Integrative analysis of noncoding mutations identifies the druggable genome in preterm birth.

Preterm birth affects ~10% of pregnancies in the US. Despite familial associations, identifying at-risk genetic loci has been challenging. We built deep learning and graphical models to score mutational effects at base resolution via integrating the pregnant myometrial epigenome and large-scale patient genomes with spontaneous preterm birth (sPTB) from European and African American cohorts. We uncovered previously unidentified sPTB genes that are involved in myometrial muscle relaxation and inflammatory responses and that are regulated by the progesterone receptor near labor onset. We studied genomic variants in these genes in our recruited pregnant women administered progestin prophylaxis. We observed that mutation burden in these genes was predictive of responses to progestin treatment for preterm birth. To advance therapeutic development, we screened ~4000 compounds, identified candidate molecules that affect our identified genes, and experimentally validated their therapeutic effects on regulating labor. Together, our integrative approach revealed the druggable genome in preterm birth and provided a generalizable framework for studying complex diseases.

Clinical implications of crown-rump length discordance at 11 to 14 weeks in dichorionic twins.

BACKGROUND: Crown-rump length discordance, defined as ≥10% discordance, has been investigated as an early sonographic marker of subsequent growth abnormalities and is associated with an increased risk of fetal loss in twin pregnancies. Previous studies have not investigated the prevalence of fetal aneuploidy or structural anomalies in twins with discordance or the independent association of crown-rump length discordance with adverse perinatal outcomes. Moreover, data are limited on cell-free DNA screening for aneuploidy in dichorionic twins with discordance. OBJECTIVE: This study aimed to evaluate whether crown-rump length discordance in dichorionic twins between 11 and 14 weeks of gestation is associated with a higher risk of aneuploidy, structural anomalies, or adverse perinatal outcomes and to assess the performance of cell-free DNA screening in dichorionic twin pregnancies with crown-rump length discordance. STUDY DESIGN: This was a secondary analysis of a multicenter retrospective cohort study that evaluated the performance of cell-free DNA screening for the common trisomies in twin pregnancies from December 2011 to February 2020. For this secondary analysis, we included live dichorionic pregnancies with crown-rump length measurements between 11 and 14 weeks of gestation. First, we compared twin pregnancies with discordant crown-rump lengths with twin pregnancies with concordant crown-rump lengths and analyzed the prevalence of aneuploidy and fetal structural anomalies in either twin. Second, we compared the prevalence of a composite adverse perinatal outcome, which included preterm birth at <34 weeks of gestation, hypertensive disorders of pregnancy, stillbirth or miscarriage, small-for-gestational-age birthweight, and birthweight discordance. Moreover, we assessed the performance of cell-free DNA screening in pregnancies with and without crown-rump length discordance. Outcomes were compared with multivariable regression to adjust for confounders. RESULTS: Of 987 dichorionic twins, 142 (14%) had crown-rump length discordance. The prevalence of aneuploidy was higher in twins with crown-rump length discordance than in twins with concordance (9.9% vs 3.9%, respectively; adjusted relative risk, 2.7; 95% confidence interval, 1.4-4.9). Similarly, structural anomalies (adjusted relative risk, 2.5; 95% confidence interval, 1.4-4.4]) and composite adverse perinatal outcomes (adjusted relative risk, 1.2; 95% confidence interval, 1.04-1.3) were significantly higher in twins with discordance. A stratified analysis demonstrated that even without other ultrasound markers, there were increased risks of aneuploidy (adjusted relative risk, 3.5; 95% confidence interval, 1.5-8.4) and structural anomalies (adjusted relative risk, 2.7; 95% confidence interval, 1.5-4.8) in twins with CRL discordance. Cell-free DNA screening had high negative predictive values for trisomy 21, trisomy 18, and trisomy 13, regardless of crown-rump length discordance, with 1 false-negative for trisomy 21 in a twin pregnancy with discordance. CONCLUSION: Crown-rump length discordance in dichorionic twins is associated with an increased risk of aneuploidy, structural anomalies, and adverse perinatal outcomes, even without other sonographic abnormalities. Cell-free DNA screening demonstrated high sensitivity and negative predictive values irrespective of crown-rump length discordance; however, 1 false-negative result illustrated that there is a role for diagnostic testing. These data may prove useful in identifying twin pregnancies that may benefit from increased screening and surveillance and are not ascertained by other early sonographic markers.

Real-World Utilization of an Intrauterine, Vacuum-Induced, Hemorrhage-Control Device.

OBJECTIVE: To assess the real-world effectiveness and safety of a U.S. Food and Drug Administration (FDA)-cleared intrauterine vacuum-induced-hemorrhage control device for postpartum hemorrhage (PPH) management. METHODS: Sixteen centers in the United States participated in this observational, postmarket registry medical record review (October 2020 through March 2022). The primary effectiveness outcome was treatment success , defined as bleeding control after insertion with no treatment escalation or bleeding recurrence. Additional outcomes included blood loss, time to device insertion, indwelling time, bleeding recurrence, and time to bleeding control. Treatment success and severe maternal morbidity measures (transfusion of 4 or more units of red blood cell, intensive care unit admission, and hysterectomy) were evaluated by blood loss before insertion. To assess safety, serious adverse events (SAEs) and adverse device effects were collected. All outcomes were summarized by mode of delivery; treatment success was summarized by bleeding cause (all causes, any atony, isolated atony, nonatony). RESULTS: In total, 800 individuals (530 vaginal births, 270 cesarean births) were treated with the device; 94.3% had uterine atony (alone or in combination with other causes). Median total blood loss at device insertion was 1,050 mL in vaginal births and 1,600 mL in cesarean births. Across all bleeding causes, the treatment success rate was 92.5% for vaginal births and was 83.7% for cesarean births (95.8% [n=307] and 88.2% [n=220], respectively, in isolated atony). Median indwelling time was 3.1 hours and 4.6 hours, respectively. In vaginal births, 14 SAEs were reported among 13 individuals (2.5%). In cesarean births, 22 SAEs were reported among 21 individuals (7.8%). Three (0.4%) SAEs were deemed possibly related to the device or procedure. No uterine perforations or deaths were reported. CONCLUSION: For both vaginal and cesarean births in real-world settings, rapid and effective bleeding control was achieved with an FDA-cleared intrauterine vacuum-induced hemorrhage-control device. The safety profile was consistent with that observed in the registrational trial (NCT02883673), and SAEs or adverse device effects were of the nature and severity expected in the setting of PPH. This device is an important new tool for managing a life-threatening condition, and timely utilization may help to improve obstetric hemorrhage outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT04995887.

Utility of Weekly Laboratory Monitoring in the Expectant Management of Hypertensive Disorders of Pregnancy.

Our retrospective cohort study evaluates the diagnostic yield of weekly laboratory surveillance in outpatient management of hypertensive disorders of pregnancy (HDP) based on patient clinical status at the time of laboratory testing. The study included 459 patients and 1,082 laboratory episodes: 356 (32.9%) episodes were performed in the setting of concerning clinical findings and 726 (67.1%) when the patient was asymptomatic. Overall, the diagnostic yield for abnormal laboratory values (n=11) was 1.0% (95% CI 0.4-1.6%) of all assessments performed and 2.4% (95% CI 1.0-3.8%) among all patients in the cohort. The prevalence of abnormal test results was higher in patients with clinical findings (2.8%, 95% CI 1.1-4.5%) compared with those who were asymptomatic (0.1%, 95% CI 0-0.2%) ( P <.01). Clinical findings suggestive of worsening disease had a 91% sensitivity (95% CI 59-100%) and a 99% (95% CI 99-100%) negative predictive value for abnormal laboratory values. Directed screening based on signs and symptoms, rather than universal weekly screening, may be a potential strategy to lower costs and reduce multiple blood draws for patients with HDP, because there is a low diagnostic yield for this practice.

Cervical Pessary for Prevention of Preterm Birth in Individuals With a Short Cervix: The TOPS Randomized Clinical Trial.

Importance: A short cervix as assessed by transvaginal ultrasound is an established risk factor for preterm birth. Study findings for a cervical pessary to prevent preterm delivery in singleton pregnancies with transvaginal ultrasound evidence of a short cervix have been conflicting. Objective: To determine if cervical pessary placement decreases the risk of preterm birth or fetal death prior to 37 weeks among individuals with a short cervix. Design, Setting, and Participants: We performed a multicenter, randomized, unmasked trial comparing a cervical pessary vs usual care from February 2017 through November 5, 2021, at 12 centers in the US. Study participants were nonlaboring individuals with a singleton pregnancy and a transvaginal ultrasound cervical length of 20 mm or less at gestations of 16 weeks 0 days through 23 weeks 6 days. Individuals with a prior spontaneous preterm birth were excluded. Interventions: Participants were randomized 1:1 to receive either a cervical pessary placed by a trained clinician (n = 280) or usual care (n = 264). Use of vaginal progesterone was at the discretion of treating clinicians. Main Outcome and Measures: The primary outcome was delivery or fetal death prior to 37 weeks. Results: A total of 544 participants (64%) of a planned sample size of 850 were enrolled in the study (mean age, 29.5 years [SD, 6 years]). Following the third interim analysis, study recruitment was stopped due to concern for fetal or neonatal/infant death as well as for futility. Baseline characteristics were balanced between participants randomized to pessary and those randomized to usual care; 98.9% received vaginal progesterone. In an as-randomized analysis, the primary outcome occurred in 127 participants (45.5%) randomized to pessary and 127 (45.6%) randomized to usual care (relative risk, 1.00; 95% CI, 0.83-1.20). Fetal or neonatal/infant death occurred in 13.3% of those randomized to receive a pessary and in 6.8% of those randomized to receive usual care (relative risk, 1.94; 95% CI, 1.13-3.32). Conclusions and Relevance: Cervical pessary in nonlaboring individuals with a singleton gestation and with a cervical length of 20 mm or less did not decrease the risk of preterm birth and was associated with a higher rate of fetal or neonatal/infant mortality. Trial Registration: ClinicalTrials.gov Identifier: NCT02901626.

PROMPT: Prospective Meta-analysis for Pessary Trials Study Protocol.

OBJECTIVE: Preterm birth, defined as birth before 37 weeks of gestation, is a leading cause of perinatal and infant mortality throughout the world. Preterm birth is also associated with long-term neurological disabilities and other significant health issues in children. A short cervix in the second trimester has been noted to be one of the strongest predictors of subsequent spontaneous preterm birth in both singleton and multiple pregnancies. Some studies have shown that cervical support in the form of an Arabin pessary lowers the risk of preterm birth in women with a singleton gestation and short cervical length; however, other studies have conflicting results. Our objective was to form an international collaborative of planned or ongoing randomized trials of pessary in singleton and twin gestations with a short cervix. STUDY DESIGN: In November 2014, an international group of investigators, who had initiated or were planning randomized trials of pessary for pregnant people with a short cervix and singleton or twin gestation to prevent preterm birth, formed a collaboration to plan a prospective individual patient data (IPD) meta-analysis of randomized trials (PROspective Meta-analysis of Pessary Trials [PROMPT]). The PROMPT investigators agreed on meta-analysis IPD hypotheses for singletons and twins, eligibility criteria, and a set of core baseline and outcome measures. The primary outcome is a composite of fetal death or preterm delivery before 32 weeks' gestation. Secondary outcomes include maternal and neonatal morbidities. The PROMPT protocol may be viewed as a written agreement among the study investigators who make up the PROMPT consortium (PROSPERO ID# CRD42018067740). RESULTS: Results will be published in phases as the individual participating studies are concluded and published. Results of the first phase of singleton and twin pessary trials are expected to be available in late 2022. Updates are planned as participating trials are completed and published. KEY POINTS: · Short cervical length predicts preterm birth.. · Results of prior cervical pessary trials are mixed.. · Meta-analysis of pessary trials protocol..

The Association of Periconception Asthma Medication Discontinuation with Adverse Obstetric Outcomes.

OBJECTIVE: This study aimed to investigate asthma medication reduction in the periconceptional period as it relates to asthma status and adverse outcomes in pregnancy. STUDY DESIGN: In a prospective cohort study, self-reported current and past asthma medications were collected and analyzes compared measures of asthma status in women who discontinued asthma medication in the 6 months prior to enrollment ("step-down") versus those who did not ("no change"). Evaluation of asthma was done at three study visits (one per trimester) and by daily diaries, including measures of lung function (percent predicted forced expiratory volume in 1 and 6 s [%FEV1, %FEV6], peak expiratory flow [%PEF], forced vital capacity [%FVC], FEV1 to FVC ratio [FEV1/FVC]), lung inflammation (fractional exhaled nitric oxide [FeNO], ppb), rate of asthma symptoms (activity limitation, night symptoms, rescue inhaler use, wheeze, shortness of breath, cough, chest tightness, chest pain), and rate of asthma exacerbations. Adverse pregnancy outcomes were also evaluated. Adjusted regression analyses examined whether adverse outcomes differed by periconceptional asthma medication changes. RESULTS: Of 279 participants included in analyses, 135 (48.4%) did not change asthma medication in the periconceptional period, whereas 144 (51.6%) reported a step down in medication. Those in the step-down group were more likely to have milder disease (88 [61.1%] in the step-down vs. 74 [54.8%] in the no change group), exhibited less activity limitation (rate ratio [RR]: 0.68, 95% confidence interval [CI]: 0.47-0.98), and experienced fewer asthma attacks (RR: 0.53, 95% CI: 0.34-0.84) during pregnancy. The step-down group had a nonsignificant increase in overall odds of experiencing an adverse pregnancy outcome (odds ratio: 1.62, 95% CI: 0.97-2.72). CONCLUSION: Over half of women with asthma reduce asthma medication in the periconceptional period. Although these women typically have milder disease, a step down in medication may be associated with an increased risk of adverse pregnancy outcomes. KEY POINTS: · Many women reduce their asthma medication in pregnancy.. · Reduction is more common among those with mild disease.. · Medication reduction may lead to adverse pregnancy outcomes..

A Randomized Controlled Clinical Trial of Prenatal Oral Hygiene Education in Pregnancy-Associated Gingivitis.

INTRODUCTION: Research shows there is a significant increase in gingival inflammation during pregnancy. This study was conducted to determine if an oral health intervention (OHI), including oral hygiene education delivered by nurse-led staff and an advanced over-the-counter (OTC) oral home care regimen, improved gingival inflammation in pregnant women with moderate-to-severe gingivitis compared with a standard oral hygiene control group. METHODS: This was a multicenter, randomized, controlled, single-masked, parallel group clinical trial conducted in obstetrics clinics of 2 medical centers. A total of 750 pregnant women between 8 and 24 weeks of pregnancy with at least 20 natural teeth and moderate-to-severe gingivitis (>30 intraoral bleeding sites) were enrolled. Participants were randomized to either the OHI group, which included oral hygiene instructions supplemented with an educational video and advanced OTC antibacterial/mechanical oral hygiene products, or the control group receiving oral hygiene instructions and standard products. Both groups received oral hygiene instructions from nurse-led staff. Experienced, masked examiners measured whole mouth gingival index (GI) and periodontal probing depths (PDs) at baseline and months 1, 2, and 3. RESULTS: Participants enrolled in this study presented with moderate-to-severe gingivitis at baseline. Both the OHI and control groups exhibited significant reductions in GI (P < .001) and PD (P < .03) from baseline that persisted throughout the study period. The OHI group exhibited modest, yet statistically greater, reductions in GI (P ≤ .044) compared with the control at all time points. The reduction in PD directionally favored the OHI group, but between-group differences were small (<0.03 mm) and not statistically significant (P > .18). DISCUSSION: Significant gingivitis was prevalent among participants in this study and identifies an opportunity to improve gingival health during pregnancy by providing oral health education during the course of prenatal care when coupled with an advanced OTC oral hygiene regimen.

Cell-free DNA screening for trisomy 21 in twin pregnancy: a large multicenter cohort study.

BACKGROUND: Analysis of cell-free DNA from maternal blood provides effective screening for trisomy 21 in singleton pregnancies. Data on cell-free DNA screening in twin gestations are promising although limited. In previous twin studies, cell-free DNA screening was primarily performed in the second trimester and many studies did not report chorionicity. OBJECTIVE: This study aimed to evaluate the screening performance of cell-free DNA for trisomy 21 in twin pregnancies in a large, diverse cohort. A secondary aim was to evaluate screening performance for trisomy 18 and trisomy 13. STUDY DESIGN: This was a retrospective cohort study of twin pregnancies from 17 centers for which cell-free DNA screening was performed from December 2011 to February 2020 by one laboratory using massively parallel sequencing technology. Medical record review was conducted for all newborns and data on the birth outcome, the presence of any congenital abnormalities, phenotypic appearance at birth, and any chromosomal testing that was undertaken in the antenatal or postnatal period were extracted. Cases with a possible fetal chromosomal abnormality with no genetic test results were reviewed by a committee of maternal-fetal medicine geneticists. Cases with a vanishing twin and inadequate follow-up information were excluded. A minimum of 35 confirmed cases of trisomy 21 was required to capture a sensitivity of at least 90% with a prevalence of at least 1.9% with 80% power. Test characteristics were calculated for each outcome. RESULTS: A total of 1764 samples were sent for twin cell-free DNA screening. Of those, 78 cases with a vanishing twin and 239 cases with inadequate follow-up were excluded, leaving a total of 1447 cases for inclusion in the analysis. The median maternal age was 35 years and the median gestational age at cell-free DNA testing was 12.3 weeks. In total, 81% of the twins were dichorionic. The median fetal fraction was 12.4%. Trisomy 21 was detected in 41 of 42 pregnancies, yielding a detection rate of 97.6% (95% confidence interval, 83.8-99.7). There was 1 false negative and no false positive cases. Trisomy 21 was detected in 38 out of 39 dichorionic twin pregnancies, yielding a detection rate of 97.4% (95% confidence interval, 82.6-99.7). Trisomy 18 was detected in 10 of the 10 affected pregnancies. There was 1 false positive case. Trisomy 13 was detected in 4 of the 5 cases, yielding a detection rate of 80% (95% confidence interval, 11.1-99.2). There was one false negative and no false positive cases. The nonreportable rate was low at 3.9 %. CONCLUSION: Cell-free DNA testing is effective in screening for trisomy 21 in twin gestations from the first trimester of pregnancy. Detection of trisomy 21 was high in dichorionic and monochorionic twins, and the nonreportable result rates were low. This study included high numbers of cases of trisomy 18 and 13 when compared with the current literature. Although screening for these conditions in twins seems to be promising, the numbers were too small to make definitive conclusions regarding the screening efficacy for these conditions. It is possible that cell-free DNA testing performance may differ among laboratories and vary with screening methodologies.

Pregnancy Outcomes in Patients After Completion of the mRNA Coronavirus Disease 2019 (COVID-19) Vaccination Series Compared With Unvaccinated Patients.

OBJECTIVE: To compare frequency of perinatal death between pregnant patients who completed the mRNA coronavirus disease 2019 (COVID-19) vaccination series and unvaccinated patients. METHODS: This retrospective cohort study included 15,865 pregnant patients who delivered 16,132 newborns after 20 weeks of gestation within a large regional health system between January 1, 2021, and December 31, 2021. Patients who received two doses of mRNA vaccine (Pfizer-BioNTech [BNT162b2] or Moderna [mRNA-1273]) were included in the vaccinated group and were compared with unvaccinated patients. Exclusions included partial vaccination, viral-vector vaccine, major congenital anomalies, and higher-order multiple gestation. Our primary outcome was perinatal death, including stillbirth and neonatal death, which was evaluated by logistic regression. Unadjusted odds ratios and adjusted odds ratios (aORs) were reported, controlling for age, body mass index (BMI), diabetes, hypertension, smoking, twin gestation, and insurance status. Propensity score matching was also performed. RESULTS: A total of 15,865 patients were included in the final analysis: 2,069 in the vaccination group and 13,796 in the control group. Only 13.0% of the cohort was included in the vaccination group; however, the vaccination rate increased over the course of the study period as the vaccine became more widely available and accepted. Vaccinated patients were older, with higher rates of people of non-Black racial non-Hispanic ethnic backgrounds, people with private insurance, and those with higher BMIs. Vaccination was associated with a lower incidence of perinatal death (0.5% vaccinated group vs 0.8% unvaccinated group, aOR 0.20 0.05-0.88). Vaccination against COVID-19 was also associated with lower rates of preterm delivery (aOR 0.63, 0.48-0.82), neonates with very low birth weight (aOR 0.35, 0.15-0.84), and neonatal intensive care unit (NICU) admission (aOR 0.66, 0.52-0.85). The association between vaccination and lower rates of perinatal death was no longer significant after propensity score matching. CONCLUSION: In a large retrospective cohort study, receipt of the primary mRNA COVID-19 vaccination series was associated with a lower rate of several adverse pregnancy outcomes, including perinatal death, preterm delivery, neonates with very low birth weight, and NICU admission. Although the decreased rates of perinatal death did not remain significant after propensity score matching, there was evidence of directional benefit for vaccinated patients.

Relationship Between Race and Gestational Weight Gain in Pregnancy and Early Life in the South Birth-Cohort Study.

OBJECTIVE: The goal of this study was to evaluate whether differences in gestational weight gain (GWG) and adverse perinatal outcomes exist for Black and White women who are overweight or have obesity (OW/OB) at entry to prenatal care. METHODS: We enrolled 183 pregnant women with BMI 25-45 kg/m2 (71% black, 29% white) prior to 14 weeks gestation. Data were collected on demographic, medical history, diet and physical activity during pregnancy. Relationships between race and maternal outcomes and infant outcomes were assessed using multivariable logistic regression models. RESULTS: The average age of pregnant women were 26 years (±4.8), with a mean BMI of 32.1 (±5.1) kg/m2 at the time of enrollment. At delivery, 60 women (33%) had GWG within Institute of Medicine recommendations and 69% had at least one comorbidity. No significant differences by race were found in GWG (in lbs) (11±7.5 vs. 11.4±7.3, p=0.2006) as well as other perinatal outcomes including maternal morbidity, LBW and PTB. Race differences were noted for gestational diabetes, total energy expenditure and average daily calorie intake, but these differences did not result in significant differences in GWG or maternal morbidity. CONCLUSION: The lack of racial differences in GWG and perinatal outcomes demonstrated in this study differs from prior literature and could potentially be attributed to small sample size. Findings suggest that race differences in GWG and perinatal outcomes may diminish for women with a BMI in the overweight or obese range at conception.

Unexpected Term Neonatal Intensive Care Unit Admissions and a Potential Role for Centralized Remote Fetal Monitoring.

OBJECTIVE: Centralized remote fetal monitoring (CRFM) has been proposed as a method to improve the performance of intrapartum fetal heart rate (FHR) monitoring and perinatal outcomes. The purpose of this study is to determine whether CRFM was associated with a reduction in unexpected term neonatal intensive care unit (NICU) admissions. STUDY DESIGN: A pre-post design was used to examine the effectiveness of CRFM which was implemented in stages across five hospitals. The exposure group was all women who underwent intrapartum monitoring via CRFM. The unexposed group was of women who delivered at the same hospitals prior to implementation of CRFM. Pregnancies with expected NICU admissions, gestational age <37 weeks, birth weight <2,500 g, or major fetal anomalies detected prenatally were excluded. The primary outcome was unexpected term NICU admission; secondary outcomes were cesarean and operative vaginal delivery (OVD), and 5-minute Apgar's score of <7 rates. Maternal and delivery characteristics were examined with Student's t, Wilcoxon's, Chi-square, and Fisher's exact tests. Multivariable logistic regression was performed to control for potential confounders. RESULTS: There were 19,392 live births included in this analysis. In the univariable analysis, the odds of unexpected term NICU admission was lower among the CRFM exposed group compared with the unexposed group (odds ratio [OR] = 0.86, 95% confidence interval [CI]: 0.75-0.99; p = 0.038). In multivariable analysis, this did not reach statistical significance (OR = 0.92, 95% CI: 0.79-1.06; p = 0.24). Cesarean and OVD were less likely in the exposed group (OR = 0.91, 95% CI: 0.85-0.97; p = 0.008) and (OR = 0.70, 95% CI: 0.59-0.83, p < 0.001), respectively, in univariable analysis. When adjusted for potential confounders, the effect remained statistically significant for cesarean delivery (OR = 0.92, 95% CI: 0.85-0.98; p = 0.012). When adjusted for hospital, OVD rate was lower at the highest volume and highest acuity site (OR = 0.48, 95% CI: 0.36-0.65, p < 0.001). CONCLUSION: In some practice settings, utilization of a CRFM system may decrease the risk of unexpected term NICU admission, cesarean, and OVD rate. KEY POINTS: · CRFM may decrease unexpected term NICU admissions in some clinical settings.. · CRFM may decrease cesarean delivery rates in some clinical settings.. · CRFM may decrease OVD rates in some clinical settings..

Early Gestational Diabetes Screening Based on ACOG Guidelines.

OBJECTIVE: A recent randomized controlled trial suggested that early gestational diabetes mellitus (GDM) screening in patients with obesity (body mass index [BMI] ≥30 kg/m2) does not improve perinatal outcomes. The American College of Obstetrics and Gynecology currently recommends early screening for gestational diabetes in patients who are overweight with one or more additional risk factors. We evaluated the effect of screening based on the number of additional risk factors for development of gestational diabetes. STUDY DESIGN: This was a secondary analysis of a multicenter randomized controlled trial of obese patients with singleton nonanomalous fetuses comparing early (14-20 weeks' gestation) with routine (24-28 weeks' gestation) GDM screening. Exclusion criteria were pregestational diabetes, major medical illnesses, bariatric surgery, chronic steroid use, and prior cesarean. Early versus routine GDM screening groups were compared and stratified by the number of additional risk factors for GDM (0, 1, 2, and ≥3). The primary outcome was an adverse perinatal composite outcome composed of: macrosomia, primary cesarean delivery, hypertensive disorders of pregnancy, shoulder dystocia, neonatal hyperbilirubinemia, and neonatal hypoglycemia. Analyses examined effects of early versus routine screening by the number of additional risk factors and their possible interaction on the incidences of the primary outcome and GDM. RESULTS: Of 913 patients, 5% had 0, 52% had 1, 33% had 2, and 10% had ≥3 additional risk factors. Baseline characteristics, including the number and type of risk factors, were similar between early and routine screening groups. Breslow-Day test for interaction between early versus routine screening and the number of additional risk factors was not significant for either the primary outcome (p = 0.37) or the diagnosis of GDM (p = 0.28). The incidence of GDM and the adverse perinatal composite outcome increased as the number of risk factors increased (p < 0.001). CONCLUSION: In patients with BMI ≥30 kg/m2 and additional risk factors, early GDM screening does not prevent adverse outcomes. KEY POINTS: · The ACOG currently recommends early screening for gestational diabetes if patients have risk factors.. · Even in patients with multiple risk factors, early screening for GDM does not improve outcomes.. · Patients with three or more risk factors may have worse outcomes if they undergo early screening..

Postpartum glucose intolerance following early gestational diabetes mellitus.

BACKGROUND: Patients with gestational diabetes mellitus are at increased risk for type 2 diabetes mellitus or glucose intolerance postpartum compared with those without diabetes mellitus. OBJECTIVE: We aimed to evaluate the association between early gestational diabetes mellitus and postpartum dysglycemia compared with gestational diabetes mellitus diagnosed by routine screening in a cohort of patients with obesity. STUDY DESIGN: This was a secondary analysis of a randomized controlled trial of patients with obesity and singleton, nonanomalous gestations that compared early gestational diabetes mellitus screening at 14 to 20 weeks of gestation with routine screening at 24 to 28 weeks of gestation. Patients were included in this analysis if they were diagnosed with gestational diabetes mellitus at the primary study site. The primary outcome was postpartum dysglycemia, defined as any abnormality on 2-hour oral glucose tolerance test 6 weeks postpartum or clinical diagnosis based on hyperglycemia requiring pharmacotherapy after delivery with deferred glucose tolerance test. Maternal characteristics and outcomes were compared in bivariable analysis, and logistic regression estimated the association between early gestational diabetes mellitus and postpartum dysglycemia. RESULTS: Of 119 patients included in this analysis, 30 were diagnosed by screening at <20 weeks of gestation and 89 at 24 to 28 weeks of gestation. Patients were overall similar in baseline characteristics. Patients with early gestational diabetes mellitus were more likely to have postpartum dysglycemia than those with gestational diabetes mellitus diagnosed with routine screening (36.7% vs 14.6%; odds ratio, 3.38; 95% confidence interval, 1.31-8.73). Most patients with early gestational diabetes mellitus who had postpartum dysglycemia were diagnosed clinically (n=7/11), whereas none of the patients with gestational diabetes mellitus established by routine testing were diagnosed with postpartum dysglycemia clinically. All (100%) patients with early gestational diabetes mellitus who completed a postpartum glucose tolerance test had dysglycemia compared with only 45% of patients with gestational diabetes mellitus diagnosed on routine screening. The proportion of patients who followed up for postpartum visits and the timing of follow-up were similar between groups. Postpartum glucose tolerance test completion was low but also similar between groups. CONCLUSION: Although postpartum glucose tolerance test completion is low, patients with gestational diabetes mellitus before 20 weeks of gestation, seem to be at higher risk for postpartum dysglycemia than those with gestational diabetes mellitus diagnosed at routine screening in a cohort of patients with obesity. Larger studies are needed to confirm these findings, but postpartum follow-up and diabetes mellitus testing may be even more important to improve long-term health in patients with early gestational diabetes mellitus.

Safety-Related Outcomes of Novel mRNA COVID-19 Vaccines in Pregnancy.

OBJECTIVE: The objective of this study was to describe the safety profile and demographic data for a cohort of pregnant individuals who received an mRNA coronavirus disease 2019 (COVID-19) vaccine. STUDY DESIGN: Prospective cohort study (with exposure matching) of individuals with active pregnancy who underwent immunization with a novel mRNA COVID-19 vaccine matched 1:2 with vaccinated age-matched female nonregnant controls was carried out. The primary outcome was defined as any vaccine-related complaints as defined in the original safety data. Secondary outcomes included specific complaints, COVID-19 screening test, and positive COVID-19 test. RESULTS: Eighty-three vaccinated pregnant persons were age-matched with 166 female controls, all of whom were vaccinated between December 2020 and January, 2021. There was no difference in race or ethnicity between the groups. The mean body mass index of pregnant patients was lower than that of controls (26.1 vs. 29.2, p = 0.002). The frequency of complaints following vaccine administration was not different between pregnant and nonpregnant patients (18.1 vs. 16.9%, p = 0.201). Pregnant individuals were more likely to report fever (4.8 vs. 0.6%, p = 0.044) and gastrointestinal symptoms (4.8 vs. 0%, p = 0.012). CONCLUSIONS: Side effect profiles of COVID-19 vaccine administration at our institution were relatively similar between pregnant and nonpregnant individuals and no serious complications occurred in either group. As COVID-19 infection in pregnancy can have significant morbidity, our data support the continued use of the vaccine for pregnant patients. KEY POINTS: · Pregnant and nonpregnant women had a similar frequency of complaints.. · No serious adverse outcomes were observed in either group.. · Pregnant women were more likely to report fever and gastrointestinal side effects which may reflect gestationally mediated physiological responses to immunization..

Universal Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Testing for Obstetric Inpatient Units Across the United States.

BACKGROUND: The purpose of this study was to estimate prevalence of asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among patients admitted to obstetric inpatient units throughout the United States as detected by universal screening. We sought to describe the relationship between obstetric inpatient asymptomatic infection rates and publicly available surrounding community infection rates. METHODS: A cross-sectional study in which medical centers reported rates of positive SARS-CoV-2 testing in asymptomatic pregnant and immediate postpartum patients over a 1-3-month time span in 2020. Publicly reported SARS-CoV-2 case rates from the relevant county and state for each center were collected from the COVID Act Now dashboard and the COVID Tracking Project for correlation analysis. RESULTS: Data were collected from 9 health centers, encompassing 18 hospitals. Participating health centers were located in Alabama, California, Illinois, Louisiana, New Jersey, North Carolina, Pennsylvania, Rhode Island, Utah, and Washington State. Each hospital had an active policy for universal SARS-CoV-2 testing on obstetric inpatient units. A total of 10 147 SARS-CoV-2 tests were administered, of which 124 were positive (1.2%). Positivity rates varied by site, ranging from 0-3.2%. While SARS-CoV-2 infection rates were lower in asymptomatic obstetric inpatient groups than the surrounding communities, there was a positive correlation between positivity rates in obstetric inpatient units and their surrounding county (P=.003, r=.782) and state (P=.007, r=.708). CONCLUSIONS: Given the correlation between community and obstetric inpatient rates, the necessity of SARS-CoV-2-related healthcare resource utilization in obstetric inpatient units may be best informed by surrounding community infection rates.

Society for Maternal-Fetal Medicine Consult Series #57: Evaluation and management of isolated soft ultrasound markers for aneuploidy in the second trimester: (Replaces Consults #10, Single umbilical artery, October 2010; #16, Isolated echogenic bowel diagnosed on second-trimester ultrasound, August 2011; #17, Evaluation and management of isolated renal pelviectasis on second-trimester ultrasound, December 2011; #25, Isolated fetal choroid plexus cysts, April 2013; #27, Isolated echogenic intracardiac focus, August 2013).

Soft markers were originally introduced to prenatal ultrasonography to improve the detection of trisomy 21 over that achievable with age-based and serum screening strategies. As prenatal genetic screening strategies have greatly evolved in the last 2 decades, the relative importance of soft markers has shifted. The purpose of this document is to discuss the recommended evaluation and management of isolated soft markers in the context of current maternal serum screening and cell-free DNA screening options. In this document, "isolated" is used to describe a soft marker that has been identified in the absence of any fetal structural anomaly, growth restriction, or additional soft marker following a detailed obstetrical ultrasound examination. In this document, "serum screening methods" refers to all maternal screening strategies, including first-trimester screen, integrated screen, sequential screen, contingent screen, or quad screen. The Society for Maternal-Fetal Medicine recommends the following approach to the evaluation and management of isolated soft markers: (1) we do not recommend diagnostic testing for aneuploidy solely for the evaluation of an isolated soft marker following a negative serum or cell-free DNA screening result (GRADE 1B); (2) for pregnant people with no previous aneuploidy screening and isolated echogenic intracardiac focus, echogenic bowel, urinary tract dilation, or shortened humerus, femur, or both, we recommend counseling to estimate the probability of trisomy 21 and a discussion of options for noninvasive aneuploidy screening with cell-free DNA or quad screen if cell-free DNA is unavailable or cost-prohibitive (GRADE 1B); (3) for pregnant people with no previous aneuploidy screening and isolated thickened nuchal fold or isolated absent or hypoplastic nasal bone, we recommend counseling to estimate the probability of trisomy 21 and a discussion of options for noninvasive aneuploidy screening through cell-free DNA or quad screen if cell-free DNA is unavailable or cost-prohibitive or diagnostic testing via amniocentesis, depending on clinical circumstances and patient preference (GRADE 1B); (4) for pregnant people with no previous aneuploidy screening and isolated choroid plexus cysts, we recommend counseling to estimate the probability of trisomy 18 and a discussion of options for noninvasive aneuploidy screening with cell-free DNA or quad screen if cell-free DNA is unavailable or cost-prohibitive (GRADE 1C); (5) for pregnant people with negative serum or cell-free DNA screening results and an isolated echogenic intracardiac focus, we recommend no further evaluation as this finding is a normal variant of no clinical importance with no indication for fetal echocardiography, follow-up ultrasound imaging, or postnatal evaluation (GRADE 1B); (6) for pregnant people with negative serum or cell-free DNA screening results and isolated fetal echogenic bowel, urinary tract dilation, or shortened humerus, femur, or both, we recommend no further aneuploidy evaluation (GRADE 1B); (7) for pregnant people with negative serum screening results and isolated thickened nuchal fold or absent or hypoplastic nasal bone, we recommend counseling to estimate the probability of trisomy 21 and discussion of options for no further aneuploidy evaluation, noninvasive aneuploidy screening through cell-free DNA, or diagnostic testing via amniocentesis, depending on clinical circumstances and patient preference (GRADE 1B); (8) for pregnant people with negative cell-free DNA screening results and isolated thickened nuchal fold or absent or hypoplastic nasal bone, we recommend no further aneuploidy evaluation (GRADE 1B); (9) for pregnant people with negative serum or cell-free DNA screening results and isolated choroid plexus cysts, we recommend no further aneuploidy evaluation, as this finding is a normal variant of no clinical importance with no indication for follow-up ultrasound imaging or postnatal evaluation (GRADE 1C); (10) for fetuses with isolated echogenic bowel, we recommend an evaluation for cystic fibrosis and fetal cytomegalovirus infection and a third-trimester ultrasound examination for reassessment and evaluation of growth (GRADE 1C); (11) for fetuses with an isolated single umbilical artery, we recommend no additional evaluation for aneuploidy, regardless of whether results of previous aneuploidy screening were low risk or testing was declined. We recommend a third-trimester ultrasound examination to evaluate growth and consideration of weekly antenatal fetal surveillance beginning at 36 0/7 weeks of gestation (GRADE 1C); (12) for fetuses with isolated urinary tract dilation A1, we recommend an ultrasound examination at ≥32 weeks of gestation to determine if postnatal pediatric urology or nephrology follow-up is needed. For fetuses with urinary tract dilation A2-3, we recommend an individualized follow-up ultrasound assessment with planned postnatal follow-up (GRADE 1C); (13) for fetuses with isolated shortened humerus, femur, or both, we recommend a third-trimester ultrasound examination for reassessment and evaluation of growth (GRADE 1C).

Society for Maternal-Fetal Medicine Consult Series #52: Diagnosis and management of fetal growth restriction: (Replaces Clinical Guideline Number 3, April 2012).

Fetal growth restriction can result from a variety of maternal, fetal, and placental conditions. It occurs in up to 10% of pregnancies and is a leading cause of infant morbidity and mortality. This complex obstetrical problem has disparate published diagnostic criteria, relatively low detection rates, and limited preventative and treatment options. The purpose of this Consult is to outline an evidence-based, standardized approach for the prenatal diagnosis and management of fetal growth restriction. The recommendations of the Society for Maternal-Fetal Medicine are as follows: (1) we recommend that fetal growth restriction be defined as an ultrasonographic estimated fetal weight or abdominal circumference below the 10th percentile for gestational age (GRADE 1B); (2) we recommend the use of population-based fetal growth references (such as Hadlock) in determining fetal weight percentiles (GRADE 1B); (3) we recommend against the use of low-molecular-weight heparin for the sole indication of prevention of recurrent fetal growth restriction (GRADE 1B); (4) we recommend against the use of sildenafil or activity restriction for in utero treatment of fetal growth restriction (GRADE 1B); (5) we recommend that a detailed obstetrical ultrasound examination (current procedural terminology code 76811) be performed with early-onset fetal growth restriction (<32 weeks of gestation) (GRADE 1B); (6) we recommend that women be offered fetal diagnostic testing, including chromosomal microarray analysis, when fetal growth restriction is detected and a fetal malformation, polyhydramnios, or both are also present regardless of gestational age (GRADE 1B); (7) we recommend that pregnant women be offered prenatal diagnostic testing with chromosomal microarray analysis when unexplained isolated fetal growth restriction is diagnosed at <32 weeks of gestation (GRADE 1C); (8) we recommend against screening for toxoplasmosis, rubella, or herpes in pregnancies with fetal growth restriction in the absence of other risk factors and recommend polymerase chain reaction for cytomegalovirus in women with unexplained fetal growth restriction who elect diagnostic testing with amniocentesis (GRADE 1C); (9) we recommend that once fetal growth restriction is diagnosed, serial umbilical artery Doppler assessment should be performed to assess for deterioration (GRADE 1C); (10) with decreased end-diastolic velocity (ie, flow ratios greater than the 95th percentile) or in pregnancies with severe fetal growth restriction (estimated fetal weight less than the third percentile), we suggest weekly umbilical artery Doppler evaluation (GRADE 2C); (11) we recommend Doppler assessment up to 2-3 times per week when umbilical artery absent end-diastolic velocity is detected (GRADE 1C); (12) in the setting of reversed end-diastolic velocity, we suggest hospitalization, administration of antenatal corticosteroids, heightened surveillance with cardiotocography at least 1-2 times per day, and consideration of delivery depending on the entire clinical picture and results of additional evaluation of fetal well-being (GRADE 2C); (13) we suggest that Doppler assessment of the ductus venosus, middle cerebral artery, or uterine artery not be used for routine clinical management of early- or late-onset fetal growth restriction (GRADE 2B); (14) we suggest weekly cardiotocography testing after viability for fetal growth restriction without absent/reversed end-diastolic velocity and that the frequency be increased when fetal growth restriction is complicated by absent/reversed end-diastolic velocity or other comorbidities or risk factors (GRADE 2C); (15) we recommend delivery at 37 weeks of gestation in pregnancies with fetal growth restriction and an umbilical artery Doppler waveform with decreased diastolic flow but without absent/reversed end-diastolic velocity or with severe fetal growth restriction with estimated fetal weight less than the third percentile (GRADE 1B); (16) we recommend delivery at 33-34 weeks of gestation for pregnancies with fetal growth restriction and absent end-diastolic velocity (GRADE 1B); (17) we recommend delivery at 30-32 weeks of gestation for pregnancies with fetal growth restriction and reversed end-diastolic velocity (GRADE 1B); (18) we suggest delivery at 38-39 weeks of gestation with fetal growth restriction when the estimated fetal weight is between the 3rd and 10th percentile and the umbilical artery Doppler is normal (GRADE 2C); (19) we suggest that for pregnancies with fetal growth restriction complicated by absent/reversed end-diastolic velocity, cesarean delivery should be considered based on the entire clinical scenario (GRADE 2C); (20) we recommend the use of antenatal corticosteroids if delivery is anticipated before 33 6/7 weeks of gestation or for pregnancies between 34 0/7 and 36 6/7 weeks of gestation in women without contraindications who are at risk of preterm delivery within 7 days and who have not received a prior course of antenatal corticosteroids (GRADE 1A); and (21) we recommend intrapartum magnesium sulfate for fetal and neonatal neuroprotection for women with pregnancies that are <32 weeks of gestation (GRADE 1A).