Magnesium sulfate and risk of hypoxic-ischemic encephalopathy in a high-risk cohort.

BACKGROUND: Hypoxic-ischemic encephalopathy contributes to morbidity and mortality among neonates ≥36 weeks of gestation. Evidence of preventative antenatal treatment is limited. Magnesium sulfate has neuroprotective properties among preterm fetuses. Hypertensive disorders of pregnancy are a risk factor for hypoxic-ischemic encephalopathy, and magnesium sulfate is recommended for maternal seizure prophylaxis among patients with preeclampsia with severe features. OBJECTIVE: (1) Determine trends in the incidence of hypertensive disorders of pregnancy, antenatal magnesium sulfate, and hypoxic-ischemic encephalopathy; (2) evaluate the association between hypertensive disorders of pregnancy and hypoxic-ischemic encephalopathy; and (3) evaluate if, among patients with hypertensive disorders of pregnancy, the odds of hypoxic-ischemic encephalopathy is mitigated by receipt of antenatal magnesium sulfate. STUDY DESIGN: We analyzed a prospective cohort of live births ≥36 weeks of gestation between 2012 and 2018 within the California Perinatal Quality Care Collaborative registry, linked with the California Department of Health Care Access and Information files. We used Cochran-Armitage tests to assess trends in hypertensive disorders, encephalopathy diagnoses, and magnesium sulfate utilization and compared demographic factors between patients with or without hypertensive disorders of pregnancy or treatment with magnesium sulfate. Hierarchical logistic regression models were built to explore if hypertensive disorders of pregnancy were associated with any severity and moderate/severe hypoxic-ischemic encephalopathy. Separate hierarchical logistic regression models were built among those with hypertensive disorders of pregnancy to evaluate the association of magnesium sulfate with hypoxic-ischemic encephalopathy. RESULTS: Among 44,314 unique infants, the diagnosis of hypoxic-ischemic encephalopathy, maternal hypertensive disorders of pregnancy, and the use of magnesium sulfate increased over time. Compared with patients with hypertensive disorders of pregnancy alone, patients with hypertensive disorders treated with magnesium sulfate represented a high-risk population. They were more likely to be publicly insured, born between 36 and 38 weeks of gestation, be small for gestational age, have lower Apgar scores, require a higher level of resuscitation at delivery, have prolonged rupture of membranes, experience preterm labor and fetal distress, and undergo operative delivery (all P<.002). Hypertensive disorders of pregnancy were associated with hypoxic-ischemic encephalopathy (adjusted odds ratio, 1.26 [95% confidence interval, 1.13-1.40]; P<.001) and specifically moderate/severe hypoxic-ischemic encephalopathy (adjusted odds ratio, 1.26 [95% confidence interval, 1.11-1.42]; P<.001). Among patients with hypertensive disorders of pregnancy, treatment with magnesium sulfate was associated with 29% reduction in the odds of neonatal hypoxic-ischemic encephalopathy (adjusted odds ratio, 0.71 [95% confidence interval, 0.52-0.97]; P=.03) and a 37% reduction in the odds of moderate/severe neonatal hypoxic-ischemic encephalopathy (adjusted odds ratio, 0.63 [95% confidence interval, 0.42-0.94]; P=.03). CONCLUSION: Hypertensive disorders of pregnancy are associated with hypoxic-ischemic encephalopathy and, specifically, moderate/severe disease. Among people with hypertensive disorders, receipt of antenatal magnesium sulfate is associated with a significant reduction in the odds of hypoxic-ischemic encephalopathy and moderate/severe disease in a neonatal cohort admitted to neonatal intensive care unit at ≥36 weeks of gestation. The findings of this observational study cannot prove causality and are intended to generate hypotheses for future clinical trials on magnesium sulfate in term infants.

Evaluation of Sleep in Pregnant Inpatients Compared With Outpatients.

OBJECTIVE: To evaluate whether antepartum hospitalization was associated with differences in sleep duration or disrupted sleep patterns. METHODS: This was a prospective cohort study with enrollment of pregnant people aged 18-55 years with singleton gestations at 16 weeks of gestation or more between 2021 and 2022. Each enrolled antepartum patient was matched by gestational age to outpatients recruited from obstetric clinics at the same institution. Participants responded to the ISI (Insomnia Severity Index) and wore actigraph accelerometer watches for up to 7 days. The primary outcome was total sleep duration per 24 hours. Secondary outcomes included sleep efficiency (time asleep/time in bed), ISI score, clinical insomnia (ISI score higher than 15), short sleep duration (less than 300 minutes/24 hours), wakefulness after sleep onset, number of awakenings, and sleep fragmentation index. Outcomes were evaluated with multivariable generalized estimating equations adjusted for body mass index (BMI), sleep aid use, and insurance type, accounting for gestational age correlations. An interaction term assessed the joint effects of time and inpatient status. RESULTS: Overall 58 participants were included: 18 inpatients and 40 outpatients. Inpatients had significantly lower total sleep duration than outpatients (mean 4.4 hours [SD 1.6 hours] inpatient vs 5.2 hours [SD 1.5 hours] outpatient, adjusted ß=-1.1, 95% CI, -1.8 to -0.3, P =.01). Awakenings (10.1 inpatient vs 13.8, P =.01) and wakefulness after sleep onset (28.3 inpatient vs 35.5 outpatient, P =.03) were lower among inpatients. There were no differences in the other sleep outcomes, and no interaction was detected for time in the study and inpatient status. Inpatients were more likely to use sleep aids (39.9% vs 12.5%, P =.03). CONCLUSION: Hospitalized pregnant patients slept about 1 hour/day less than outpatients. Fewer awakenings and reduced wakefulness after sleep onset among inpatients may reflect increased use of sleep aids in hospitalized patients.

Physical activity among pregnant inpatients and outpatients and associations with anxiety.

OBJECTIVE: Physical activity is linked to lower anxiety, but little is known about the association during pregnancy. This is especially important for antepartum inpatients, who are known to have increased anxiety yet may not be able to achieve target levels of physical activity during hospitalization. We compared physical activity metrics between pregnant inpatients and outpatients and explored correlations with anxiety. MATERIALS AND METHODS: This was a prospective cohort between 2021 and 2022 of pregnant people aged 18-55 years carrying singleton gestations ≥ 16 weeks. Three exposure groups were matched for gestational age: 1) outpatients from general obstetric clinics; 2) outpatients from high-risk Maternal-Fetal Medicine obstetric clinics; and 3) antepartum inpatients. Participants wore Actigraph GT9X Link accelerometer watches for up to 7 days to measure physical activity. The primary outcome was mean daily step count. Secondary outcomes were metabolic equivalent tasks (METs), hourly kilocalories (kcals), moderate to vigorous physical activity (MVPA) bursts, and anxiety (State-Trait Anxiety Inventory [STAI]). Step counts were compared using multivariable generalized estimating equations adjusting for maternal age, body-mass index, and insurance type as a socioeconomic construct, accounting for within-group clustering by gestational age. Spearman correlations were used to correlate anxiety scores with step counts. RESULTS: 58 participants were analyzed. Compared to outpatients, inpatients had significantly lower mean daily steps (primary outcome, adjusted beta -2185, 95 % confidence interval [CI] -3146, -1224, p < 0.01), METs (adjusted beta -0.18, 95 % CI -0.23, -0.13, p < 0.01), MVPAs (adjusted beta -38.2, 95 % CI -52.3, -24.1, p < 0.01), and kcals (adjusted beta -222.9, 95 % CI -438.0, -7.8, p = 0.04). Over the course of the week, steps progressively decreased for inpatients (p-interaction 0.01) but not for either of the outpatient groups. Among the entire cohort, lower step counts correlated with higher anxiety scores (r = 0.30, p = 0.02). CONCLUSION: We present antenatal population norms and variance for step counts, metabolic equivalent tasks, moderate to vigorous physical activity bursts, and kcals, as well as correlations with anxiety. Antepartum inpatients had significantly lower physical activity than outpatients, and lower step counts correlated with higher anxiety levels. These results highlight the need for physical activity interventions, particularly for hospitalized pregnant people.

Intrahepatic Cholestasis of Pregnancy and Transaminitis in Women with COVID-19: A Case Series.

Objective The four initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected pregnant women presenting at term gestation to our institution presented with transaminitis. Three of the four were diagnosed with intrahepatic cholestasis of pregnancy (IHCP). Growing evidence exists of an associated transaminitis in nonpregnant SARS-CoV-2 patients. However, there are limited data of hepatic involvement of SARS-CoV-2 in pregnancy, and no previous studies have assessed the association with IHCP in patients with coronavirus disease 2019 (COVID-19). Study Design This was a retrospective, single-center case series of four consecutive pregnant women with a positive result for SARS-CoV-2 presenting with transaminitis in third trimester. Results The clinical courses of four pregnant women with COVID-19 and transaminitis, three of four of whom were diagnosed with IHCP, are described. Testing for SARS-CoV-2 was done through a reverse transcription polymerase chain reaction test of a nasopharyngeal swab. Conclusion As we await larger studies ascertaining the incidence of IHCP in SARS-CoV-2, this prevalence highlights the importance of diagnosing IHCP among women with COVID-19 as a potential etiology of transaminitis, as IHCP risks may be ameliorated with earlier delivery. Moreover, delineating a hepatobiliary association in pregnancy may provide further information about the mechanism of liver impairment in SARS-CoV-2 in all patients.

Hydroxychloroquine in Lupus Pregnancy and Risk of Preeclampsia.

OBJECTIVE: Systemic lupus erythematosus (SLE) disproportionately affects women during childbearing years, and hydroxychloroquine (HCQ) is the standard first-line treatment. Preeclampsia complicates up to one-third of pregnancies in lupus patients, although reports vary by parity and multifetal gestation. We investigated whether taking HCQ early in pregnancy may reduce the risk of preeclampsia. METHODS: We studied 1,068 live birth singleton pregnancies among 1,020 privately insured patients with SLE (2007-2016). HCQ treatment was defined as three months preconception through the first trimester, and prescription fills were a proxy for taking HCQ. Modified Poisson regression estimated risk ratios (RRs) and 95% confidence intervals (CIs), stratified by parity. Propensity scores accounted for confounders, and stratified analyses examined effect modification. RESULTS: Approximately 15% of pregnant patients were diagnosed with preeclampsia. In 52% of pregnancies, patients had one or more HCQ fills. Pregnant patients exposed to HCQ had more comorbidities, SLE activity, and azathioprine treatment. We found no evidence of a statistical association between HCQ and preeclampsia among nulliparous (RR 1.26 [95% CI 0.82-1.93]) and multiparous pregnancies (RR 1.20 [95% CI 0.80-1.70]). Additional controls for confounding decreased the RRs toward the null (nulliparous pregnancy, propensity score-adjusted [PS-adj] RR 1.09 [95% CI 0.68-1.76]; multiparous pregnancy, PS-adj RR 1.01 [95% CI 0.66-1.53]). CONCLUSION: Using a large insurance-based database, we did not observe a decreased risk of preeclampsia associated with HCQ treatment in pregnancy, although we cannot rule out residual and unmeasured confounding and misclassification. Further studies leveraging large population-based data and prospective collection could characterize how HCQ influences preeclampsia risk in pregnant patients with SLE and among persons at greater risk of hypertensive disorders of pregnancy.

Pregnancy Outcomes in a Diverse US Lupus Cohort.

OBJECTIVE: Although the population of patients with systemic lupus erythematosus (SLE) is racially and ethnically diverse, many study populations are homogeneous. Further, data are often lacking on critical factors, such as antiphospholipid antibodies (aPLs). We investigated live birth rates in patients with SLE at Kaiser Permanente Northern California, including race and ethnicity and aPL data. METHODS: Electronic health records of pregnancies with outcomes observed from 2011 to 2020 were identified among patients with SLE. Prevalent SLE was defined as two or more International Classification of Diseases-coded visits seven or more days apart before the last menstrual period. We summarized patient characteristics, medication orders, health care use, and medication use. Pregnancy outcomes (live birth, stillbirth, spontaneous abortion, ectopic pregnancy, and molar pregnancy) were presented overall and stratified by race and ethnicity, aPL status, and nephritis history. RESULTS: We identified 657 pregnancies among 453 patients with SLE. The cohort was diverse, reflecting the Northern California population (27% Asian, 26% Hispanic, 26% Non-Hispanic White, 13% Non-Hispanic Black, 5% multiracial, and approximately 2% Pacific Islander and Native American). Approximately 74% of observed pregnancies ended in live birth, 23% resulted in spontaneous abortion, 2% were ectopic or molar pregnancies, and <1% were stillbirths. There was limited variability in live births by race and ethnic group (72%-79%), aPL status (69.5%-77%), and nephritis history (71%-75%). CONCLUSION: Our findings are consistent with previous studies; however, some methodologic differences may yield a range of live birth rates. We found that approximately 74% of pregnancies in patients with SLE ended in live birth, with modest variability in spontaneous abortion by race and ethnicity, nephritis history, and aPL status.

Multiomic signals associated with maternal epidemiological factors contributing to preterm birth in low- and middle-income countries.

Preterm birth (PTB) is the leading cause of death in children under five, yet comprehensive studies are hindered by its multiple complex etiologies. Epidemiological associations between PTB and maternal characteristics have been previously described. This work used multiomic profiling and multivariate modeling to investigate the biological signatures of these characteristics. Maternal covariates were collected during pregnancy from 13,841 pregnant women across five sites. Plasma samples from 231 participants were analyzed to generate proteomic, metabolomic, and lipidomic datasets. Machine learning models showed robust performance for the prediction of PTB (AUROC = 0.70), time-to-delivery (r = 0.65), maternal age (r = 0.59), gravidity (r = 0.56), and BMI (r = 0.81). Time-to-delivery biological correlates included fetal-associated proteins (e.g., ALPP, AFP, and PGF) and immune proteins (e.g., PD-L1, CCL28, and LIFR). Maternal age negatively correlated with collagen COL9A1, gravidity with endothelial NOS and inflammatory chemokine CXCL13, and BMI with leptin and structural protein FABP4. These results provide an integrated view of epidemiological factors associated with PTB and identify biological signatures of clinical covariates affecting this disease.

Vaginal Progesterone Is Associated with Intrahepatic Cholestasis of Pregnancy.

OBJECTIVE: The frequency of intrahepatic cholestasis of pregnancy (ICP) peaks during the third trimester of pregnancy when plasma progesterone levels are the highest. Furthermore, twin pregnancies are characterized by higher progesterone levels than singletons and have a higher frequency of cholestasis. Therefore, we hypothesized that exogenous progestogens administered for reducing the risk of spontaneous preterm birth may increase the risk of cholestasis. Utilizing the large IBM MarketScan Commercial Claims and Encounters Database, we investigated the frequency of cholestasis in patients treated with vaginal progesterone or intramuscular 17α-hydroxyprogesterone caproate for the prevention of preterm birth. STUDY DESIGN: We identified 1,776,092 live-born singleton pregnancies between 2010 and 2014. We confirmed second and third trimester administration of progestogens by cross-referencing the dates of progesterone prescriptions with the dates of scheduled pregnancy events such as nuchal translucency scan, fetal anatomy scan, glucose challenge test, and Tdap vaccination. We excluded pregnancies with missing data regarding timing of scheduled pregnancy events or progesterone treatment prescribed only during the first trimester. Cholestasis of pregnancy was identified based on prescriptions for ursodeoxycholic acid. We used multivariable logistic regression to estimate adjusted (for maternal age) odds ratios for cholestasis in patients treated with vaginal progesterone, and in patients treated with 17α-hydroxyprogesterone caproate compared with those not treated with any type of progestogen (the reference group). RESULTS: The final cohort consisted of 870,599 pregnancies. Among patients treated with vaginal progesterone during the second and third trimester, the frequency of cholestasis was significantly higher than the reference group (0.75 vs. 0.23%, adjusted odds ratio [aOR]: 3.16, 95% confidence interval [CI]: 2.23-4.49). In contrast, there was no significant association between 17α-hydroxyprogesterone caproate and cholestasis (0.27%, aOR: 1.12, 95% CI: 0.58-2.16) CONCLUSION: Using a robust dataset, we observed that vaginal progesterone but not intramuscular 17α-hydroxyprogesterone caproate was associated with an increased risk for ICP. KEY POINTS: · Previous studies have been underpowered to detect potential association between progesterone and ICP.. · Vaginal progesterone was significantly associated with ICP.. · Intramuscular 17α-hydroxyprogesterone was not associated with ICP..

Severity of small-for-gestational-age and morbidity and mortality among very preterm neonates.

OBJECTIVE: Evaluate the association between small for gestational age (SGA) severity and morbidity and mortality in a contemporary, population of very preterm infants. STUDY DESIGN: This secondary analysis of a California statewide database evaluated singleton infants born during 2008-2018 at 24-32 weeks' gestation, with a birthweight <15th percentile. We analyzed neonatal outcomes in relation to weight for gestational age (WGA) and symmetry of growth restriction. RESULTS: An increase in WGA by one z-score was associated with decreased major morbidity or mortality risk (aRR 0.73, 95% CI 0.68-0.77) and other adverse outcomes. The association was maintained across gestational ages and did not differ by fetal growth restriction diagnosis. Symmetric growth restriction was not associated with neonatal outcomes after standardizing for gestational age at birth. CONCLUSIONS: Increasing SGA severity had a significant impact on neonatal outcomes among very preterm infants.

Trends in Spontaneous and Medically Indicated Preterm Birth in Twins versus Singletons: A California Cohort 2007 to 2011.

OBJECTIVE: The study aimed to describe preterm birth (PTB) rates, subtypes, and risk factors in twins compared with singletons to better understand reasons for the decline in PTB rate between 2007 and 2011. STUDY DESIGN: This was a retrospective population-based analysis using the California linked birth certificates and maternal-infant hospital discharge records from 2007 to 2011. The main outcomes were overall, spontaneous (following spontaneous labor or preterm premature rupture of membranes), and medically indicated PTB at various gestational age categories: <37, <32, and 34 to 36 weeks in twins and singletons. RESULTS: Among the 2,290,973 singletons and 28,937 twin live births pairs included, overall PTB <37 weeks decreased by 8.46% (6.77-6.20%) in singletons and 7.17% (55.31-51.35%) in twins during the study period. In singletons, this was primarily due to a 24.91% decrease in medically indicated PTB with almost no change in spontaneous PTB, whereas in twins indicated PTB declined 7.02% and spontaneous PTB by 7.39%. CONCLUSION: Recent declines in PTB in singletons appear to be largely due to declines in indicated PTB, whereas both spontaneous and indicated PTB declined in twins. KEY POINTS: · The declines in PTB noted between 2006 and 2014 occurred in both singleton and twins.. · Declines were mostly in medically indicated PTB.. · Interventions proposed as causing the declines in singletons would not apply to twins..

Antihypertensive Medication Use before and during Pregnancy and the Risk of Severe Maternal Morbidity in Individuals with Prepregnancy Hypertension.

OBJECTIVE: Our objective is to examine severe maternal morbidity (SMM) and patterns of antihypertensive medication use before and during pregnancy among individuals with chronic hypertension. STUDY DESIGN: We examined 11,759 pregnancies resulting in a live birth or stillbirth to individuals with chronic hypertension and one or more antihypertensive prescription 6 months before pregnancy (Optum, 2007-17). We examined whether study outcomes were associated with the use of medication as compared to no use during pregnancy. In addition, patterns of medication use based on the Food and Drug Administration guidance and literature were evaluated. Medication use was divided into prepregnancy and during pregnancy use and classified as pregnancy recommended (PR) or not pregnancy recommended (nPR) or no medication use. SMM was defined per the Centers for Disease Control and Prevention definition of 21 indicators. Risk ratios (RR) reflecting the association of SMM with the use of antihypertensive medications were computed using modified Poisson regression with robust standard errors and adjusted for maternal age, education, and birth year. RESULTS: Overall, 83% of individuals filled an antihypertensive prescription during pregnancy and 6.3% experienced SMM. The majority of individuals with a prescription prior to pregnancy had a prescription for the same medication in pregnancy. Individuals with any versus no medication use in pregnancy had increased adjusted RR (aRR) of SMM (1.18, 95% confidence interval [CI]: 0.96-1.44). Compared to the use of PR medications before and during pregnancy, aRRs were 1.42 (95% CI: 1.18-1.69, 12.4% of sample) for nPR use before and during pregnancy, 1.52 (1.23-1.86; 12.4%) for nPR (before) and PR (during) use, and 2.67 (1.73-4.15) for PR and nPR use. Patterns with no medication use during pregnancy were not statistically significant. CONCLUSION: Pattern of antihypertensive medication use before and during pregnancy may be associated with an elevated risk of SMM. Further research is required to elucidate whether this association is related to the severity of hypertension, medication effectiveness, or suboptimal quality of care. KEY POINTS: · Individuals with any medication use compared to no medication use in pregnancy had an increased risk of SMM.. · Specific medication use patterns were associated with an elevated risk of SMM.. · Pattern of antihypertensive medication use before and during pregnancy may be associated with an increased risk of SMM..

Postpartum Readmission for Hypertension After Discharge on Labetalol or Nifedipine.

OBJECTIVE: To assess whether readmission for hypertension by 6 weeks postpartum differed between patients discharged on nifedipine or labetalol. METHODS: This cohort study included patients with delivery admissions from 2006 to 2017 who were discharged from the hospital on nifedipine or labetalol and were included in a large, national adjudicated claims database. We identified patients' discharge medication based on filled outpatient prescriptions. We compared rates of hospital readmission for hypertension between patients discharged postpartum on labetalol alone, nifedipine alone, or combined nifedipine and labetalol. Patients with chronic hypertension without superimposed preeclampsia were excluded. Comparisons based on medication were performed using logistic regression models with adjustment for prespecified confounders. Comparisons were also stratified by hypertensive disorder of pregnancy severity. RESULTS: Among 1,582,335 patients overall, 14,112 (0.89%) were discharged postpartum on labetalol, 9,001 (0.57%) on nifedipine, and 1,364 (0.09%) on both medications. Postpartum readmissions for hypertension were more frequent for patients discharged on labetalol compared with nifedipine (641 patients vs 185 patients, 4.5% vs 2.1%, adjusted odds ratio [aOR] 1.63, 95% CI 1.43-1.85). Readmissions for hypertension were more frequent for patients discharged on labetalol compared with nifedipine for both mild (4.5% vs 2.7%, aOR 1.57, 95% CI 1.29-1.93) and severe hypertensive disorders of pregnancy (261 patients vs 72 patients, 5.7% vs 3.2%, aOR 1.63, 95% CI 1.43-1.85). Readmissions for hypertension were more frequent on combined nifedipine and labetalol compared with nifedipine (3.1% vs 2.1%), but the odds were lower after confounder adjustment (aOR 0.80, 95% CI 0.64-0.99). CONCLUSION: Postpartum discharge on labetalol was associated with increased risk of readmission for hypertension compared with discharge on nifedipine.

Leukocyte telomere dynamics across gestation in uncomplicated pregnancies and associations with stress.

BACKGROUND: Short leukocyte telomere length is a biomarker associated with stress and morbidity in non-pregnant adults. Little is known, however, about maternal telomere dynamics in pregnancy. To address this, we examined changes in maternal leukocyte telomere length (LTL) during uncomplicated pregnancies and explored correlations with perceived stress. METHODS: In this pilot study, maternal LTL was measured in blood collected from nulliparas who delivered live, term, singleton infants between 2012 and 2018 at a single institution. Participants were excluded if they had diabetes or hypertensive disease. Samples were collected over the course of pregnancy and divided into three time periods: < 200/7 weeks (Timepoint 1); 201/7 to 366/7 weeks (Timepoint 2); and 370/7 to 9-weeks postpartum (Timepoint 3). All participants also completed a survey assessing a multivariate profile of perceived stress at the time of enrollment in the first trimester. LTL was measured using quantitative polymerase chain reaction (PCR). Wilcoxon signed-rank tests were used to compare LTL differences within participants across all timepoint intervals. To determine whether mode of delivery affected LTL, we compared postpartum Timepoint 3 LTLs between participants who had vaginal versus cesarean birth. Secondarily, we evaluated the association of the assessed multivariate stress profile and LTL using machine learning analysis. RESULTS: A total of 115 samples from 46 patients were analyzed. LTL (mean ± SD), expressed as telomere to single copy gene (T/S) ratios, were: 1.15 ± 0.26, 1.13 ± 0.23, and 1.07 ± 0.21 for Timepoints 1, 2, and 3, respectively. There were no significant differences in LTL between Timepoints 1 and 2 (LTL T/S change - 0.03 ± 0.26, p = 0.39); 2 and 3 (- 0.07 ± 0.29, p = 0.38) or Timepoints 1 and 3 (- 0.07 ± 0.21, p = 0.06). Participants who underwent cesareans had significantly shorter postpartum LTLs than those who delivered vaginally (T/S ratio: 0.94 ± 0.12 cesarean versus 1.12 ± 0.21 vaginal, p = 0.01). In secondary analysis, poor sleep quality was the main stress construct associated with shorter Timepoint 1 LTLs (p = 0.02) and shorter mean LTLs (p = 0.03). CONCLUSIONS: In this cohort of healthy pregnancies, maternal LTLs did not significantly change across gestation and postpartum LTLs were shorter after cesarean than after vaginal birth. Significant associations between sleep quality and short LTLs warrant further investigation.

Stress and Its Consequences-Biological Strain.

Understanding the role of stress in pregnancy and its consequences is important, particularly given documented associations between maternal stress and preterm birth and other pathological outcomes. Physical and psychological stressors can elicit the same biological responses, known as biological strain. Chronic stressors, like poverty and racism (race-based discriminatory treatment), may create a legacy or trajectory of biological strain that no amount of coping can relieve in the absence of larger-scale socio-behavioral or societal changes. An integrative approach that takes into consideration simultaneously social and biological determinants of stress may provide the best insights into the risk of preterm birth. The most successful computational approaches and the most predictive machine-learning models are likely to be those that combine information about the stressors and the biological strain (for example, as measured by different omics) experienced during pregnancy.

Early prediction of preeclampsia in pregnancy with cell-free RNA.

Liquid biopsies that measure circulating cell-free RNA (cfRNA) offer an opportunity to study the development of pregnancy-related complications in a non-invasive manner and to bridge gaps in clinical care1-4. Here we used 404 blood samples from 199 pregnant mothers to identify and validate cfRNA transcriptomic changes that are associated with preeclampsia, a multi-organ syndrome that is the second largest cause of maternal death globally5. We find that changes in cfRNA gene expression between normotensive and preeclamptic mothers are marked and stable early in gestation, well before the onset of symptoms. These changes are enriched for genes specific to neuromuscular, endothelial and immune cell types and tissues that reflect key aspects of preeclampsia physiology6-9, suggest new hypotheses for disease progression and correlate with maternal organ health. This enabled the identification and independent validation of a panel of 18 genes that when measured between 5 and 16 weeks of gestation can form the basis of a liquid biopsy test that would identify mothers at risk of preeclampsia long before clinical symptoms manifest themselves. Tests based on these observations could help predict and manage who is at risk for preeclampsia-an important objective for obstetric care10,11.

Proteomic signatures predict preeclampsia in individual cohorts but not across cohorts - implications for clinical biomarker studies.

BACKGROUND: Early identification of pregnant women at risk for preeclampsia (PE) is important, as it will enable targeted interventions ahead of clinical manifestations. The quantitative analyses of plasma proteins feature prominently among molecular approaches used for risk prediction. However, derivation of protein signatures of sufficient predictive power has been challenging. The recent availability of platforms simultaneously assessing over 1000 plasma proteins offers broad examinations of the plasma proteome, which may enable the extraction of proteomic signatures with improved prognostic performance in prenatal care. OBJECTIVE: The primary aim of this study was to examine the generalizability of proteomic signatures predictive of PE in two cohorts of pregnant women whose plasma proteome was interrogated with the same highly multiplexed platform. Establishing generalizability, or lack thereof, is critical to devise strategies facilitating the development of clinically useful predictive tests. A second aim was to examine the generalizability of protein signatures predictive of gestational age (GA) in uncomplicated pregnancies in the same cohorts to contrast physiological and pathological pregnancy outcomes. STUDY DESIGN: Serial blood samples were collected during the first, second, and third trimesters in 18 women who developed PE and 18 women with uncomplicated pregnancies (Stanford cohort). The second cohort (Detroit), used for comparative analysis, consisted of 76 women with PE and 90 women with uncomplicated pregnancies. Multivariate analyses were applied to infer predictive and cohort-specific proteomic models, which were then tested in the alternate cohort. Gene ontology (GO) analysis was performed to identify biological processes that were over-represented among top-ranked proteins associated with PE. RESULTS: The model derived in the Stanford cohort was highly significant (p = 3.9E-15) and predictive (AUC = 0.96), but failed validation in the Detroit cohort (p = 9.7E-01, AUC = 0.50). Similarly, the model derived in the Detroit cohort was highly significant (p = 1.0E-21, AUC = 0.73), but failed validation in the Stanford cohort (p = 7.3E-02, AUC = 0.60). By contrast, proteomic models predicting GA were readily validated across the Stanford (p = 1.1E-454, R = 0.92) and Detroit cohorts (p = 1.1.E-92, R = 0.92) indicating that the proteomic assay performed well enough to infer a generalizable model across studied cohorts, which makes it less likely that technical aspects of the assay, including batch effects, accounted for observed differences. CONCLUSIONS: Results point to a broader issue relevant for proteomic and other omic discovery studies in patient cohorts suffering from a clinical syndrome, such as PE, driven by heterogeneous pathophysiologies. While novel technologies including highly multiplex proteomic arrays and adapted computational algorithms allow for novel discoveries for a particular study cohort, they may not readily generalize across cohorts. A likely reason is that the prevalence of pathophysiologic processes leading up to the "same" clinical syndrome can be distributed differently in different and smaller-sized cohorts. Signatures derived in individual cohorts may simply capture different facets of the spectrum of pathophysiologic processes driving a syndrome. Our findings have important implications for the design of omic studies of a syndrome like PE. They highlight the need for performing such studies in diverse and well-phenotyped patient populations that are large enough to characterize subsets of patients with shared pathophysiologies to then derive subset-specific signatures of sufficient predictive power.

Trends in eclampsia in the United States, 2009-2017: a population-based study.

BACKGROUND: Reducing the prevalence of eclampsia, a major cause of maternal and perinatal morbidity, is a maternal health priority. However, sparse data exist examining trends in the USA prevalence of eclampsia. OBJECTIVE: The aim of this study was to assess temporal trends in the prevalence of eclampsia among live births in the United States from 2009 to 2017. STUDY DESIGN: This population-based cross-sectional study included live births in 41 USA states and the District of Columbia between 2009 and 2017. The prevalence of eclampsia among all women, women with chronic hypertension and hypertensive disorders of pregnancy were reported by 1000 live births. Risk ratios adjusted for maternal characteristics were used to assess temporal trends. RESULTS: Of 27 866 714 live births between 2009 and 2017, 83 000 (0.30%) were associated with eclampsia. The adjusted risk of eclampsia decreased 10% during the 7 most recent years of the cohort, with an adjusted risk ratio of 0.90 [95% confidence interval (95% CI): 0.87-0.93] in 2017 relative to 2009. Relative to 2009, the adjusted risk of eclampsia in 2017 was substantially lower among women with chronic hypertension (adjusted risk ratio: 0.51; 95% CI: 0.46-0.57) and women with hypertensive pregnancy disorders (adjusted risk ratio: 0.43; 95% CI: 0.40-0.47). Among nonhypertensive women, there was a slight increase in the adjusted risk of eclampsia in 2017 relative to 2009 (adjusted risk ratio: 1.14; 95% CI: 1.10-1.17). CONCLUSION: Despite reductions in the eclampsia prevalence among women with chronic hypertension and hypertensive disorders of pregnancy, public health initiatives are needed to reduce the overall eclampsia prevalence, especially in nonhypertensive women.

Association of Epilepsy and Severe Maternal Morbidity.

OBJECTIVE: To evaluate severe maternal morbidity (SMM) among patients with epilepsy and patients without epilepsy. METHODS: We retrospectively examined SMM using linked birth certificate and maternal hospital discharge records in California between 2007 and 2012. Epilepsy present at delivery admission was the exposure and was subtyped into generalized, focal and other less specified, or unspecified. The outcomes were SMM and nontransfusion SMM from delivery up to 42 days' postpartum, identified using Centers for Disease Control and Prevention indicators. Multivariable logistic regression models were used to adjust for confounders, which were selected a priori. We also estimated the association between epilepsy and SMM independent of comorbidities by using a validated obstetric comorbidity score. Severe maternal morbidity indicators were then compared using the same multivariable logistic regression models. RESULTS: Of 2,668,442 births, 8,145 (0.3%) were to patients with epilepsy; 637 (7.8%) had generalized, 6,250 (76.7%) had focal or other less specified, and 1,258 (15.4%) had unspecified subtypes. Compared with patients without epilepsy, patients with epilepsy had greater odds of SMM (4.3% vs 1.4%, adjusted odds ratio [aOR] 2.91, 95% CI 2.61-3.24) and nontransfusion SMM (2.9% vs 0.7%, aOR 4.16, 95% CI 3.65-4.75). Epilepsy remained significantly associated with increased SMM and nontransfusion SMM after additional adjustment for the obstetric comorbidity score, though the effects were attenuated. When grouped by organ system, all SMM indicators were significantly more common among patients with epilepsy-most notably those related to hemorrhage and transfusion. CONCLUSION: Severe maternal morbidity was significantly increased in patients with epilepsy, and SMM indicators across all organ systems contributed to this.

Integrated trajectories of the maternal metabolome, proteome, and immunome predict labor onset.

Estimating the time of delivery is of high clinical importance because pre- and postterm deviations are associated with complications for the mother and her offspring. However, current estimations are inaccurate. As pregnancy progresses toward labor, major transitions occur in fetomaternal immune, metabolic, and endocrine systems that culminate in birth. The comprehensive characterization of maternal biology that precedes labor is key to understanding these physiological transitions and identifying predictive biomarkers of delivery. Here, a longitudinal study was conducted in 63 women who went into labor spontaneously. More than 7000 plasma analytes and peripheral immune cell responses were analyzed using untargeted mass spectrometry, aptamer-based proteomic technology, and single-cell mass cytometry in serial blood samples collected during the last 100 days of pregnancy. The high-dimensional dataset was integrated into a multiomic model that predicted the time to spontaneous labor [R = 0.85, 95% confidence interval (CI) [0.79 to 0.89], P = 1.2 × 10-40, N = 53, training set; R = 0.81, 95% CI [0.61 to 0.91], P = 3.9 × 10-7, N = 10, independent test set]. Coordinated alterations in maternal metabolome, proteome, and immunome marked a molecular shift from pregnancy maintenance to prelabor biology 2 to 4 weeks before delivery. A surge in steroid hormone metabolites and interleukin-1 receptor type 4 that preceded labor coincided with a switch from immune activation to regulation of inflammatory responses. Our study lays the groundwork for developing blood-based methods for predicting the day of labor, anchored in mechanisms shared in preterm and term pregnancies.

Association of preconception paternal health and adverse maternal outcomes among healthy mothers.

BACKGROUND: Maternal morbidity continues to be an issue of national and global concern. Paternal preconception health may play a significant role in pregnancy outcomes and has received less attention than maternal health. OBJECTIVE: This study aimed to examine the association between preconception paternal health and the risk for adverse maternal outcomes among healthy mothers. STUDY DESIGN: This was a retrospective analysis of live births from 2009 through 2016 to healthy women aged 20 to 45 years recorded in the IBM Marketscan research database. Infants were linked to paired mothers and fathers using family ID. Preconception paternal health was assessed using the number of metabolic syndrome component diagnoses and the most common individual chronic disease diagnoses (hypertension, diabetes mellitus, obesity, hyperlipidemia, chronic obstructive pulmonary disease, cancer, and depression). Women with metabolic syndrome components were excluded to avoid potential confounding of maternal and paternal factors. Adverse maternal outcomes that were assessed included (1) abnormal placentation including placenta accreta spectrum, placenta previa, and placental abruption; (2) preeclampsia with and without severe features including eclampsia; and (3) severe maternal morbidity, identified as any indicator from the Centers for Disease Control and Prevention Index of life-threatening complications at the time of delivery to 6 weeks postpartum. The trend between preconception paternal health and each maternal outcome was determined using the Cochran-Armitage Trend test. The independent association of paternal health with maternal outcomes was also determined using generalized estimating equations models, accounting for some mothers who contributed multiple births during the study period, and by adjusting for maternal age, paternal age, region of birth, year of birth, maternal smoking, and average number of outpatient visits per year. RESULTS: Among 669,256 births to healthy mothers, there was a significant trend between all adverse maternal outcomes and worsening preconception paternal health defined either as the number of metabolic syndrome diagnoses or number of chronic disease diagnoses (P<.001; Cochran-Armitage Trend test). In the generalized estimating equations model, the odds for preeclampsia without severe features increased in a dose-dependent fashion and were 21% higher (95% confidence interval, 1.17-1.26) among women whose partners had ≥2 metabolic syndrome diagnoses than among women whose partners had no metabolic syndrome diagnosis. The odds for preeclampsia with severe features and eclampsia increased in a dose-dependent fashion and were 19% higher (95% confidence interval, 1.09-1.30) among women whose partners had ≥2 metabolic syndrome diagnoses than among women whose partners had no metabolic syndrome diagnosis. The odds for severe maternal morbidity were 9% higher (95% confidence interval, 1.002-1.19) among women whose partners had ≥2 metabolic syndrome diagnoses than among women whose partners had no metabolic syndrome diagnosis. The odds for abnormal placentation were similar between the groups (adjusted odds ratio, 0.96; 95% confidence interval, 0.89-1.03). CONCLUSION: Among healthy mothers, we report that preconception paternal health is significantly associated with increased odds of preeclampsia with and without severe features and weakly associated with increased odds of severe maternal morbidity. These findings suggest that paternally derived factors may play significant roles in the development of adverse maternal outcomes in healthy women with a low a priori risk of obstetrical complications.