were compared. The composite of severe maternal outcomes was defined as death, ICU admission, ventilator use, DVT/PE, sepsis, hemorrhage, DIC, unplanned operative procedure, or stroke. Patients in the REF group were matched 1:1 with those in all other obesity groups based on propensity score using the baseline characteristics of age, race-ethnicity, previous cesarean, pre-existing diabetes, chronic hypertension, parity, cigarette use, and insurance status. Multivariable Poisson regression was used to estimate adjusted relative risks (aRR) and 95% confidence intervals (CI) for the association between BMI and the composite outcome. Because cesarean delivery may be in the causal pathway between obesity and adverse maternal outcomes, models were then adjusted for mode of delivery to evaluate potential mediation.

Results: A total of 52,162 pregnant patients are included in the analysis. Risk of composite maternal outcomes was increased for SMO compared with REF, but not for OB and MO [OB aRR 1.06 95%CI (0.99-1.14); MO aRR 1.10 (95%CI 0.97-1.25); SMO aRR 1.32 95%CI (1.02-1.70)]. However, in the mediation analysis, cesarean appears to mediate 46% (95%CI 31% - 50%) of the risk of severe morbidity for SMO compared with REF.

Conclusion: Super morbid obesity is significantly associated with increased serious maternal morbidity and mortality; however, cesarean appears to mediate this association. Obesity and morbid obesity are not associated with maternal morbidity and mortality.
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http://dx.doi.org/10.1055/a-1877-8918DOI Listing
June 2022

Differential Gene Expression in Cord Blood of Infants Diagnosed with Cerebral Palsy: a Pilot Analysis of the BEAM Cohort.

Dev Neurosci 2022 Jun 15. Epub 2022 Jun 15.

The Beneficial Effects of Antenatal Magnesium (BEAM) clinical trial was conducted between 1997-2007, and demonstrated a significant reduction in cerebral palsy (CP) in preterm infants who were exposed to peripartum magnesium sulfate (MgSO4). However, the mechanism by which MgSO4 confers neuroprotection remains incompletely understood. Cord blood samples from this study were interrogated during an era when next generation sequencing was not widely accessible and few gene expression differences or biomarkers were identified between treatment groups. Our goal was to use bulk RNA deep sequencing to identify differentially expressed genes comparing the following four groups: newborns who ultimately developed CP treated with MgSO4 or placebo, and controls (newborns who ultimately did not develop CP) treated with MgSO4 or placebo. Those who died after birth were excluded. We found that MgSO4 upregulated expression of SCN5A only in the control group, with no change in gene expression in cord blood of newborns who ultimately developed CP. Regardless of MgSO4 exposure, expression of NPBWR1 and FTO were upregulated in cord blood of newborns who ultimately developed CP compared with controls. These data support that MgSO4 may not exert its neuroprotective effect through changes in gene expression. Moreover, NPBWR1 and FTO may be useful as biomarkers, and may suggest new mechanistic pathways to pursue in understanding the pathogenesis of CP. The small number of cases ultimately available for this secondary analysis, with male predominance and mild CP phenotype, is a limitation of the study. In addition, differentially expressed genes were not validated by qRT-PCR.
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http://dx.doi.org/10.1159/000525483DOI Listing
June 2022

Cervical Ripening Efficacy of Synthetic Osmotic Cervical Dilator Compared With Oral Misoprostol at Term: A Randomized Controlled Trial.

Obstet Gynecol 2022 06 2;139(6):1083-1091. Epub 2022 May 2.

Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, New York; the Department of Obstetrics and Gynecology, University of Texas Medical Branch at Galveston, Galveston, Texas; and NEOX s.r.o., Prague, Czech Republic.

Objective: To evaluate whether a synthetic osmotic cervical dilator is noninferior to oral misoprostol for cervical ripening.

Methods: In an open-label, noninferiority randomized trial, pregnant women undergoing induction of labor at 37 weeks of gestation or more with Bishop scores less than 6 were randomized to either mechanical cervical dilation or oral misoprostol. Participants in the mechanical dilation group underwent insertion of synthetic osmotic cervical dilator rods, and those in the misoprostol group received up to six doses of 25 micrograms orally every 2 hours. After 12 hours of ripening, oxytocin was initiated, with artificial rupture of membranes. Management of labor was at the physician's discretion. The primary outcome was the proportion of women achieving vaginal delivery within 36 hours of initiation of study intervention. Secondary outcomes included increase in Bishop score, mode of delivery, induction-to-delivery interval, total length of hospital stay, and patient satisfaction. On the basis of a noninferiority margin of 10%, an expected primary outcome frequency of 65% for misoprostol and 71% for mechanical methods, and 85% power, a sample size of 306 participants was needed.

Results: From November 2018 through January 2021, 307 women were randomized, with 151 evaluable participants in the synthetic osmotic cervical dilator group and 152 in the misoprostol group (there were four early withdrawals). The proportion of women achieving vaginal delivery within 36 hours was higher with mechanical cervical dilation compared with misoprostol (61.6% vs 59.2%), with an absolute difference of 2.4% (95% CI -9% to 13%), indicating noninferiority for the prespecified margin. No differences were noted in the mode of delivery. Tachysystole was more frequent in the misoprostol group (70 [46.4%] vs 35 [23.3%]; P=.01). Participants in the synthetic osmotic cervical dilator group reported better sleep, less unpleasant abdominal sensations, and lower pain scores (P<.05).

Conclusion: Synthetic osmotic cervical dilator is noninferior to oral misoprostol for cervical ripening. Advantages of synthetic osmotic cervical dilator include a better safety profile and patient satisfaction, less tachysystole, lower pain scores, and U.S. Food and Drug Administration approval.

Clinical Trial Registration: ClinicalTrials.gov, NCT03670836.

Funding Source: Medicem Technology s.r.o., Czech Republic.
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http://dx.doi.org/10.1097/AOG.0000000000004799DOI Listing
June 2022

Reply to comment on migraine and adverse pregnancy outcomes: the nuMoM2b study.

Am J Obstet Gynecol 2022 Jun 4. Epub 2022 Jun 4.

Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA.

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http://dx.doi.org/10.1016/j.ajog.2022.05.069DOI Listing
June 2022

Comparison of Cesarean Deliveries in a Multicenter U.S. Cohort Using the 10-Group Classification System.

Am J Perinatol 2022 Jun 3. Epub 2022 Jun 3.

Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon.

Objective:  We sought to (1) use the Robson 10-Group Classification System (TGCS), which classifies deliveries into 10 mutually exclusive groups, to characterize the groups that are primary contributors to cesarean delivery frequencies, (2) describe inter-hospital variations in cesarean delivery frequencies, and (3) evaluate the contribution of patient characteristics by TGCS group to hospital variation in cesarean delivery frequencies.

Study Design:  This was a secondary analysis of an observational cohort of 115,502 deliveries from 25 hospitals between 2008 and 2011. The TGCS was applied to the cohort and each hospital. We identified and compared the TGCS groups with the greatest relative contributions to cohort and hospital cesarean delivery frequencies. We assessed variation in hospital cesarean deliveries attributable to patient characteristics within TGCS groups using hierarchical logistic regression.

Results:  A total of 115,211 patients were classifiable in the TGCS (99.7%). The cohort cesarean delivery frequency was 31.4% (hospital range: 19.1-39.3%). Term singletons in vertex presentation with a prior cesarean delivery (group 5) were the greatest relative contributor to cohort (34.8%) and hospital cesarean delivery frequencies (median: 33.6%; range: 23.8-45.5%). Nulliparous term singletons in vertex (NTSV) presentation (groups 1 [spontaneous labor] and 2 [induced or absent labor]: 28.9%), term singletons in vertex presentation with a prior cesarean delivery (group 5: 34.8%), and preterm singletons in vertex presentation (group 10: 9.8%) contributed to 73.2% of the relative cesarean delivery frequency for the cohort and were correlated with hospital cesarean delivery frequencies (Spearman's rho = 0.96). Differences in patient characteristics accounted for 34.1% of hospital-level cesarean delivery variation in group 2.

Conclusion:  The TGCS highlights the contribution of NTSV presentation to cesarean delivery frequencies and the impact of patient characteristics on hospital-level variation in cesarean deliveries among nulliparous patients with induced or absent labor.

Key Points: · We report on the cesarean delivery frequencies in a multicenter U.S.

Cohort: . · NTSV gestations (groups 1 and 2) are a primary driver of cesarean deliveries.. · Patient characteristics contributed most to hospital variation in cesarean deliveries in group 2..
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http://dx.doi.org/10.1055/s-0042-1748527DOI Listing
June 2022

The fetal sequencing consortium: The value of multidisciplinary dialog and collaboration.

Prenat Diagn 2022 06 9;42(7):807-810. Epub 2022 Jun 9.

Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, New York, USA.

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http://dx.doi.org/10.1002/pd.6190DOI Listing
June 2022

International Society for Prenatal Diagnosis Updated Position Statement on the use of genome-wide sequencing for prenatal diagnosis.

Prenat Diagn 2022 05;42(6):796-803

North Thames Genomic Laboratory Hub, Great Ormond Street NHS Foundation Trust, London, UK.

The research and clinical use of genome-wide sequencing for prenatal diagnosis of fetuses at risk for genetic disorders have rapidly increased in recent years. Current data indicate that the diagnostic rate is comparable and for certain indications higher than that of standard testing by karyotype and chromosomal microarray. Responsible clinical implementation and diagnostic use of prenatal sequencing depends on standardized laboratory practices and detailed pre-test and post-test counseling. This Updated Position Statement on behalf of the International Society for Prenatal Diagnosis recommends best practices for the clinical use of prenatal exome and genome sequencing from an international perspective. We include several new points for consideration by researchers and clinical service and laboratory providers.
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http://dx.doi.org/10.1002/pd.6157DOI Listing
May 2022

Discovering a new part of the phenotypic spectrum of Coffin-Siris syndrome in a fetal cohort.

Genet Med 2022 Aug 18;24(8):1753-1760. Epub 2022 May 18.

Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark; Pediatrics and Adolescent Medicine, Centre for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark.

Purpose: Genome-wide sequencing is increasingly being performed during pregnancy to identify the genetic cause of congenital anomalies. The interpretation of prenatally identified variants can be challenging and is hampered by our often limited knowledge of prenatal phenotypes. To better delineate the prenatal phenotype of Coffin-Siris syndrome (CSS), we collected clinical data from patients with a prenatal phenotype and a pathogenic variant in one of the CSS-associated genes.

Methods: Clinical data was collected through an extensive web-based survey.

Results: We included 44 patients with a variant in a CSS-associated gene and a prenatal phenotype; 9 of these patients have been reported before. Prenatal anomalies that were frequently observed in our cohort include hydrocephalus, agenesis of the corpus callosum, hypoplastic left heart syndrome, persistent left vena cava, diaphragmatic hernia, renal agenesis, and intrauterine growth restriction. Anal anomalies were frequently identified after birth in patients with ARID1A variants (6/14, 43%). Interestingly, pathogenic ARID1A variants were much more frequently identified in the current prenatal cohort (16/44, 36%) than in postnatal CSS cohorts (5%-9%).

Conclusion: Our data shed new light on the prenatal phenotype of patients with pathogenic variants in CSS genes.
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http://dx.doi.org/10.1016/j.gim.2022.04.010DOI Listing
August 2022

Association of Body Mass Index With the Use of Health Care Resources in Low-Risk Nulliparous Pregnancies After 39 Weeks of Gestation.

Obstet Gynecol 2022 05 5;139(5):866-876. Epub 2022 Apr 5.

Departments of Obstetrics and Gynecology, The Ohio State University, Columbus, Ohio, Northwestern University, Chicago, Illinois, University of Alabama at Birmingham, Birmingham, Alabama, University of Utah Health Sciences Center, Salt Lake City, Utah, Stanford University, Stanford, California, Columbia University, New York, New York, Brown University, Providence, Rhode Island, University of Texas Medical Branch, Galveston, Texas, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, University of Texas Health Science Center at Houston-Children's Memorial Hermann Hospital, Houston, Texas, MetroHealth Medical Center-Case Western Reserve University, Cleveland, Ohio, University of Texas Southwestern Medical Center, Dallas, Texas, University of Pennsylvania, Philadelphia, Pennsylvania, Duke University, Durham, North Carolina, and University of Pittsburgh, Pittsburgh, Pennsylvania; and the George Washington University Biostatistics Center, Washington, DC; and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland.

Objective: To compare health care medical resource utilization in low-risk nulliparous pregnancies according to body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) categories.

Methods: This is a secondary analysis of a multicenter randomized controlled trial of induction of labor between 39 0/7 39 and 4/7 weeks of gestation compared with expectant management in low-risk nulliparous pregnant people, defined as those without standard obstetric indications for delivery at 39 weeks. Body mass index at randomization was categorized into four groups (lower than 25, 25-29, 30-39, and 40 or higher). The primary outcome of this analysis was time spent in the labor and delivery department from admission to delivery. Secondary outcomes included length of stay (LOS) postdelivery, total hospital LOS, and antepartum, intrapartum, and postpartum resource utilization, which were defined a priori. Multivariable generalized linear modeling and logistic regressions were performed, and 99% CIs were calculated.

Results: A total of 6,058 pregnant people were included in the analysis; 640 (10.6%) had BMIs of lower than 25, 2,222 (36.7%) had BMIs between 25 and 29, 2,577 (42.5%) had BMIs of 30-39, and 619 (10.2%) had BMIs of 40 or higher. Time spent in the labor and delivery department increased from 15.1±9.2 hours for people with BMIs of lower than 25 to 23.5±13.6 hours for people with BMIs of 40 or higher, and every 5-unit increase in BMI was associated with an average 9.8% increase in time spent in the labor and delivery department (adjusted estimate per 5-unit increase in BMI 1.10, 99% CI 1.08-1.11). Increasing BMI was not associated with an increase in antepartum resource utilization, except for blood tests and urinalysis. However, increasing BMI was associated with higher odds of intrapartum resource utilization, longer total hospital LOS, and postpartum resource utilization. For example, every 5-unit increase in BMI was associated with an increase of 26.1% in the odds of antibiotic administration, 57.6% in placement of intrauterine pressure catheter, 5.1% in total inpatient LOS, 31.0 in postpartum emergency department visit, and 23.9% in postpartum hospital admission.

Conclusion: Among low-risk nulliparous people, higher BMI was associated with longer time from admission to delivery, total hospital LOS, and more frequent utilization of intrapartum and postpartum resources.

Clinical Trial Registration: ClinicalTrials.gov, NCT01990612.
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http://dx.doi.org/10.1097/AOG.0000000000004753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9142136PMC
May 2022

Migraine and adverse pregnancy outcomes: the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be.

Am J Obstet Gynecol 2022 May 2. Epub 2022 May 2.

Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA.

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http://dx.doi.org/10.1016/j.ajog.2022.04.049DOI Listing
May 2022

Placental multi-omics integration identifies candidate functional genes for birthweight.

Nat Commun 2022 05 2;13(1):2384. Epub 2022 May 2.

Department of Obstetrics and Gynecology, Columbia University, New York, NY, USA.

Abnormal birthweight is associated with increased risk for cardiometabolic diseases in later life. Although the placenta is critical to fetal development and later life health, it has not been integrated into largescale functional genomics initiatives, and mechanisms of birthweight-associated variants identified by genome wide association studies (GWAS) are unclear. The goal of this study is to provide functional mechanistic insight into the causal pathway from a genetic variant to birthweight by integrating placental methylation and gene expression with established GWAS loci for birthweight. We identify placental DNA methylation and gene expression targets for several birthweight GWAS loci. The target genes are broadly enriched in cardiometabolic, immune response, and hormonal pathways. We find that methylation causally influences WNT3A, CTDNEP1, and RANBP2 expression in placenta. Multi-trait colocalization identifies PLEKHA1, FES, CTDNEP1, and PRMT7 as likely functional effector genes. These findings reveal candidate functional pathways that underpin the genetic regulation of birthweight via placental epigenetic and transcriptomic mechanisms. Clinical trial registration; ClinicalTrials.gov, NCT00912132.
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http://dx.doi.org/10.1038/s41467-022-30007-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9061712PMC
May 2022

Placental protein levels in maternal serum are associated with adverse pregnancy outcomes in nulliparous patients.

Am J Obstet Gynecol 2022 Apr 26. Epub 2022 Apr 26.

RTI International, Research Triangle Park, NC.

Background: The Eunice Kennedy Shriver National Institute of Child Health and Human Development Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be was established to investigate the underlying causes and pathophysiological pathways associated with adverse pregnancy outcomes in nulliparous gravidas.

Objective: This study aimed to study placental physiology and identify novel biomarkers concerning adverse pregnancy outcomes, including preterm birth (medically indicated and spontaneous), preeclampsia, small-for-gestational-age neonates, and stillbirth. We measured levels of placental proteins in the maternal circulation in the first 2 trimesters of pregnancy.

Study Design: Maternal serum samples were collected at 2 study visits (6-13 weeks and 16-21 weeks), and levels of 9 analytes were measured. The analytes we measured were vascular endothelial growth factor, placental growth factor, endoglin, soluble fms-like tyrosine kinase-1, A disintegrin and metalloproteinase domain-containing protein 12, pregnancy-associated plasma protein A, free beta-human chorionic gonadotropin, inhibin A, and alpha-fetoprotein. The primary outcome was preterm birth between 20 0/7 and 36 6/7 weeks of gestation. The secondary outcomes were spontaneous preterm births, medically indicated preterm births, preeclampsia, small-for-gestational-age neonates, and stillbirth.

Results: A total of 10,038 eligible gravidas were enrolled in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be cohort, from which a nested case-control study was performed comparing 800 cases with preterm birth (466 spontaneous preterm births, 330 medically indicated preterm births, and 4 unclassified preterm births), 568 with preeclampsia, 406 with small-for-gestational-age birth, and 49 with stillbirth with 911 controls who delivered at term without complications. Although levels of each analyte generally differed between cases and controls at 1 or 2 visits, the odds ratios revealed a <2-fold difference between cases and controls in all comparisons. Receiver operating characteristic curves, generated to determine the relationship between analyte levels and preterm birth and the other adverse pregnancy outcomes, resulted in areas under the receiver operating characteristic curves that were relatively low (range, 0.50-0.64) for each analyte. Logistic regression modeling demonstrated that areas under the receiver operating characteristic curves for predicting adverse pregnancy outcomes were greater using baseline clinical characteristics and combinations of analytes than baseline characteristics alone, but areas under the receiver operating characteristic curves remained relatively low for each outcome (range, 0.65-0.78).

Conclusion: We have found significant associations between maternal serum levels of analytes evaluated early in pregnancy and subsequent adverse pregnancy outcomes in nulliparous gravidas. However, the test characteristics for these analytes do not support their use as clinical biomarkers to predict adverse pregnancy outcomes, either alone or in combination with maternal clinical characteristics.
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http://dx.doi.org/10.1016/j.ajog.2022.03.064DOI Listing
April 2022

Information is power: The experiences, attitudes and needs of individuals who chose to have prenatal genomic sequencing for fetal anomalies.

Prenat Diagn 2022 06 4;42(7):947-954. Epub 2022 May 4.

Department of Pediatrics, Columbia University Irving Medical Center, New York, New York, USA.

Objective: This study sought to evaluate the experiences of individuals who chose to participate in a study and receive prenatal genomic sequencing (pGS) for fetuses with congenital structural anomalies.

Method: Individuals who received research results of prenatal sequencing were invited to participate in semi-structured interviews about their experiences. A constructivist grounded theory approach was used to code and analyze interviews.

Results: Thirty-three participants from 27 pregnancies were interviewed. Participants were motivated to enroll in the study to find out more about their fetus' condition and prepare for the future. The waiting period was a time of significant anxiety for participants. Most participants felt relief and closure upon receiving results, regardless of the category of result, and had a clear understanding of the implications of the results.

Conclusion: Participants' experiences with pGS were often intertwined with the experience of having a fetus with an abnormality. Participants were satisfied with the decision to participate in research and the support they received from the healthcare team, although waiting for results was associated with anxiety. The healthcare team plays an integral role in setting expectations and validating feelings of anxiety, fear and uncertainty.
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http://dx.doi.org/10.1002/pd.6153DOI Listing
June 2022

Fetal central nervous system anomalies: When should we offer exome sequencing?

Prenat Diagn 2022 05 20;42(6):736-743. Epub 2022 Apr 20.

Genetics and Genomic Medicine, UCL GOS Institute of Child Health, UCL, London, England, UK.

Objective: To investigate the detection of pathogenic variants using exome sequencing in an international cohort of fetuses with central nervous system (CNS) anomalies.

Methods: We reviewed trio exome sequencing (ES) results for two previously reported unselected cohorts (Prenatal Assessment of Genomes and Exomes (PAGE) and CUIMC) to identify fetuses with CNS anomalies with unremarkable karyotypes and chromosomal microarrays. Variants were classified according to ACMG guidelines and association of pathogenic variants with specific types of CNS anomalies explored.

Results: ES was performed in 268 pregnancies with a CNS anomaly identified using prenatal ultrasound. Of those with an isolated, single, CNS anomaly, 7/97 (7.2%) had a likely pathogenic/pathogenic (LP/P) variant. This includes 3/23 (13%) fetuses with isolated mild ventriculomegaly and 3/10 (30%) fetuses with isolated agenesis of the corpus callosum. Where there were multiple anomalies within the CNS, 12/63 (19%) had LP/P variants. Of the 108 cases with CNS and other organ system anomalies, 18 (16.7%) had LP/P findings.

Conclusion: ES is an important tool in the prenatal evaluation of fetuses with any CNS anomaly. The rate of LP/P variants tends to be highest in fetuses with multiple CNS anomalies and multisystem anomalies, however, ES may also be of benefit for isolated CNS anomalies.
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http://dx.doi.org/10.1002/pd.6145DOI Listing
May 2022

Associations of Maternal Prenatal Stress and Depressive Symptoms With Childhood Neurobehavioral Outcomes in the ECHO Cohort of the NICHD Fetal Growth Studies: Fetal Growth Velocity as a Potential Mediator.

J Am Acad Child Adolesc Psychiatry 2022 Mar 30. Epub 2022 Mar 30.

Columbia University, New York.

Objective: Maternal prenatal stress and mood symptoms are associated with risk for child psychopathology. Within the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies (ECHO-FGS), a racially and ethnically diverse cohort, we studied associations between prenatal stress and depressive symptoms with child neurobehavior, and potential mediation by fetal growth velocity (FGV) in low-risk pregnancies.

Method: For 730 mother-child pairs, we had serial ultrasound measurements, self-reports of prenatal stress and depression, observations of child executive functions and motor skills from 4 to 8 years, and maternal reports of child psychiatric problems. We tested associations between prenatal stress and depressive symptoms with child neurobehavior in regression analyses, and associations with FGV in mixed effect models. Post hoc we tested severity of prenatal symptoms; FGV at 25, 50, and 75 percentiles; and moderation by biological sex and by race and ethnicity.

Results: Prenatal stress and depressive symptoms were associated with child psychiatric problems, and prenatal depressive symptoms with decrements in executive functions and motor skills, especially in biological male children. Neither prenatal stress nor depressive symptoms were associated with FGV.

Conclusion: In one of the largest cohorts with observed child outcomes, and the first with broad representation of race and ethnicity in the United States, we found that prenatal stress and depressive symptoms were associated with greater reports of child psychiatric symptoms. Only prenatal depressive symptoms were associated with observed decrements in cognitive abilities, most significantly in biological male children. Stress during low-risk pregnancies may be less detrimental than theorized. There was no mediation by FGV. These findings support the need to attend to even small changes in prenatal distress, as these may have long-lasting implications.
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http://dx.doi.org/10.1016/j.jaac.2022.03.021DOI Listing
March 2022

The association between maternal pre-pregnancy BMI, gestational weight gain and child adiposity: A racial-ethnically diverse cohort of children.

Pediatr Obes 2022 Aug 15;17(8):e12911. Epub 2022 Mar 15.

Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA.

Background: The prevalence of obesity in US children has more than tripled in the past 40 years; hence, it is critical to identify potentially modifiable factors that may mitigate the risk.

Objectives: To examine the association between maternal pre-pregnancy body mass index (BMI), gestational weight gain (GWG) and child adiposity as measured by BMI, waist circumference and percent body fat in a racial-ethnically diverse cohort.

Methods: In a prospective cohort study of healthy women without chronic disease, we examined the association between pre-pregnancy BMI, GWG and child adiposity. Children ages 4-8 years (n = 816) in the Environmental Influences on Child Health Outcomes-NICHD Fetal Growth Studies were assessed. Trained study staff ascertained maternal pre-pregnancy BMI, GWG and child adiposity.

Results: The odds of child obesity (≥95th BMI percentile) increased independently for each unit increase in maternal pre-pregnancy BMI [OR = 1.12 (95% CI: 1.08, 1.17)] and for each 5-kg increase in GWG [OR = 1.25 (95% CI: 1.07, 1.47)]. The odds of child waist circumference (≥85th percentile) also increased independently for pre-pregnancy BMI [OR = 1.09 (95% CI: 1.05, 1.12)] and GWG [OR = 1.18 (95% CI: 1.04, 1.34)].

Conclusions: Maternal pre-pregnancy BMI and GWG were each independently and positively associated with child obesity and high child waist circumference.
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http://dx.doi.org/10.1111/ijpo.12911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9283205PMC
August 2022

The Non-pregnant and Pregnant Human Cervix: a Systematic Proteomic Analysis.

Reprod Sci 2022 05 9;29(5):1542-1559. Epub 2022 Mar 9.

Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY, USA.

Appropriate timing of cervical remodeling (CR) is key to normal term parturition. To date, mechanisms behind normal and abnormal (premature or delayed) CR remain unclear. Recent studies show regional differences exist in human cervical tissue structure. While the entire cervix contains extracellular matrix (ECM), the internal os is highly cellular containing 50-60% cervical smooth muscle (CSM). The external os contains 10-20% CSM. Previously, we reported ECM rigidity and different ECM proteins influence CSM cell function, highlighting the importance of understanding not only how cervical cells orchestrate cervical ECM remodeling in pregnancy, but also how changes in specific ECM proteins can influence resident cellular function. To understand this dynamic process, we utilized a systematic proteomic approach to understand which soluble ECM and cellular proteins exist in the different regions of the human cervix and how the proteomic profiles change from the non-pregnant (NP) to the pregnant (PG) state. We found the human cervix proteome contains at least 4548 proteins and establish the types and relative abundance of cellular and soluble matrisome proteins found in the NP and PG human cervix. Further, we report the relative abundance of proteins involved with elastic fiber formation and ECM organization/degradation were significantly increased while proteins involved in RNA polymerase I/promoter opening, DNA methylation, senescence, immune system, and compliment activation were decreased in the PG compared to NP cervix. These findings establish an initial platform from which we can further comprehend how changes in the human cervix proteome results in normal and abnormal CR.
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http://dx.doi.org/10.1007/s43032-022-00892-4DOI Listing
May 2022

Timing of Maternal Discharge after Cesarean Delivery and Risk of Maternal Readmission.

Am J Perinatol 2022 07 4;39(10):1042-1047. Epub 2022 Mar 4.

Birmingham, Alabama.

Objective: Despite legislation and hospital policies (present in some institutions) mandating a minimum length of stay in an effort to decrease the frequency of hospital readmissions, the effectiveness of this approach remains uncertain.We hypothesized that following cesarean delivery (CD), the rates of maternal readmission or unscheduled health care visits are lower in patients discharged on postoperative day (POD) 3 or ≥4 as compared with those discharged earlier on POD 2.

Methods: This is a secondary analysis of a multicenter randomized trial comparing adjunctive azithromycin for unscheduled CD to prevent infection. Groups were compared based on the duration of hospitalization measured in days from delivery (POD 0) to day of discharge and categorized as POD 2, 3, and ≥4. The primary outcome was the composite of any maternal postpartum readmission, unscheduled clinic, or emergency room (ER) visit, within 6 weeks of delivery. Secondary outcomes included components of the primary outcome and neonatal readmissions. We excluded women with hypertensive disorders of pregnancy and infections diagnosed prior to POD 2.

Results: A total of 1,391 patients were included. The rate of the primary outcome of any readmission increased with POD at discharge: 5.9% for POD 2, 9.4% for POD 3, and 10.9% for POD ≥4 group (trend for  = 0.03). The primary outcome increased with later discharge (POD ≥4 when compared with POD 2). Among components of the composite, ER and unscheduled clinic visits, but not maternal readmissions, increased with the timing of discharge for patients discharged on POD ≥4 when compared with POD 2. Using logistic regression, discharge on POD 3 and on POD ≥4 was significantly associated with the composite (adjusted odds ratios [aOR] 2.6, 95% confidence interval [CI] [1.3-5.3]; aOR 2.9, 95% CI [1.3-6.4], respectively) compared with POD 2.

Conclusion: The risk of maternal readmission composite following uncomplicated but unscheduled CD was not lower in patients discharged home on POD 3 or ≥4 compared with patients discharged earlier (POD 2).

Key Points: · Risk of maternal readmission is higher in patients discharged on POD 3 or 4 compared with POD 2.. · No significant differences by the timing of discharge were observed for any neonatal readmissions.. · Timing of discharge should include an individualized approach with the option of discharge by POD 2..
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http://dx.doi.org/10.1055/s-0042-1743248DOI Listing
July 2022

Prediction of Cerebral Palsy or Death among Preterm Infants Who Survive the Neonatal Period.

Am J Perinatol 2022 Mar 4. Epub 2022 Mar 4.

Department of Obstetrics and Gynecology, University of Pittsburgh, Pittsburgh, Pennsylvania.

Objective:  To assess whether neonatal morbidities evident by the time of hospital discharge are associated with subsequent cerebral palsy (CP) or death.

Study Design:  This is a secondary analysis of data from a multicenter placebo-controlled trial of magnesium sulfate for the prevention of CP. The association between prespecified intermediate neonatal outcomes ( = 11) and demographic and clinical factors ( = 10) evident by the time of discharge among surviving infants ( = 1889) and the primary outcome of death or moderate/severe CP at age 2 ( = 73) was estimated, and a prediction model was created.

Results:  Gestational age in weeks at delivery (odds ratio [OR]: 0.74, 95% confidence interval [CI]: 0.67-0.83), grade III or IV intraventricular hemorrhage (IVH) (OR: 5.3, CI: 2.1-13.1), periventricular leukomalacia (PVL) (OR: 46.4, CI: 20.6-104.6), and male gender (OR: 2.5, CI: 1.4-4.5) were associated with death or moderate/severe CP by age 2. Outcomes not significantly associated with the primary outcome included respiratory distress syndrome, bronchopulmonary dysplasia, seizure, necrotizing enterocolitis, neonatal hypotension, 5-minute Apgar score, sepsis, and retinopathy of prematurity. Using all patients, the receiver operating characteristic curve for the final prediction model had an area under the curve of 0.84 (CI: 0.78-0.89). Using these data, the risk of death or developing CP by age 2 can be calculated for individual surviving infants.

Conclusion:  IVH and PVL were the only neonatal complications evident at discharge that contributed to an individual infant's risk of the long-term outcomes of death or CP by age 2. A model that includes these morbidities, gestational age at delivery, and gender is predictive of subsequent neurologic sequelae.

Key Points: · Factors known at hospital discharge are identified which are independently associated with death or CP by age 2.. · A model was created and validated using these findings to counsel parents.. · The risk of death or CP can be calculated at the time of hospital discharge..
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http://dx.doi.org/10.1055/a-1788-6281DOI Listing
March 2022

Fetal Growth Biometry as Predictors of Shoulder Dystocia in a Low-Risk Obstetrical Population.

Am J Perinatol 2022 03 3. Epub 2022 Mar 3.

Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

Objective: This study aimed to evaluate fetal biometrics as predictors of shoulder dystocia (SD) in a low-risk obstetrical population.

Study Design: Participants were enrolled as part of a U.S.-based prospective cohort study of fetal growth in low-risk singleton gestations ( = 2,802). Eligible women had liveborn singletons ≥2,500 g delivered vaginally. Sociodemographic, anthropometric, and pregnancy outcome data were abstracted by research staff. The diagnosis of SD was based on the recorded clinical impression of the delivering physician. Simple logistic regression models were used to examine associations between fetal biometrics and SD. Fetal biometric cut points, selected by Youden's J and clinical determination, were identified to optimize predictive capability. A final model for SD prediction was constructed using backward selection. Our dataset was randomly divided into training (60%) and test (40%) datasets for model building and internal validation.

Results: A total of 1,691 women (98.7%) had an uncomplicated vaginal delivery, while 23 (1.3%) experienced SD. There were no differences in sociodemographic or maternal anthropometrics between groups. Epidural anesthesia use was significantly more common (100 vs. 82.4%;  = 0.03) among women who experienced SD compared with those who did not. Amniotic fluid maximal vertical pocket was also significantly greater among SD cases (5.8 ± 1.7 vs. 5.1 ± 1.5 cm; odds ratio = 1.32 [95% confidence interval: 1.03,1.69]). Several fetal biometric measures were significantly associated with SD when dichotomized based on clinically selected cut-off points. A final prediction model was internally valid with an area under the curve of 0.90 (95% confidence interval: 0.81, 0.99). At a model probability of 1%, sensitivity (71.4%), specificity (77.5%), positive (3.5%), and negative predictive values (99.6%) did not indicate the ability of the model to predict SD in a clinically meaningful way.

Conclusion: Other than epidural anesthesia use, neither sociodemographic nor maternal anthropometrics were significantly associated with SD in this low-risk population. Both individually and in combination, fetal biometrics had limited ability to predict SD and lack clinical usefulness.

Key Points: · SD unpredictable in low-risk women.. · Fetal biometry does not reliably predict SD.. · Epidural use associated with increased SD risk.. · SD prediction models clinically inefficient..
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http://dx.doi.org/10.1055/a-1787-6991DOI Listing
March 2022

Predictive performance of newborn small for gestational age by a United States intrauterine vs birthweight-derived standard for short-term neonatal morbidity and mortality.

Am J Obstet Gynecol MFM 2022 05 18;4(3):100599. Epub 2022 Feb 18.

Background: The use of birthweight standards to define small for gestational age may fail to identify neonates affected by poor fetal growth as they include births associated with suboptimal fetal growth.

Objective: This study aimed to compare intrauterine vs birthweight-derived standards to define newborn small for gestational age to predict neonatal morbidity and mortality.

Study Design: This was a secondary analysis of a multicenter observational study of 118,422 births. Live-born singleton, nonanomalous newborns born at 23 to 41 weeks of gestation were included. Those with missing gestational age estimation or without a first- or second-trimester ultrasound to confirm dating, birthweight, or neonatal outcome data were excluded. Birthweight percentile was computed using an intrauterine standard (Hadlock) and a birthweight-derived standard (Olsen). We compared the test characteristics of small for gestational age (birthweight of <10th percentile) by each standard to predict a composite neonatal morbidity and mortality outcome (death before discharge, neonatal intensive care unit admission >48 hours, respiratory distress syndrome, sepsis, necrotizing enterocolitis, grade 3 or 4 intraventricular hemorrhage, or seizures). Severe composite morbidity was analyzed as a secondary outcome and was defined as death, neonatal intensive care unit admission >7 days, necrotizing enterocolitis, grade 3 or 4 intraventricular hemorrhage, or seizures. The areas under the curve using receiver-operating characteristic methodology and proportions of the primary outcome by small for gestational age status were compared by gestational age category at birth (<34, 34 0/7 to 36 6/7, ≥37 weeks).

Results: Of 115,502 mother-newborn dyads in the parent study, 78,203 (67.7%) were included, with most exclusions occurring because of missing or inadequate dating information, multiple gestations, or delivery outside the gestational age range. The primary composite outcome occurred in 9.5% (95% confidence interval, 9.3-9.7), and the severe composite outcome occurred in 5.3% (95% confidence interval, 5.1-5.4). Small for gestational age was diagnosed by intrauterine and birthweight-derived standards in 14.8% and 7.4%, respectively (P<.001). Neonates considered small for gestational age only by the intrauterine standard experienced the primary outcome more than twice as often as those considered non-small for gestational age by both standards (18.4% vs 7.9%; P<.001). For the prediction of the primary outcome, small for gestational age by the intrauterine standard had higher sensitivity (29% vs 15%; P<.001) but lower specificity (87% vs 93%; P<.001) than by the birthweight standard. Both standards had weak performance overall, although the intrauterine standard had a higher area under the curve (0.58 vs 0.53; P<.001). When subanalyzed by gestational age at birth, the difference in areas under the curve was only present among preterm deliveries 34 to 36 competed weeks. Neither standard demonstrated any discrimination for morbidity prediction among term births (area under the curve, 0.50 for both). When the prediction of severe morbidity was compared, the intrauterine still had better overall prediction than the birthweight standard (areas under the curve, 0.65 vs 0.57; P<.001), although this also varied by gestational age at birth.

Conclusion: Among nonanomalous neonates, neither intrauterine nor birthweight-derived standards for small for gestational age accurately predicted neonatal morbidity and mortality, with no discriminatory ability at term. Small for gestational age intrauterine standards performed better than birthweight standards.
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http://dx.doi.org/10.1016/j.ajogmf.2022.100599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9097811PMC
May 2022

Association between aspirin use during pregnancy and cardiovascular risk factors 2-7 years after delivery: The nuMoM2b Heart Health Study.

Pregnancy Hypertens 2022 Jun 4;28:28-34. Epub 2022 Feb 4.

University of Utah School of Medicine, 30 N 1900 E, Salt Lake City, UT 84132, United States. Electronic address:

Objectives: To evaluate the association between aspirin use during first pregnancy and later maternal cardiovascular risk.

Study Design: In this secondary analysis of a prospective cohort, we included participants who carried their first pregnancy to 20 + weeks, had data regarding aspirin use, and attended a study visit 2-7 years following delivery. The exposure was aspirin use during the first pregnancy. We calculated aspirin use propensity scores from logistic regression models including baseline variables associated with aspirin use in pregnancy and cardiovascular risk. Outcomes of interest were incident cardiovascular-related diagnoses 2-7 years following delivery. Robust Poisson regression calculated the risk of outcomes by aspirin exposure, adjusting for the aspirin use propensity score.

Main Outcome Measures: The primary outcome was a composite of incident cardiovascular diagnoses at the time of the study visit: cardiovascular events, chronic hypertension, metabolic syndrome, prediabetes or type 2 diabetes, dyslipidemia, and chronic kidney disease.

Results: Of 4,480 women included, 84 (1.9%) reported taking aspirin during their first pregnancy. 52.6% of participants in the aspirin-exposed group and 43.0% in the unexposed group had the primary outcome. After adjusting for the aspirin use propensity scores, aspirin use during the first pregnancy was not associated with any of the outcomes.

Conclusion: We did not detect an association between aspirin use during the first pregnancy and cardiovascular-related diagnoses 2-7 years later. Our study was only powered to detect a large difference in relative risk, so we cannot rule out a smaller difference that may be clinically meaningful.
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http://dx.doi.org/10.1016/j.preghy.2022.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9133043PMC
June 2022

Sleep-disordered Breathing in Pregnancy and after Delivery: Associations with Cardiometabolic Health.

Am J Respir Crit Care Med 2022 05;205(10):1202-1213

RTI International, Research Triangle Park, North Carolina.

Knowledge gaps exist regarding health implications of sleep-disordered breathing (SDB) identified in pregnancy and/or after delivery. To determine whether SDB in pregnancy and/or after delivery is associated with hypertension (HTN) and metabolic syndrome (MS). nuMoM2b-HHS (Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be Heart Health Study) ( = 4,508) followed participants initially recruited during their first pregnancy. Participants returned for a visit 2-7 years after pregnancy. This study examined a subgroup who underwent SDB assessments during their first pregnancy ( = 1,964) and a repeat SDB assessment after delivery ( = 1,222). Two SDB definitions were considered: ) apnea-hypopnea index (AHI) ⩾ 5 and ) oxygen desaturation index (ODI) ⩾ 5. Associations between SDB and incident HTN and MS were evaluated with adjusted risk ratios (aRRs). The aRR for MS given an AHI ⩾ 5 during pregnancy was 1.44 (95% confidence interval [CI], 1.08-1.93), but no association with HTN was found. ODI ⩾ 5 in pregnancy was associated with both an increased risk for HTN (aRR, 2.02; 95% CI, 1.30-3.14) and MS (aRR, 1.53; 95% CI, 1.19-1.97). Participants with an AHI ⩾ 5 in pregnancy that persisted after delivery were at higher risk for both HTN (aRR, 3.77; 95% CI, 1.84-7.73) and MS (aRR, 2.46; 95% CI, 1.59-3.76). Similar associations were observed for persistent ODI ⩾ 5 after delivery. An AHI ⩾ 5 in pregnancy was associated with an increased risk of MS. An ODI ⩾ 5 in pregnancy was significantly associated with both HTN and MS. Participants with persistent elevations in AHI and ODI during pregnancy and at 2-7 years after delivery were at the highest risk for HTN and MS. Clinical trial registered with www.clinicaltrials.gov (NCT02231398).
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http://dx.doi.org/10.1164/rccm.202104-0971OCDOI Listing
May 2022

Elevated prenatal maternal sex hormones, but not placental aromatase, are associated with child neurodevelopment.

Horm Behav 2022 04 4;140:105125. Epub 2022 Feb 4.

Department of Psychology, University of Texas at Austin, Austin, TX, USA.

Fetal exposure to testosterone may contribute to vulnerability for autism spectrum disorder (ASD). It is hypothesized that placental aromatase prevents fetal exposure to maternal testosterone, however, this pathway and the implications for child neurodevelopment have not been fully explored. We examined the relationships between prenatal maternal testosterone and estradiol at 19.2 ± 1.3 weeks, cord blood testosterone and estradiol at birth, placental aromatase mRNA expression, and neurodevelopment using the Social Communication Questionnaire (SCQ), the Behavioral Assessment System for Children, 3rd Edition (BASC-3), and the Empathizing Quotient for Children (EQ-C) at 4.5-6.5 years of age in a sample of 270 Nulliparous-Mothers-to-be (nuMoM2b) study participants. Maternal testosterone levels were positively associated with SCQ scores, but the association was not significant after adjusting for maternal age at delivery, nor was there a significant interaction with sex. Maternal estradiol levels were negatively associated with BASC-3 Clinical Probability scores among males (n = 139). We report a significant interaction effect of cord blood testosterone and fetal sex on both total SCQ scores and t-scores on the Developmental Social Disorders subscale. Placental aromatase was not associated with any neurodevelopmental or hormone measure, but under conditions of low placental aromatase expression, high maternal testosterone was positively associated with SCQ scores in males (n = 46). No other associations between hormone levels and neurodevelopment were significant. Our findings provide a foundation for further investigation of the mechanisms through which maternal sex hormones and placental steroidogenesis may affect fetal hormone production and neurobehavior.
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http://dx.doi.org/10.1016/j.yhbeh.2022.105125DOI Listing
April 2022

An evaluation of seasonal maternal-neonatal morbidity related to trainee cycles.

Am J Obstet Gynecol MFM 2022 05 2;4(3):100583. Epub 2022 Feb 2.

Department of Obstetrics & Gynecology, University of Texas Health Science Center at Houston, McGovern Medical School-Children's Memorial Hermann Hospital, Houston, TX (Dr Blackwell).

Background: The existence of the "July phenomenon" (worse outcomes related to the presence of new physician trainees in teaching hospitals) has been debated in the literature and media. Previous studies of the phenomenon in obstetrics are limited by the quality and detail of data.

Objective: To evaluate whether the months of June to August, when transitions in trainees occur, are associated with increased maternal and neonatal morbidity.

Study Design: Secondary analysis of an observational cohort of 115,502 mother-infant pairs that delivered at 25 hospitals from March 2008 to February 2011. Inclusion criteria were an individual who had a singleton, nonanomalous live fetus at the onset of labor, and delivered at a hospital with trainees. The primary outcomes were composites of maternal and neonatal morbidity. We evaluated the outcomes by academic quarter during which the delivery occurred, beginning July 1, and by duration of the academic year as a continuous variable. To account for clustering in outcomes at a given delivery location, we applied hierarchical logistic regression with adjustment for hospital as a random effect.

Results: Of 115,502 deliveries, 99,929 met the inclusion criteria. Race and ethnicity, insurance, body mass index, drug use, and the availability of 24/7 maternal-fetal medicine, anesthesia, and neonatology varied by quarter. In adjusted analysis, the frequency of the composite maternal and neonatal morbidity did not differ by quarter. No differences in composite morbidity were observed when using day of the year as a continuous variable (maternal morbidity adjusted odds ratio, 1.00; 95% confidence interval, 0.99-1.00 and neonatal morbidity adjusted odds ratio, 1.00; 95% confidence interval, 1.00-1.01) and after adjustment for hospital as a random effect. Odds of major surgical complications in quarter 2 were twice those in quarter 1. Neonatal injury and intensive care unit were less frequent in later quarters.

Conclusion: Maternal and neonatal morbidity in teaching hospitals was not associated with the academic quarter during which delivery occurred, and there was no evidence of a "July phenomenon".
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http://dx.doi.org/10.1016/j.ajogmf.2022.100583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9081218PMC
May 2022

Association of second trimester uterine artery Doppler parameters with maternal hypertension 2-7 years after delivery.

Int J Cardiol Cardiovasc Risk Prev 2021 Sep 12;10:200105. Epub 2021 Aug 12.

RTI International, USA.

Background: Reduced uterine artery compliance is associated with adverse pregnancy outcomes (APOs) and may indicate underlying maternal cardiovascular pathology. We investigated associations between second trimester uterine artery Doppler (UAD) parameters and incident maternal hypertension 2-7 years after delivery.

Methods: A cohort of 10,038 nulliparous US participants was recruited early in pregnancy. A subgroup of 3739, without baseline hypertension and with complete follow-up visits 2-7 years after delivery, were included in this analysis. We investigated UAD indicators of compliance including: 1) early diastolic notch; 2) resistance index (RI); and 3) pulsatility index (PI). We defined hypertension as systolic blood pressure ≥130 mmHg, diastolic ≥80 mmHg, or antihypertensive medication use. We calculated odds ratios (OR) and 95 % confidence intervals (95%CI) for associations between UAD parameters and hypertension, adjusting for age, obesity, race/ethnicity, insurance, smoking, and APOs.

Results: A total of 187 (5 %) participants developed hypertension after the index pregnancy. Presence of early diastolic notch on UAD was not associated with incident hypertension. Increased RI and PI correlated with higher odds of hypertension (RI: adjusted OR 1.15 [95 % CI 1.03-1.30]; PI: adjusted OR 1.03 [95%CI 1.01-1.05] for each 0.1 unit increase). Maximum RI above 0.84 or maximum PI above 2.3 more than doubled the odds of incident hypertension (RI: adjusted OR 2.49, 95%CI 1.45-4.26; PI: adjusted OR 2.36, 95%CI 1.45-3.86).

Conclusion: Higher resistance and pulsatility indices measured on second trimester UAD were associated with increased odds of incident hypertension 2-7 years later, and may be biomarkers of higher maternal cardiovascular risk.
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http://dx.doi.org/10.1016/j.ijcrp.2021.200105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8790099PMC
September 2021
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