Maternal-fetal Dyads Research Articles

Progesterone for Neurodevelopment in Fetuses With Congenital Heart Defects

Neurodevelopmental outcomes for children with congenital heart defects (CHD) have improved minimally over the past 20 years. To assess the feasibility and tolerability of maternal progesterone therapy as well as the magnitude of the effect on neurodevelopment for fetuses with CHD. This double-blinded individually randomized parallel-group clinical trial of vaginal natural progesterone therapy vs placebo in participants carrying fetuses with CHD was conducted between July 2014 and November 2021 at a quaternary care children's hospital. Participants included maternal-fetal dyads where the fetus had CHD identified before 28 weeks' gestational age and was likely to need surgery with cardiopulmonary bypass in the neonatal period. Exclusion criteria included a major genetic or extracardiac anomaly other than 22q11 deletion syndrome and known contraindication to progesterone. Statistical analysis was performed June 2022 to April 2024. Participants were 1:1 block-randomized to vaginal progesterone or placebo by diagnosis: hypoplastic left heart syndrome (HLHS), transposition of the great arteries (TGA), and other CHD diagnoses. Treatment was administered twice daily between 28 and up to 39 weeks' gestational age. The primary outcome was the motor score of the Bayley Scales of Infant and Toddler Development-III; secondary outcomes included language and cognitive scales. Exploratory prespecified subgroups included cardiac diagnosis, fetal sex, genetic profile, and maternal fetal environment. The 102 enrolled fetuses primarily had HLHS (n = 52 [50.9%]) and TGA (n = 38 [37.3%]), were more frequently male (n = 67 [65.7%]), and without genetic anomalies (n = 61 [59.8%]). The mean motor score differed by 2.5 units (90% CI, -1.9 to 6.9 units; P = .34) for progesterone compared with placebo, a value not statistically different from 0. Exploratory subgroup analyses suggested treatment heterogeneity for the motor score for cardiac diagnosis (P for interaction = .03) and fetal sex (P for interaction = .04), but not genetic profile (P for interaction = .16) or maternal-fetal environment (P for interaction = .70). In this randomized clinical trial of maternal progesterone therapy, the overall effect was not statistically different from 0. Subgroup analyses suggest heterogeneity of the response to progesterone among CHD diagnosis and fetal sex. ClinicalTrials.gov Identifier: NCT02133573.

Impact of Gestational Exposure to Individual and Combined Per- and Polyfluoroalkyl Substances on a Placental Structure and Efficiency: Findings from the Ma'anshan Birth Cohort.

Prenatal exposure to perfluoroalkyl and polyfluoroalkyl substances (PFASs) is inevitable among pregnant women. Nevertheless, there is a scarcity of research investigating the connections between prenatal PFAS exposure and the placental structure and efficiency. Based on 712 maternal-fetal dyads in the Ma'anshan Birth Cohort, we analyzed associations between individual and mixed PFAS exposure and placental measures. We repeatedly measured 12 PFAS in the maternal serum during pregnancy. Placental weight, scaling exponent, chorionic disc area, and disc eccentricity were used as the outcome variables. Upon adjusting for confounders and implementing corrections for multiple comparisons, we identified positive associations between branched perfluorohexane sulfonate (br-PFHxS) and 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA) with placental weight. Additionally, a positive association was observed between br-PFHxS and the scaling exponent, where a higher scaling exponent signified reduced placental efficiency. Based on neonatal sex stratification, female infants were found to be more susceptible to the adverse effects of PFAS exposure. Mixed exposure modeling revealed that mixed PFAS exposure was positively associated with placental weight and scaling exponent, particularly during the second and third trimesters. Furthermore, br-PFHxS and 6:2 Cl-PFESA played major roles in the placental measures. This study provides the first epidemiological evidence of the relationship between prenatal PFAS exposure and placental measures.

Successful Prediction of Fetal Exposure to Dual BCRP/P-gp Drug Substrates Using the Efflux Ratio-Relative Expression Factor Approach and PBPK M&S.

To inform fetal drug safety, it is important to determine or predict fetal drug exposure throughout pregnancy. The former is not possible in the first or second trimester. In contrast, at the time of birth, fetal drug exposure, relative to maternal exposure, can be estimated as Kp,uu (unbound fetal umbilical venous (UV) plasma area under the curve (AUC)/unbound maternal plasma (MP) AUC), provided the observed UV/MP values, spanning the dosing interval, are available from multiple maternal-fetal dyads. However, this fetal Kp,uu cannot be extrapolated to other drugs. To overcome the above limitations, we have used an efflux ratio-relative expression factor (ER-REF) approach to successfully predict the fetal Kp,uu of P-gp substrates. Because many drugs taken by pregnant people are also BCRP substrates, here, we extend this approach to drugs that are effluxed by both placental BCRP and P-gp or P-gp alone. To verify our predictions, we chose drugs for which UV/MP data were available at term: glyburide and imatinib (both BCRP and P-gp substrates) and nelfinavir (only P-gp substrate). First, the ER of the drugs was determined using Transwells and MDCKII cells expressing either BCRP or P-gp. Then, the ER was scaled using the proteomics-informed REF value to predict the fetal Kp,uu of the drug at term. The ER-REF predicted fetal Kp,uu of glyburide (0.43), imatinib (0.42), and nelfinavir (0.40) fell within two-fold of the corresponding in vivo fetal Kp,uu (0.44, 0.37, and 0.46, respectively). These data confirm that the ER-REF approach can successfully predict fetal drug exposure to BCRP/P-gp and P-gp substrates, at term.

Perinatal Stressors and Consequences for Neonates with Critical Congenital Heart Disease.

The prenatal diagnosis of congenital heart disease (CHD) is a traumatic event that can cause expectant parents to experience anxiety, depression, and toxic stress. Prenatal exposure to stress may impact neonatal postoperative outcomes. In addition, expectant parents may have other psychosocial stressors that may compound maternal stress. We investigated the relationship between stress in pregnancies complicated by prenatally diagnosed CHD and their neonatal outcomes. A pilot retrospective cohort study of pregnancies with prenatally diagnosed critical CHD (2019-2021) was performed. The collected data included pregnancy characteristics and neonatal and postoperative outcomes (including the need for exogenous corticosteroid treatment (ECT)). In order to quantify prenatal stressors, a composite prenatal stress score (PSS) was established and utilized. In total, 41 maternal-fetal dyads were evaluated. Thirteen (32%) neonates had single-ventricle anatomy. The need for ECT after CHD surgery was associated with higher pregnant patient PSS (p = 0.01). PSS did not correlate with birthweight, infection, or hypoglycemia in the neonatal period. Prenatal stress is multifactorial; higher PSS is correlates with post-bypass ECT, suggesting that a stressful intrauterine environment may be associated with worse neonatal postoperative outcomes.

Neighborhood location and nutritional resources as a risk factor for congenital heart disease in the fetus.

Congenital heart disease (CHD) is the most common birth defect, influenced by maternal health, environmental conditions, and genetics. Maternal health and nutrition, particularly maternal diabetes, is a modifiable risk factor for development of CHD in the fetus. However, the importance of food access during pregnancy on the development of CHD remains unknown. The objective of this study was to investigate the association between maternal neighborhood characteristics, particularly food access, and occurrence of prenatally diagnosed CHD. A retrospective case series studied maternal-fetal dyads with prenatally diagnosed CHD between 2019 and 2021 in Washington, DC. Moran's I of maternal addresses evaluated geographic clustering of disease. Negative binomial regression assessed association between census tract demographics and population-adjusted CHD rate. A total of 307 dyads were analyzed. Global Moran's I showed significant CHD clustering (p-value = .004). However, degree of clustering was not clinically meaningful. After adjusting for neighborhood socioeconomic status, residing in food deserts was not a predictor for CHD. However, neighborhoods with a higher percentage of households receiving Supplemental Nutrition Assistance Program (SNAP) benefits were associated with higher rates of conotruncal heart defects (Incident Rate Ratio [IRR] = 1.04, CI = 1.01-1.08) and aggregate CHD (IRR = 1.03, CI = 1.01-1.05). Neighborhood location and food access were not associated with CHD. However, increased enrollment in SNAP was associated with higher rates of CHD. The association between CHD and SNAP benefits warrants further exploration. Understanding food access and maternal nutrition may illuminate disparities in the burden of CHD.

Association between Maternal FUT2 204A>G (rs492602) Genetic Polymorphism and Congenital Heart Disease in the Indian Population: A Study in Maternal-fetal Dyads

Background: FUT2 secretor genetic variants are strongly associated with absorption and circulatory levels of vitamin B12, thereby affecting folate metabolism pathway. The aim of this study was to evaluate the association between maternal FUT2 204A>G (rs492602) genetic polymorphism and CHD in the Indian population.Materials and method: One hundred and ten pregnant women who were vitamin B12 deficient with fetuses diagnosed with CHD were included in the case group and an equal number of healthy pregnant women with normal fetuses were selected as the control group. DNA was extracted from blood and umbilical cord tissue samples, and genotyped for FUT2 rs492602 polymorphism using allele-specific polymerase chain reaction. Hardy–Weinberg equilibrium test was used to calculate allele and genotype frequencies.Results: Significant increase in the frequency of AG (odds ratio=2.25; 95% CI: 1.25–4.05; p=0.009) and GG (odds ratio=3.51; 95% CI: 1.47-8.43; p=0.006) genotypes as well as G allele of FUT2 rs492602 were observed in the maternal case group. Furthermore, in the fetus case group, there was a significantly higher incidence of GG genotype (odds ratio=2.87; 95% CI: 1.26–6.57; p=0.018) and G allele (odds ratio=1.70; 95% CI: 1.15–2.53; p=0.009).Conclusion: FUT2 rs492602 are associated with CHD in the Indian population. Maternal genetic polymorphism that regulates vitamin B12 metabolic pathway might influence fetal cardiac development, thus serving as a predictor for CHD.Keywords: congenital heart disease, FUT2, single nucleotide polymorphism (SNP), vitamin B12

Prenatal Congenital Heart Disease—It Takes a Multidisciplinary Village

Prenatal diagnosis of congenital heart disease (CHD) allows for thoughtful multidisciplinary planning about location, timing, and need for medical interventions at birth. We sought to assess the accuracy of our prenatal cardiac diagnosis, and postnatal needs for patients with CHD utilizing a multidisciplinary approach. We performed a retrospective chart review of fetal CHD patients between 1/1/18 and 4/30/19. Maternal and infant charts were reviewed for delivery planning, subspecialty care needs, genetic evaluation, prenatal and postnatal cardiac diagnoses, need for prostaglandin (PGE) and neonatal cardiac intervention. 82 maternal-fetal dyads met inclusion criteria during the study period and delivered at a median of 38w2d gestation. 32 (39%) dyads had CHD and other anomalies or genetic abnormalities. All dyads met with a genetic counselor and neonatologist. 11 patients delivered at outside hospitals as planned (all with isolated CHD not requiring neonatal intervention), and 5 chose a palliative delivery. 30 patients were counseled to expect a neonatal cardiac intervention and 25 (83%) underwent an intervention within the expected time period. No neonates required an uncounseled cardiac intervention. 29 patients planned for PGE at birth and 31 received PGE. Of the 79 postnatal echocardiograms, 60 (76%) were entirely consistent with the fetal diagnosis. A multidisciplinary approach to the prenatal diagnosis of CHD in maternal-fetal dyads is optimal and utilizing this method we were able to accurately predict postnatal physiology and ensure that patients delivered in the correct location with an appropriate supportive structure in place.

Isolated Absent Septum Pellucidum: A Retrospective Study of Fetal Diagnosis and Postnatal Outcomes

BackgroundAbsent septum pellucidum (ASP) is a brain abnormality often associated with neuroanatomic abnormalities including septo-optic dysplasia (SOD). We aimed to determine how frequently prenatally diagnosed isolated ASP is confirmed by postnatal imaging and to examine clinical outcomes for ASP. MethodsThis was a retrospective study of maternal-fetal dyads referred to Children's National Hospital from January 1, 2012, to June 30, 2019. We included cases with fetal diagnosis of isolated or complex ASP. Diagnosis was based on ASP and the presence or absence of additional neuroanatomic findings. Data included obstetric and birth history, genetic testing, imaging, and neurodevelopmental outcomes. ResultsASP was diagnosed in 35 fetuses. Of 17 fetuses with isolated ASP, 10 had postnatal evaluation. In five (50%) isolated ASP cases, postnatal imaging revealed additional brain abnormalities. The five children with postnatally confirmed isolated ASP had lower rates of hydrocephalus (0% vs 54%) and abnormal feeding (0% vs 20%), hearing (0% vs 14%), and vision (0% vs 14%) than those with complex ASP (n = 17). Children with isolated ASP had lower rates of developmental delay (33% vs 50%) and seizures (11% vs 30%) than children with complex ASP. One child with prenatal isolated ASP was diagnosed with SOD (10%). ConclusionsFew children with prenatally diagnosed isolated ASP had SOD diagnosed postnatally. Overall, children with isolated ASP demonstrate better outcomes than children with complex ASP. Fetal magnetic resonance imaging is a useful tool to evaluate the septum pellucidum and may reveal additional abnormalities that can impact prognosis and affect prenatal counseling.

Outcome of Agenesis of the Corpus Callosum Diagnosed by Fetal MRI

BackgroundFetal magnetic resonance imaging (MRI) is increasingly utilized for prenatal diagnosis of agenesis of the corpus callosum (ACC). This study aimed to (1) describe cases of ACC diagnosed by fetal MRI, (2) determine the frequency of postnatal confirmation by MRI, and (3) understand postnatal outcomes of infants with ACC. MethodsMaternal records from Children's National Hospital between January 2012 and June 2019 with a prenatal neurological consultation, fetal MRI, and ACC on imaging were included. Maternal, prenatal, and postnatal infant data were collected. Each case was categorized as complete or partial ACC and isolated or complex ACC by fetal MRI and group comparisons of outcomes were analyzed. ResultsA total of 127 maternal-fetal dyads with ACC were categorized into 45 isolated-complete, 17 isolated-partial, 46 complex-complete, and 19 complex-partial ACC. Of 75 live births, 72 had postnatal evaluations. In 43 of 59 (73%) cases with postnatal neuroimaging, prenatal ACC subcategory was confirmed. Children with isolated or complex and with partial or complete ACC had similar rates of developmental delays and epilepsy. Complex ACC cases had worse outcomes than isolated ACC, with complex ACC having more postnatal dysmorphisms and abnormal feeding and vision compared with isolated ACC. Similar neurodevelopmental outcomes were seen for partial and complete ACC. ConclusionsChildren with isolated or complex ACC and with partial or complete ACC have a range of neurodevelopmental outcomes. Fetal and postnatal brain MRI is a valuable tool to understand differences of the corpus callosum that can guide genetic testing, prenatal counseling, and postnatal care.

Neurological and clinical outcomes in infants and children with a fetal diagnosis of asymmetric ventriculomegaly, interhemispheric cyst, and dysgenesis of the corpus callosum.

Advances in prenatal imaging have facilitated improvements in the fetal diagnosis of congenital anomalies. Asymmetric ventriculomegaly, interhemispheric cyst, and dysgenesis of the corpus callosum (AVID) is a constellation of congenital anomalies reported in fetal imaging. However, few data are available regarding postnatal outcomes of infants and children with a fetal diagnosis of AVID. The authors sought to report the neurodevelopmental outcomes of patients diagnosed with AVID before birth at a single institution. An institutional fetal imaging database was queried to identify cases with ventriculomegaly, interhemispheric cyst, and dysgenesis of the corpus callosum over a 10-year study period from 2000 to 2019. Overall, 41 maternal-infant dyads who met imaging criteria for AVID were identified; medical records were reviewed for prenatal variables including gestational age at birth, perinatal complications including fetal demise, and postnatal variables including demographics, mortality, hydrocephalus diagnosis and management, epilepsy, and neurodevelopmental outcomes at 2 years or the last follow-up. Among 41 patients, 25 (61%) were male. A slight majority of patients (55%) were born before 36 weeks of gestational age, and 27 patients (68%) were delivered via cesarean section because their head size precluded vaginal delivery. There were 8 incidences of fetal demise, 1 pregnancy was terminated, and 32 patients were born alive. Neonatal or early infant death occurred in 5 patients. Two children died during follow-up after the neonatal period (ages 7 months and 7 years). Twenty-six children survived to at least the 2-year follow-up, all of whom required treatment for hydrocephalus. Of those 26 children, 12 (46%) had a diagnosis of epilepsy, 14 (54%) could sit independently, 4 (16%) were in mainstream school, 16 (62%) had expressive language, and 7 (28%) had near-normal development without seizures. Among 41 maternal-fetal dyads with AVID, a majority of children survived to the 2-year follow-up, although all developed hydrocephalus. Many continued to have seizures, but expressive language use, attendance at mainstream school, and near-normal development without seizures were not infrequent. These data are critical for prenatal counseling and to establish the natural history of a diagnosis with limited outcome data.

Estimation of Fetal-to-Maternal Unbound Steady-State Plasma Concentration Ratio of P-Glycoprotein and/or Breast Cancer Resistance Protein Substrate Drugs Using a Maternal-Fetal Physiologically Based Pharmacokinetic Model.

Pregnant women are frequently prescribed drugs to treat chronic diseases such as human immunodeficiency virus infection, but little is known about the benefits and risks of these drugs to the fetus that are driven by fetal drug exposure. The latter can be estimated by fetal-to-maternal unbound plasma concentration at steady state (Kp,uu,fetal). For drugs that are substrates of placental efflux transporters [i.e., P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP)], Kp,uu,fetal is expected to be <1. Here, we estimated the in vivo Kp,uu,fetal of selective P-gp and BCRP substrate drugs by maternal-fetal physiologically based pharmacokinetic (m-f-PBPK) modeling of umbilical vein (UV) plasma and maternal plasma (MP) concentrations obtained simultaneously at term from multiple maternal-fetal dyads. To do so, three drugs were selected: nelfinavir (P-gp substrate), efavirenz (BCRP substrate), and imatinib (P-gp/BCRP substrate). An m-f-PBPK model for each drug was developed and validated for the nonpregnant population and pregnant women using the Simcyp simulator (v20). Then, after incorporating placental passive diffusion clearance, the in vivo Kp,uu,fetal of the drug was estimated by adjusting the placental efflux clearance until the predicted UV/MP values best matched the observed data (Kp,uu,fetal) of nelfinavir = 0.41, efavirenz = 0.39, and imatinib = 0.35. Furthermore, Kp,uu,fetal of nelfinavir and efavirenz at gestational weeks (GWs) 25 and 15 were predicted to be 0.34 and 0.23 (GW25) and 0.33 and 0.27 (GW15). These Kp,uu,fetal values can be used to adjust dosing regimens of these drugs to optimize maternal-fetal drug therapy throughout pregnancy, to assess fetal benefits and risks of these dosing regimens, and to determine if these estimated in vivo Kp,uu,fetal values can be predicted from in vitro studies.SIGNIFICANCE STATEMENTThe in vivo fetal-to-maternal unbound steady-state plasma concentration ratio (Kp,uu,fetal) of nelfinavir [P-glycoprotein (P-gp) substrate], efavirenz [breast cancer resistance protein (BCRP) substrate], and imatinib (P-gp and BCRP substrate) was successfully estimated using maternal-fetal physiologically based pharmacokinetic (m-f-PBPK) modeling. These Kp,uu,fetal values can be used to adjust dosing regimens of these drugs to optimize maternal-fetal drug therapy throughout pregnancy, to assess fetal benefits and risks of these dosing regimens, and to determine if these estimated in vivo Kp,uu,fetal values can be predicted from in vitro studies.

Identifying Unique Inflammatory Cytokine Profiles in Maternal-Fetal Dyads with COVID-19

Dysregulated immunity plays a critical role in determining COVID-19 disease severity. Pregnancy increases the risk for severe morbidity, yet little is known about how this altered immune state influences maternal-fetal immunity. We investigated cytokine responses to SARS-CoV-2 in maternal-fetal dyad pairs.

Analysis of six pyrethroid insecticide metabolites in cord serum using a novel gas chromatography-ion trap mass spectrometry method

Pyrethroid insecticides are commonly used for residential and commercial pest control in the US. Pregnant women and their fetuses are vulnerable to pesticide exposures during critical windows of neurodevelopment. Biomonitoring for exposure requires accurate and sensitive methods to assess exposures during pregnancy. The objective of this study was to develop a sensitive analytical method to measure pyrethroid metabolite concentrations in cord serum. Six pyrethroid metabolites, cis- and trans-3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropanecarboxylic acid (c/t-DCCA), trans-chrysanthemum dicarboxylic acid (t-CDCA), cis-3-(2,2-dibromovinyl)-2,2-dimethyl-cyclopropane carboxylic acid (c-DBCA), 4-fluoro-3-phenoxybenzoic acid (FPBA), and 3-phenoxybenzoic acid (3PBA) were extracted from cord serum by a dichloromethane liquid-liquid extraction, derivatized by 1,1,1,3,3,3-hexafluoro-2-propanol carboxylic acid esterification, and then measured by gas chromatography/ion trap mass spectrometry. Limits of detection ranged from 0.02 to 0.6 ng/mL. Sixty-three cord serum samples were collected from maternal-fetal dyads in central New Jersey to test for pyrethroid metabolites. Non-specific metabolites, 3PBA, t-DCCA, and t-CDCA, were detected most frequently, present in 29%, 6.3% and 6.3% of samples, respectively. Sensitivities were comparable or greater than other published studies assessing pyrethroid metabolites in cord blood. Comparisons with other literature-reported studies emphasize the importance of method sensitivity when assessing exposures at biologically relevant concentrations.

Abstract 14242: Homogeneous Fetal Access to Cardiac Care in a Heterogeneous State

Introduction: Timely prenatal diagnosis of congenital heart disease (CHD) allows for families to participate in complex decisions and plan for the care of their child. This study sought to investigate if the timing of the first fetal echocardiogram (FE) and the characteristics of fetal counseling were impacted by parental socioeconomic factors. Hypothesis: We hypothesized that the scheduling of initial FE would be delayed due to distance from hospital, rurality of maternal home and median income. Methods: We performed a retrospective chart review of all fetal patients referred to our institution from 1/1/17 to 12/31/18 with a diagnosis of CHD. We looked at the gestational age at the first FE, age of mother, zip code of residence, rurality index, distance from our hospital and maternal ethnicity. Counseling was evaluated based on documentation in the FE report regarding use of interpreter, time billed for counseling, individuals accompanying mother, and treatment option chosen. Results: 138 maternal-fetal dyads met inclusion criteria, 29 dyads had a diagnosis of single ventricle heart disease. The median gestational age (GA) at first FE was 24 weeks 4 days. The median income was $57,019 ($42,624-$83,695), and the median distance to the hospital was 51 miles (3.2-379.9miles). There was no difference in income, distance from hospital or rurality index and timing of first FE. There was no significant difference between maternal ethnicity and age of mother, GA at initial FE, number of follow-up FEs or family accompanying mother to the visit. There was no difference in maternal ethnicity and use of interpreter with time counseled. Patients who lived in rural areas did have increased counseling time (p&lt;.05). Importantly, there was no difference between socioeconomic factors and ultimate parental choices (termination, palliative delivery or surgery). Conclusions: Oregon comprises a heterogeneous population from a large geographical catchment. While prenatal counseling and family decision making is multifaceted we demonstrated that dyads were referred from across the state and received care in a uniformly timely manner, and once at our center received consistent counseling despite differences in parental socioeconomic factors.

Consistent localization of SARS-CoV-2 spike glycoprotein and ACE2 over TMPRSS2 predominance in placental villi of 15 COVID-19 positive maternal-fetal dyads

IntroductionWhile the COVID-19 pandemic continues to have a significant global health impact, rates of maternal to infant vertical transmission remain low (<5%). Parenchymal changes of placentas from COVID-19 infected mothers have been reported by several groups, but the localization and relative abundance of SARS-CoV-2 viral proteins and cellular entry machinery has not been fully characterized within larger placental tissue cohorts. MethodsAn extended placental tissue cohort including samples from 15 COVID-19 positive maternal-fetal dyads (with n = 5 cases with evidence of fetal transmission) in comparison with 10 contemporary COVID-19 negative controls. Using comparative immunofluorescence, we examined the localization and relative tissue abundance of SARS-CoV2 spike glycoprotein (CoV2 SP) along with the co-localization of two SARS-CoV2 viral entry proteins angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). Results/conclusionsCoV2 SP was present within the villous placenta in COVID-19 positive pregnancies with and without evidence of fetal transmission. We further identified the predominance of ACE2 expression in comparison with TMPRSS2. Importantly, both CoV2 SP and ACE2 expression consistently localized primarily within the outer syncytiotrophoblast layer placental villi, a key physiologic interface between mother and fetus. Overall this study provides an important basis for the ongoing evaluation of SARS-CoV-2 physiology in pregnancy and highlights the importance of the placenta as a key source of primary human tissue for ongoing diagnostic and therapeutic research efforts to reduce the global burden of COVID-19.

0853 Fetal Heart Rate Variability Increases During Maternal Sleep Apnea Events

Abstract Introduction While studies have established that SDB during pregnancy increases the risk of adverse maternal outcomes, fetal effects are less well studied. Evidence suggests that fetal heart rate decelerations, an indicator of fetal distress, may be elicited by SDB. We examined the relationship between maternal SDB events and fetal heart rate (FHR) and fetal heart rate variability (FHRV). Methods Obese (BMI≥30kg/m2) non-smoking women carrying singleton fetuses underwent overnight polysomnography (34-37 weeks gestational age), with simultaneous fetal heart rate monitoring. Standard methods were used to score sleep, SDB events (apneas/hypopneas) and to analyze fetal heart rate parameters. Using linear mixed effect models, we examined changes in mean FHR and FHR variability (expressed by FHR SD) between the 10-second period immediately before individual SDB events, during events to the end of the associated oxygen desaturation period, and the 10-second period immediately following the SDB event. Results Valid PSG and FHR data were obtained from 85 third trimester maternal-fetal dyads. Across all participants, there were 2779 maternal SDB events (apneas or hypopneas). Mean AHI for individual subjects was 9.04 (SD 13.75). 39 women had OSA (AHI≥5), which was mostly mild. Mean FHR did not change significantly during and after episodes of SDB episodes compared to pre-event FHR, and did not change afterwards compared to during events, in unadjusted or adjusted (sleep stage, apnea type, degree of desaturation, age) analyses. In unadjusted analyses, FHRV significantly increased during SDB episodes compared to pre-SDB FHRV. After SDB events, FHRV was significantly lower than during SDB events. In fully adjusted models, these findings remained highly significant. FHRV was not significantly different after SDB events compared to pre-SDB event FHRV in unadjusted or adjusted models. Conclusion We observed consistent changes in FHR variability during and after maternal SDB events. Mean FHRV significantly increased during maternal SDB episodes compared to baseline FHRV, and decreased after SDB episodes. In contrast, mean FHR did not change significantly before, during and after SDB episodes. These data demonstrate that the fetus reacts to maternal SDB events, and raise questions about persistent effects of maternal SDB on the developing fetus. Support NIH HD079411

1033: Obesity-induced epigenetic changes associated with adverse perinatal outcomes

Maternal obesity is associated with higher risk of fetal/neonatal mortality and morbidity. We aim to determine if maternal obesity alters major epigenetic modifications, DNA and RNA methylation, by affecting gene expression of methylation writers and erasers in the placenta. A cross-sectional study included maternal-fetal dyads presenting for scheduled cesarean delivery. Unlabored women at 37 weeks gestation or greater, with non-anomalous singleton pregnancy were enrolled if they had no maternal risk factors for placental diseases. Classified by prepregnancy BMI, two groups of women were eligible: 18.5 to 24.9 (non-obese) and greater than 30.0 (obese). Any medical complications of pregnancy, concern for fetal growth restriction or macrosomia, were exclusion criteria. Placental samples were obtained to measure DNA methylation, DNA methyltransferase Dnmt1/3a/3b and demethylase Tet1/2/3, RNA methylation, RNA methyltransferases and demethylases, and m6A RNA reader YTHDF1/3. Data were compared between obese and non-obese women. 12 obese (mean BMI 42.4 [IQR: 35.6-46.6]) and 12 non-obese patients (mean BMI 23.2 [IQR: 22.8-24.1]) have been enrolled. Placental DNA methylation levels were significantly higher in obese subjects. There was no difference of Dnmt1, 3a and 3b mRNA and protein expression between obese and non-obese subjects; however, the DNA demethylases Tet1, 2 and 3 were inhibited by obesity. Obesity reduced m6A levels but did not affect the expression of Mettl3 and Mettl14. Obesity suppressed the expression of key components of the Mettl3-Mettl14-WTAP complex including RBM15, WTAP and KIAA1429. Finally, maternal diabetes repressed the RNA reader YTHDF3, but did not affect the RNA demethylases FTO and ALKBH5. Our study demonstrates that DNA and RNA methylation plays an important role in the regulation of placental gene expression in non-complicated obese pregnancies by showing increased DNA methylation and decreased RNA methylation. These epigenetic findings may help explain the observed differences in perinatal outcomes between obese and non-obese pregnancies.

Maternal Caffeine Consumption and Racial Disparities in Fetal Telomere Length.

Background and Objectives:The identification of risk factors for shorter telomere length, especially during fetal development, would be important towards caffeine consumption recommendations for pregnant women on a global scale. The purpose of this study was to evaluate the association between caffeine intake and fetal telomere length as well as racial/ethnic differences in telomere length regardless of maternal caffeine consumption status.Methods:Caffeine intake was measured using a food frequency questionnaire (FFQ). Three generalized linear models (GLM) were compared based on binary categorical variables of caffeine levels using data mean value of 117.3 mg as cut-off; the World Health Organization (WHO) recommendations of 300 mg; and the American College of Obstetricians and Gynecologists (ACOG) recommendations of 200 mg. The association between caffeine consumption and telomere length (telomere to single-copy [T/S] ratio) was then assessed.Results:Among 57 maternal-fetal dyads, 77.2% reported less than 200 mg of caffeine (ACOG) and 89.5% less than 300 mg (WHO). Both WHO and ACOG models found that caffeine intake was significantly and positively associated with longer telomere length (p<0.05); and sodium (p<0.05). Other” race (p<0.001) and “white” race (p<0.001) were also significantly and positively associated with longer telomere length in the same models. Increasing maternal age shortened telomere length significantly in all models (p<0.001).Conclusion and Global Health implications:Caffeine intake, maternal age, and race may be associated with alterations in fetal telomere length. This indicates that caffeine consumption during pregnancy may have long-term implications for fetal development. The racial/ethnic differences in telomere length found in this study warrant larger studies to further confirm these associations.

Effects of Maternal Carbohydrate and Fat Intake on Fetal Telomere Length.

Telomere length can be affected by dietary factors in adults. We investigated the association between maternal carbohydrate and fat intake during pregnancy and telomere length in neonatal cord blood leukocytes. We hypothesized that high fat consumption and high carbohydrate consumption would be associated with shortened fetal telomere length. We collected umbilical cord blood at delivery from women admitted for labor and delivery in a university hospital (N = 62) and extracted genomic DNA using quantitative polymerase chain reaction. We quantified telomere length using the telomere-to-single copy gene ratio method (T:S ratio). High carbohydrate intake was defined as consumption of >175 g/day and high fat intake as >35 g/day. We performed generalized linear regression modeling and bootstrap statistical analyses to derive precise estimates of association. Of the 62 maternal-fetal dyads included in this study, 79% were classified as high carbohydrate consumers and 37% were classified as high fat consumers. High fat consumption had a significant negative effect on T:S ratio (P < 0.05). Although high carbohydrate consumption was associated with a decreased T:S ratio, this relation did not attain statistical significance. To our knowledge, this study is the first evidence of an association between maternal high fat consumption and shortened fetal telomere length. These findings could enhance our understanding of the role of maternal diet in fetal programming.

Dynamics of Vitamin D Metabolism in Maternal-Fetal Dyads.

Metabolites of vitamin D in maternal-neonatal dyads remain relatively unexplored. The goal of this study was to evaluate concentrations of 25(OH)D3, 24,25(OH)2D3, and 3-epi-25(OH)D3 in maternal-infant pairs at delivery. Serum samples of maternal and infant cord blood were collected on 131 mother-infant pairs at delivery. Vitamin D metabolites were analyzed in triplicate using liquid chromatography-tandem mass spectrometry. Statistical analysis was conducted using the Fisher exact test, Wilcoxon rank sum test, and Spearman correlation coefficients. Mean 25(OH)D3 concentrations in maternal and cord blood were 32.9 and 18.5 ng/mL, respectively; mean maternal and cord 24,25(OH)2D3 were 2.0 versus 1.1 ng/mL, respectively. Absolute concentrations of 3-epi-25(OH)D3 were similar in maternal and cord samples (2.4 vs 2.2 ng/mL), whereas the proportion of the total 25(OH)D as the 3-epimer was 6.5% in maternal samples and 10.5% in cord samples. This suggests that the fetus contributes significantly to 3-epi-25(OH)D3 production. In contrast, the ratio of 25(OH)D3:24,25(OH)2D3 was identical in maternal and cord samples (18.5) suggesting equivalent CYP24A1 activity in mother and fetus. Maternal and cord metabolite levels were highly correlated (r = 0.78, 0.90, 0.89 for 25(OH)D3, 24,25(OH)2D3, and 3-epi-25(OH)D3, respectively, P = 0.001 for all). Serum concentrations of all metabolites were lower in nonwhite infants compared with white infants. Maternal and cord concentrations of 25(OH)D3 were positively associated with birth weight (r = 0.21, P = 0.02; r = 0.25, P = 0.003, respectively). This data suggests that although maternal and cord concentrations of vitamin D metabolites are highly correlated, regulation of specific vitamin D metabolites in the mother and the neonate may be mediated independently.