Neurodevelopmental Outcomes After Late Preterm Antenatal Corticosteroids: The ALPS Follow-Up Study.

Importance: The Antenatal Late Preterm Steroids (ALPS) trial changed clinical practice in the United States by finding that antenatal betamethasone at 34 to 36 weeks decreased short-term neonatal respiratory morbidity. However, the trial also found increased risk of neonatal hypoglycemia after betamethasone. This follow-up study focused on long-term neurodevelopmental outcomes after late preterm steroids. Objective: To evaluate whether administration of late preterm (34-36 completed weeks) corticosteroids affected childhood neurodevelopmental outcomes. Design, Setting, and Participants: Prospective follow-up study of children aged 6 years or older whose birthing parent had enrolled in the multicenter randomized clinical trial, conducted at 13 centers that participated in the Maternal-Fetal Medicine Units (MFMU) Network cycle from 2011-2016. Follow-up was from 2017-2022. Exposure: Twelve milligrams of intramuscular betamethasone administered twice 24 hours apart. Main Outcome and Measures: The primary outcome of this follow-up study was a General Conceptual Ability score less than 85 (-1 SD) on the Differential Ability Scales, 2nd Edition (DAS-II). Secondary outcomes included the Gross Motor Function Classification System level and Social Responsiveness Scale and Child Behavior Checklist scores. Multivariable analyses adjusted for prespecified variables known to be associated with the primary outcome. Sensitivity analyses used inverse probability weighting and also modeled the outcome for those lost to follow-up. Results: Of 2831 children, 1026 enrolled and 949 (479 betamethasone, 470 placebo) completed the DAS-II at a median age of 7 years (IQR, 6.6-7.6 years). Maternal, neonatal, and childhood characteristics were similar between groups except that neonatal hypoglycemia was more common in the betamethasone group. There were no differences in the primary outcome, a general conceptual ability score less than 85, which occurred in 82 (17.1%) of the betamethasone vs 87 (18.5%) of the placebo group (adjusted relative risk, 0.94; 95% CI, 0.73-1.22). No differences in secondary outcomes were observed. Sensitivity analyses using inverse probability weighting or assigning outcomes to children lost to follow-up also found no differences between groups. Conclusion and Relevance: In this follow-up study of a randomized clinical trial, administration of antenatal corticosteroids to persons at risk of late preterm delivery, originally shown to improve short-term neonatal respiratory outcomes but with an increased rate of hypoglycemia, was not associated with adverse childhood neurodevelopmental outcomes at age 6 years or older.

The Association between Prenatal Nicotine Exposure and Offspring's Hearing Impairment.

OBJECTIVE: The objective of this study is to evaluate whether there is an association between in-utero exposure to nicotine and subsequent hearing dysfunction. PATIENTS AND METHODS: Secondary analysis of a multicenter randomized trial to prevent congenital cytomegalovirus (CMV) infection among gravidas with primary CMV infection was conducted. Monthly intravenous immunoglobulin hyperimmune globulin therapy did not influence the rate of congenital CMV. Dyads with missing urine, fetal or neonatal demise, infants diagnosed with a major congenital anomaly, congenital CMV infection, or with evidence of middle ear dysfunction were excluded. The primary outcome was neonatal hearing impairment in one or more ears defined as abnormal distortion product otoacoustic emissions (DPOAEs; 1 to 8 kHz) that were measured within 42 days of birth. DPOAEs were interpreted using optimized frequency-specific level criteria. Cotinine was measured via enzyme-linked immunosorbent assay kits in maternal urine collected at enrollment and in the third trimester (mean gestational age 16.0 and 36.7 weeks, respectively). Blinded personnel ran samples in duplicates. Maternal urine cotinine >5 ng/mL at either time point was defined as in-utero exposure to nicotine. Multivariable logistic regression included variables associated with the primary outcome and with the exposure (p < 0.05) in univariate analysis. RESULTS: Of 399 enrolled patients in the original trial, 150 were included in this analysis, of whom 46 (31%) were exposed to nicotine. The primary outcome occurred in 18 (12%) newborns and was higher in nicotine-exposed infants compared with those nonexposed (15.2 vs. 10.6%, odds ratio [OR] 1.52, 95% confidence interval [CI] 0.55-4.20), but the difference was not significantly different (adjusted odds ratio [aOR] = 1.0, 95% CI 0.30-3.31). This association was similar when exposure was stratified as heavy (>100 ng/mL, aOR 0.72, 95% CI 0.15-3.51) or mild (5-100 ng/mL, aOR 1.28, 95% CI 0.33-4.95). There was no association between nicotine exposure and frequency-specific DPOAE amplitude. CONCLUSION: In a cohort of parturients with primary CMV infection, nicotine exposure was not associated with offspring hearing dysfunction assessed with DPOAEs. KEY POINTS: · Nicotine exposure was quantified from maternal urine.. · Nicotine exposure was identified in 30% of the cohort.. · Exposure was not associated with offspring hearing dysfunction..

Impact of aspirin on fetal growth in diabetic pregnancies according to White classification.

BACKGROUND: Current US Preventive Services Task Force and other guidelines recommend low-dose aspirin for all pregnant women with pregestational diabetes mellitus to prevent preeclampsia and small-for-gestational-age birth. The Maternal-Fetal Medicine Units High-Risk Aspirin trial did not show a reduction in either preeclampsia or small-for-gestational-age birth in diabetic women. OBJECTIVE: Our objective was to reassess the impact of aspirin on fetal growth in diabetic pregnancies overall and according to White classification. We hypothesized that aspirin improves fetal growth in pregnancies with vascular complications of diabetes at highest risk for poor fetal growth. STUDY DESIGN: We conducted secondary analysis of the cohort of diabetic women enrolled in the Maternal-Fetal Medicine Units High-Risk Aspirin trial. The impact of aspirin prophylaxis on birthweight was assessed in the overall cohort and in 2 groups categorized according to White classification as nonvascular (White class B, C, D) or vascular (White class R, F, RF). Birthweight was converted to Z-score normalized for gestational age at delivery and neonatal sex. Difference in birthweight Z-score between aspirin and placebo was tested with a 2-sample t test. The effect of vascular group, aspirin vs placebo randomization, and the interaction of the 2 on normalized birthweight percentile was estimated with linear regression with a multivariable model including covariates body mass index, tobacco use, race, and parity. The percentage of small and large-for-gestational-age newborns born to aspirin- vs placebo-treated women was compared between groups using Pearson exact χ2 analysis, and an adjusted model was estimated by logistic regression. RESULTS: All 444 women with pregestational diabetes and complete outcome data were included (53 vascular, 391 nonvascular). Aspirin was significantly associated with a higher birthweight Z-score (0.283; 95% confidence interval, 0.023-0.544) in the overall cohort (P = .03). In the adjusted model, the association of aspirin with higher birthweight Z-score was confined to neonates of women with nonvascular diabetes (0.341; 95% confidence interval, 0.677-0.006; P = .044). An opposite but nonsignificant effect was observed among neonates from women with vascular diabetes (-0.416; 95% confidence interval, -1.335 to 0.503; P = .6). This difference in the relationship of aspirin and birthweight Z-score by vascular group was significant at P = .046. Aspirin-randomized women with nonvascular diabetes had more large-for-gestational-age births than those treated with placebo (40.2 vs 26.6%; P = .005). Small-for-gestational-age births occurred at the same frequency with aspirin vs placebo randomization in the overall cohort (8% in each group) and in each vascular group. CONCLUSION: Inconsistent with our hypothesis, aspirin did not reduce small-for-gestational-age births in the overall cohort or either group. The increased incidence of large-for-gestational-age infants in aspirin-treated diabetic gestations is of potential concern given the known increased maternal and neonatal morbidity associated with macrosomia.

Smoking, 17 Alpha-Hydroxyprogesterone Caproate, and Preterm Birth.

Objective The objective of this study was to determine if maternal smoking modifies the effectiveness of 17 α-hydroxyprogesterone caproate (17OHP-C). Study Design Secondary analysis of the Maternal-Fetal Medicine Units Network trial of 17OHP-C. The prevalence of preterm birth (PTB) by smoking status and treatment group was compared by chi-squared analysis and analysis of variance was used to compare gestational age (GA) at birth. Multivariable modeling was used to estimate the effect of smoking on 17OHP-C treatment. Results In this study, 459 women were included. Maternal smoking significantly modified the effectiveness of 17OHP-C treatment. In smokers, 17OHP-C significantly reduced the prevalence of multiple outcomes (PTB < 37 and < 35 weeks, spontaneous PTB < 37 and < 35 weeks), while in nonsmokers, only PTB < 37 weeks was reduced. Delivery GA was later in 17OHP-C versus placebo treated smokers (36.4 vs. 34.3 weeks, p = 0.041) but not nonsmokers (36.3 vs. 35.5 weeks, p = nonsignificant). In multivariable modeling, 17OHP-C was more effective in smokers than nonsmokers as measured by multiple outcomes (PTB < 37 weeks [p = 0.041] and < 35 weeks [p = 0.036] and spontaneous PTB < 37 weeks [p = 0.029]). Conclusion In this cohort of women with a prior PTB, maternal smoking status significantly modified the effectiveness of 17OHP-C treatment.

Does 17-alpha hydroxyprogesterone caproate prevent recurrent preterm birth in obese women?

OBJECTIVE: We sought to determine if maternal weight or body mass index (BMI) modifies the effectiveness of 17-alpha hydroxyprogesterone caproate (17OHP-C). STUDY DESIGN: We performed a secondary analysis of the Maternal-Fetal Medicine Units Network Trial for the Prevention of Recurrent Preterm Delivery by 17-Alpha Hydroxyprogesterone Caproate. Binomial regression models were estimated to determine the relative risk (RR) of preterm birth (PTB) in women randomized to 17OHP-C vs placebo according to BMI category and maternal weight. Adjusted models considered inclusion of potential confounders. RESULTS: In all, 443 women with complete data were included. 17OHP-C is effective in preventing PTB <37 weeks only in women with prepregnancy BMI <30 kg/m(2) (RR, 0.54; 95% confidence interval, 0.43-0.68). Above this BMI threshold there is a nonsignificant trend toward an increased risk of PTB (RR, 1.55; 95% confidence interval, 0.83-2.89) with 17OHP-C treatment. When analyzing by maternal weight, a similar threshold is observed at 165 lb, above which 17OHP-C is no longer effective. CONCLUSION: The effectiveness of 17OHP-C is modified by maternal weight and BMI, and treatment does not appear to reduce the rate of PTB in women who are obese or have a weight >165 lb. This finding may be due to subtherapeutic serum levels in women with increased BMI or weight. Studies of adjusted-dose 17OHP-C in women who are obese or who weigh >165 lb are warranted, and current recommendations regarding the uniform use of 17OHP-C regardless of maternal BMI and weight may deserve reassessment.

Preeclampsia in high risk women is characterized by risk group-specific abnormalities in serum biomarkers.

OBJECTIVE: To determine if early pregnancy serum biomarkers in high-risk women who develop preeclampsia vary according to risk factor. STUDY DESIGN: We performed a secondary analysis of the Maternal-Fetal Medicine Units Network randomized controlled trial of low-dose aspirin for the prevention of preeclampsia in high-risk women. Serum biomarker levels at enrollment (before initiation of aspirin or placebo) were compared between women who did and did not develop preeclampsia, both for the group as a whole and within each of 4 high-risk groups (insulin-dependent diabetes, hypertension, multiple gestation, and previous preeclampsia) using a regression model adjusting for gestational age at collection and prepregnancy body mass index. RESULTS: 1258 women were included (233 with insulin-dependent diabetes, 387 with chronic hypertension, 315 with a multiple gestation, 323 with previous preeclampsia). Multiple early pregnancy serum biomarkers differed between women who did and did not develop preeclampsia. Each high-risk group had a unique and largely nonoverlapping pattern of biomarker abnormality. Differences between those who did and did not develop preeclampsia were noted in vascular cell adhesion molecule in the diabetes group; human chorionic gonadotropin, soluble tumor necrosis factor receptor-2, tumor necrosis factor-alpha, selectin and angiogenin in the chronic hypertension group; interleukin-6, placental growth factor, soluble fms-like tyrosine kinase plus endoglin to placental growth factor ratio in the multiple gestation group; and angiogenin in the previous preeclampsia group. CONCLUSION: Patterns of serum biomarkers vary by high-risk group. These data support the hypothesis that multiple pathogenic pathways lead to the disease recognized clinically as preeclampsia.

Changes in metabolic acidosis following birth in intensive care unit neonates.

BACKGROUND: Little is known about how and why metabolic acidosis changes within the first six hours of life in intensive care unit neonates. OBJECTIVE: To determine changes in pH and base excess between paired umbilical cord arterial and neonatal arterial blood samples during the first 6 h of life, to identify factors associated with the direction and magnitude of change, and to examine morbidity and mortality in newborns with acidosis at birth or as neonates. STUDY DESIGN: Retrospective cohort study of all deliveries from a single institution between 2016-2020 with paired umbilical cord arterial and neonatal arterial samples obtained within 6 h of life meeting rigorous criteria to ensure sample integrity. The primary outcomes were the direction and magnitude of change of pH and base excess. Multiple factors were assessed for possible correlation with pH and base excess change. The secondary outcome was the association between a composite outcome of death or cerebral palsy and pathologic acidosis (pH ≤ 7.1) at birth or as a neonate. RESULTS: 102 patients met inclusion criteria. Newborn arterial gasses were obtained at a median of 1.5 h (74 % < 2 h). pH improved in 71 % of cases and worsened in 29 %, and base excess improved in 52 % and worsened in 48 %, with wide observed ranges in both parameters. The paired pH and base excess values were moderately (r = 0.38) and strongly (r = 0.63) positively correlated, respectively, but were not correlated with time since birth (r = 0.14). Low birth weight, prematurity or respiratory failure were associated with worsening or less improvement, while worse initial acidosis was associated with greater improvement. Death or survival with cerebral palsy was more common with pathologic acidosis in either cord or newborn sample as compared with those without acidosis (27.3 % vs 3.7 %, p = 0.003), and was more common in those with isolated neonatal acidosis as compared to those without acidosis (50 % vs 3.7 %, p = 0.016). CONCLUSIONS: Changes in pH and base excess occurred over a wide range between delivery and the first newborn blood gas in the first 6 h of life, and we identified several factors associated with direction of change. Metabolic acidosis at birth cannot reliably be inferred from neonatal arterial values. Neonatal acidosis, including acidosis following a normal pH and base excess at birth, was associated with morbidity and mortality.

Breastfeeding Initiation, Duration, and Associated Factors Among People With Hepatitis C Virus Infection.

OBJECTIVE: To characterize breastfeeding behaviors and identify factors associated with breastfeeding initiation among people with hepatitis C virus (HCV) infection. METHODS: We conducted a secondary analysis of a multicenter observational cohort of pregnant people with singleton gestations and HCV seropositivity. This analysis includes individuals with data on breastfeeding initiation and excludes those with human immunodeficiency virus (HIV) co-infection. The primary outcome was self-reported initiation of breastfeeding or provision of expressed breast milk. Secondary outcomes included duration of breastfeeding. Demographic and obstetric characteristics were compared between those who initiated breastfeeding and those who did not to identify associated factors. Univariable and multivariable analyses were performed. RESULTS: Overall, 579 individuals (75.0% of participants in the parent study) were included. Of those, 362 (62.5%) initiated breastfeeding or provided breast milk to their infants, with a median duration of breastfeeding of 1.4 months (interquartile range 0.5-6.0). People with HCV viremia , defined as a detectable viral load at any point during pregnancy, were less likely to initiate breastfeeding than those who had an undetectable viral load (59.4 vs 71.9%, adjusted odds ratio [aOR] 0.61, 95% CI, 0.41-0.92). People with private insurance were more likely to initiate breastfeeding compared with those with public insurance or no insurance (80.0 vs 60.1%; aOR 2.43, 95% CI, 1.31-4.50). CONCLUSION: Although HCV seropositivity is not a contraindication to breastfeeding regardless of viral load, rates of breastfeeding initiation were lower among people with HCV viremia than among those with an undetectable viral load. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT01959321 .

Risk Factors for Perinatal Transmission of Hepatitis C Virus.

OBJECTIVE: To estimate the rate of perinatal transmission of hepatitis C virus (HCV) infection, to identify risk factors for perinatal transmission of HCV infection, and to determine the viremic threshold for perinatal transmission. METHODS: This was a prospective, multicenter, observational study of pregnant individuals at less than 24 weeks of gestation screened for HCV infection from 2012 to 2018 in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Individuals found to be HCV antibody-positive were followed throughout pregnancy. Children were followed for evidence of perinatal transmission at 2-6 months (HCV RNA testing) and at 18-24 months (HCV RNA and antibody testing) of life. The primary outcome was perinatal transmission, defined as positive test results at either follow-up time point. RESULTS: A total of 109,379 individuals were screened for HCV infection. Of the 1,224 participants who screened positive, 772 (63.1%) enrolled and 432 of those 772 (56.0%) had data available to assess primary outcome. The overall rate of perinatal transmission was 6.0% (26/432, 95% CI 4.0-8.7%). All children with HCV infection were born to individuals with demonstrable viremia. In viremic participants (n=314), the perinatal transmission rate was 8.0% (95% CI 5.2-11.5%). Risk factors for perinatal transmission included HCV RNA greater than 106 international units/mL (adjusted odds ratio [aOR] 8.22, 95% CI 3.16-21.4) and vaginal bleeding reported at any time before delivery (aOR 3.26, 95% CI 1.32-8.03). A viremic threshold for perinatal transmission could not be established. CONCLUSION: Perinatal transmission of HCV infection was limited to viremic individuals. High viral loads and antepartum bleeding were associated with perinatal transmission.

Repeat anatomic surveys performed for an initial incomplete study: the sonographer and physician factors.

BACKGROUND: Repeat obstetrical anatomic surveys are often performed because of incomplete initial studies despite conflicting evidence on their utility. OBJECTIVE: To determine the frequency and yield of repeat obstetrical anatomic surveys performed because of incomplete initial studies and to determine patient and provider factors associated with the recommendation for a second study. STUDY DESIGN: A 10-year retrospective cohort study of women having an initial anatomic survey at 18 weeks to 21 weeks and 6/7 days of gestation at a single nonreferral county hospital. We identified the number of patients needed to scan to detect an anatomic abnormality for the overall cohort and for women having a repeat study. Select patient, sonographer, and reading physician factors were compared between the repeat-ultrasound and no-repeat-ultrasound groups by the 2-sample t test, chi-squared analysis, or analysis of variance, as appropriate. Multivariate logistic regression was used to assess the significance of multiple factors contributing to the recommendation for repeat ultrasounds. RESULTS: A total of 18,911 women had an initial anatomic survey between 18 weeks and 21 weeks and 6/7 days of gestation, and 2310 (12.2%) had a repeat ultrasound because of an incomplete initial study. For the overall cohort, there were 642 structural anomalies detected, with the number of patients needed to scan being 29. Among the 2310 repeat ultrasounds, only 7 structural anomalies were detected, whereas the number of patients needed to scan was 330, representing only 1.1% of all prenatally-identified anomalies. The frequency of recommended repeat ultrasounds varied by performing sonographer (4.5%-45.8%) and reading physician (7.1%-21.6%), both with P<.001 by 1-way analysis of variance. Clinical factors significantly impacting the odds of repeat ultrasounds included body mass index, gestational age, and previous cesarean delivery, but were less impactful than the sonographer and physician. CONCLUSION: The primary determinants of the perceived need for a repeat ultrasound are the sonographer and physician reader, with clinical factors having less but still significant importance. Repeat anatomic surveys account for a significant fraction of our total anatomic surveys and are of limited diagnostic utility. Recommendation of repeat anatomic surveys should be considered within the context of these findings.

Early pregnancy glycaemia predicts postpartum diabetes mellitus.

OBJECTIVE: To determine the association between early pregnancy glycaemia, as measured by glycosylated haemoglobin A1c (HbA1c) at the first prenatal visit, and persistent postpartum diabetes mellitus (DM). STUDY DESIGN: All women first diagnosed with DM during pregnancy who had both HbA1c prior to 24 weeks and postpartum DM testing were included. The proportions of women with normal (<5.7%), prediabetic (5.7-6.4%) and elevated (≥6.5%) early HbA1c who tested positive for postpartum DM were compared. Test characteristics of HbA1c to predict persistent postpartum DM were calculated. RESULTS: One hundred and twenty-one women met the study inclusion criteria. HbA1c was obtained at a median gestational age of 9 weeks. Twenty-two women (18.2%) had persistent postpartum DM, which was highly correlated with early HbA1c: 16 (73%) women had an elevated HbA1c, five (22.7%) women had a prediabetic HbA1c and only one (4.5%) woman had a normal HbA1c. Of 65 women with gestational DM and a normal early HbA1c, only one (1.5%) had persistent DM within the first year (negative predictive value 98.5%). Sixteen of 18 women with an elevated early HbA1c had persistent postpartum DM (positive predictive value 88.9%). These percentages were significant overall and between groups (p < 0.001). No clinical or demographic factors were highly predictive of postpartum DM. CONCLUSIONS: Early pregnancy glycaemia, as measured by HbA1c at the first prenatal visit, is highly predictive of persistent postpartum DM, and may allow clinically important risk stratification to prioritize postpartum testing and care. Postpartum DM is rare amongst women with gestational DM who begin the pregnancy with a normal HbA1c, while postpartum DM is highly likely for those with an elevated HbA1c in early pregnancy. Nearly three-quarters of women who tested positive for DM post partum had an elevated HbA1c in early pregnancy, indicating that they had undiagnosed DM prior to conception.

Amniocentesis to diagnose congenital cytomegalovirus infection following maternal primary infection.

BACKGROUND: Congenital cytomegalovirus infection following maternal primary cytomegalovirus infection affects approximately 0.4% of newborns in the United States but may be hard to diagnose prenatally. OBJECTIVE: To evaluate the current sensitivity and specificity of amniocentesis in detecting congenital cytomegalovirus infection. STUDY DESIGN: Secondary analysis of a multicenter randomized placebo-controlled trial designed to evaluate whether cytomegalovirus hyperimmune globulin reduces congenital cytomegalovirus infection in neonates of individuals diagnosed with primary cytomegalovirus infection before 24 weeks of gestation. At randomization, subjects had no clinical evidence of fetal infection. Eligible subjects were randomized to monthly infusions of cytomegalovirus hyperimmune globulin or placebo until delivery. Although not required by the trial protocol, amniocentesis following randomization was permitted. The fetuses and neonates were tested for the presence of cytomegalovirus at delivery. Comparisons were made between those with and without amniocentesis and between those with cytomegalovirus-positive and negative results, using chi-square or Fisher exact test for categorical variables and the Wilcoxon rank sum test or t test for continuous variables. A P value of <.05 was considered significant. RESULTS: From 2012 to 2018, 397 subjects were included, of whom 55 (14%) underwent amniocentesis. Cytomegalovirus results were available for 53 fetuses and neonates. Fourteen amniocenteses were positive (25%). Gestational age at amniocentesis was similar between those with and without cytomegalovirus present, as was the interval between maternal diagnosis and amniocentesis. The prevalence of fetal or neonatal infection was 26% (14/53). The neonates of all 12 subjects with a positive amniocentesis and available results had cytomegalovirus infection confirmed at delivery, as did 2 neonates from the group of 41 subjects with a negative amniocentesis, with a sensitivity of 86% (95% confidence interval, 57-98), specificity of 100% (95% confidence interval, 91-100), positive predictive value of 100% (95% confidence interval, 74-100), and negative predictive value of 95% (95% confidence interval, 83-99). Amniocentesis-positive pregnancies were delivered at an earlier gestational age (37.4 vs 39.6 weeks; P<.001) and had lower birthweights (2583±749 vs 3428±608 g, P=.004) than amniocentesis-negative pregnancies. CONCLUSION: Amniocentesis results are an accurate predictor of congenital cytomegalovirus infection.

Noninvasive Prediction of Congenital Cytomegalovirus Infection After Maternal Primary Infection.

OBJECTIVE: To develop and internally validate a noninvasive method for the prediction of congenital cytomegalovirus (CMV) infection after primary maternal CMV infection. METHODS: We conducted a secondary analysis of a multicenter randomized placebo-controlled trial of CMV hyperimmune globulin to prevent congenital infection. Women were eligible if they had primary CMV infection, defined as detectable plasma CMV-specific immunoglobulin (Ig)M and CMV-specific IgG with avidity less than 50% before 24 weeks of gestation or IgG seroconversion before 28 weeks, and were carrying a singleton fetus without ultrasonographic findings suggestive of CMV infection. Antibody assays were performed in a single reference laboratory. Congenital infection was defined as CMV detection in amniotic fluid, neonatal urine or saliva, or postmortem tissue. Using backward elimination, we developed logit models for prediction of congenital infection using factors known at randomization. The performance of the model was assessed using leave-one-out cross-validation (a method of internal validation). RESULTS: Of 399 women enrolled in the trial, 344 (86%) had informative data for this analysis. Congenital infection occurred in 68 pregnancies (20%). The best performing model included government-assisted insurance, IgM index 4.5 or higher, IgG avidity less than 32%, and whether CMV was detectable by polymerase chain reaction in maternal plasma at the time of randomization. Cross-validation showed an average area under the curve of 0.76 (95% CI 0.70-0.82), indicating moderate discriminatory ability. More parsimonious one-, two-, and three-factor models performed significantly less well than the four-factor model. Examples of prediction with the four-factor model: for a woman with government-assisted insurance, avidity less than 32%, IgM index 4.5 or higher, and detectable plasma CMV, probability of congenital infection was 0.69 (95% CI 0.53-0.82); for a woman with private insurance, avidity 32% or greater, IgM index less than 4.5, and undetectable plasma CMV, probability of infection was 0.03 (95% CI 0.02-0.07). CONCLUSION: We developed models to predict congenital CMV infection in the presence of primary maternal CMV infection and absence of ultrasonographic findings suggestive of congenital infection. These models may be useful for patient counseling and decision making.

Clinical and economic evaluation of a proteomic biomarker preterm birth risk predictor: cost-effectiveness modeling of prenatal interventions applied to predicted higher-risk pregnancies within a large and diverse cohort.

OBJECTIVES: Preterm birth occurs in more than 10% of U.S. births and is the leading cause of U.S. neonatal deaths, with estimated annual costs exceeding $25 billion USD. Using real-world data, we modeled the potential clinical and economic utility of a prematurity-reduction program comprising screening in a racially and ethnically diverse population with a validated proteomic biomarker risk predictor, followed by case management with or without pharmacological treatment. METHODS: The ACCORDANT microsimulation model used individual patient data from a prespecified, randomly selected sub-cohort (N = 847) of a multicenter, observational study of U.S. subjects receiving standard obstetric care with masked risk predictor assessment (TREETOP; NCT02787213). All subjects were included in three arms across 500 simulated trials: standard of care (SoC, control); risk predictor/case management comprising increased outreach, education and specialist care (RP-CM, active); and multimodal management (risk predictor/case management with pharmacological treatment) (RP-MM, active). In the active arms, only subjects stratified as higher risk by the predictor were modeled as receiving the intervention, whereas lower-risk subjects received standard care. Higher-risk subjects' gestational ages at birth were shifted based on published efficacies, and dependent outcomes, calibrated using national datasets, were changed accordingly. Subjects otherwise retained their original TREETOP outcomes. Arms were compared using survival analysis for neonatal and maternal hospital length of stay, bootstrap intervals for neonatal cost, and Fisher's exact test for neonatal morbidity/mortality (significance, p < .05). RESULTS: The model predicted improvements for all outcomes. RP-CM decreased neonatal and maternal hospital stay by 19% (p = .029) and 8.5% (p = .001), respectively; neonatal costs' point estimate by 16% (p = .098); and moderate-to-severe neonatal morbidity/mortality by 29% (p = .025). RP-MM strengthened observed reductions and significance. Point estimates of benefit did not differ by race/ethnicity. CONCLUSIONS: Modeled evaluation of a biomarker-based test-and-treat strategy in a diverse population predicts clinically and economically meaningful improvements in neonatal and maternal outcomes.

Preterm birth, defined as delivery before 37 weeks' gestation, is the leading cause of illness and death in newborns. In the United States, more than 10% of infants are born prematurely, and this rate is substantially higher in lower-income, inner-city and Black populations. Prematurity associates with greatly increased risk of short- and long-term medical complications and can generate significant costs throughout the lives of affected children. Annual U.S. health care costs to manage short- and long-term prematurity complications are estimated to exceed $25 billion.Clinical interventions, including case management (increased patient outreach, education and specialist care), pharmacological treatment and their combination can provide benefit to pregnancies at higher risk for preterm birth. Early and sensitive risk detection, however, remains a challenge.We have developed and validated a proteomic biomarker risk predictor for early identification of pregnancies at increased risk of preterm birth. The ACCORDANT study modeled treatments with real-world patient data from a racially and ethnically diverse U.S. population to compare the benefits of risk predictor testing plus clinical intervention for higher-risk pregnancies versus no testing and standard care. Measured outcomes included neonatal and maternal length of hospital stay, associated costs and neonatal morbidity and mortality. The model projected improved outcomes and reduced costs across all subjects, including ethnic and racial minority populations, when predicted higher-risk pregnancies were treated using case management with or without pharmacological treatment. The biomarker risk predictor shows high potential to be a clinically important component of risk stratification for pregnant women, leading to tangible gains in reducing the impact of preterm birth.

Diagnosis of rupture of membranes: AmniSure, clinical assessment, and the Food and Drug Administration warning.

BACKGROUND: An accurate diagnosis of rupture of membranes is critical to the rendering of appropriate maternity care in both preterm and term patients. Immunoassays, such as the one detecting placental alpha microglobulin-1 (AmniSure) in cervicovaginal secretions, have replaced the traditional speculum-based assessment in some clinical settings; however, the Food and Drug Administration recently issued a warning regarding the potential risks of using the test in isolation. OBJECTIVE: The study aimed to report the performance of AmniSure as a first-line nurse-administered screening test for rupture of membranes in our teaching county hospital obstetrical triage unit and as part of a clinical protocol to diagnose rupture of membranes. STUDY DESIGN: We conducted a retrospective secondary analysis of 310 randomly selected term and preterm patients with concern for rupture of membranes screened with the AmniSure test. We systematically reviewed medical records to determine membrane status at the time of the AmniSure test. We calculated test characteristics of the AmniSure test used independently and in conjunction with speculum-based assessment. RESULTS: Of 302 women evaluated for retrospective determination of membrane status at 17 to 41 weeks' gestation (median, 36.6 weeks' gestation), 208 (68.9%) were intact and 94 (31.1%) were ruptured at the time of the AmniSure test using a gold standard of retrospective membrane status determined by medical record review. A total of 4 false-negative AmniSure results and 16 false-positive AmniSure results were identified. The AmniSure test used independently had a sensitivity of 95.7%, specificity of 92.3%, positive predictive value of 84.9%, and negative predictive value of 98.0%. A rupture of membranes protocol combining AmniSure and clinical assessment had a sensitivity of 98.2%, specificity of 99.5%, positive predictive value of 100.0%, and negative predictive value of 100.0%. CONCLUSION: The AmniSure has a high sensitivity as a first-line nurse-administered screening test for membrane rupture. Consistent with the Food and Drug Administration warning, the sensitivity, specificity, positive predictive value, and negative predictive value are improved when it is used as part of a clinical protocol and not in isolation. Determination of membrane status remains challenging in a small subset of patients, especially those with an equivocal speculum-based assessment; therefore, engaging women in their care and careful follow-up for identifying persistent or recurrent symptoms are required.

Exposure to group B Streptococcal antibiotic prophylaxis and early childhood body mass index in a vaginal birth cohort.

Purpose: Perinatal antibiotic exposure may be associated with changes in both early infancy gut microbiota and later childhood obesity. Our objective was to evaluate if group B Streptococcus (GBS) antibiotic prophylaxis is associated with higher body mass index (BMI) in early childhood.Materials and methods: This is a retrospective cohort study of mother/child dyads in a single hospital system over a 6-year period. All women with term, singleton, vertex, vaginal deliveries who received no antibiotics or received antibiotics only for GBS prophylaxis and whose children had BMIs available at 2-5 years of age were included. Children were divided into three groups for comparison: children born to GBS positive mothers that received antibiotics solely for GBS prophylaxis, children born to GBS negative women that received no antibiotics (healthy controls), and children born to GBS positive mothers who received no antibiotics. The primary outcome was the earliest available child BMI Z-score at 2-5 years of age. Multivariable linear regression was used to estimate differences in child BMI Z-scores between groups, adjusted for maternal BMI, age, race, parity, tobacco use, and child birthweight.Results: Of 4825 women, 786 (16.3%) were GBS positive and received prophylactic antibiotics, 3916 (81.2%) were GBS negative and received no antibiotics, and 123 (2.5%) were GBS positive but received no antibiotics. Childhood BMI Z-scores were similar between children exposed to intrapartum GBS prophylaxis and healthy controls who were unexposed in both unadjusted (mean (SE), 0.04 (0.04) versus -0.3 (0.02), p = .11) and adjusted (0.01 (0.05) versus -0.04 (0.03), p = .3) models.Conclusions: Exposure to intrapartum antibiotic prophylaxis for GBS was not associated with higher early childhood BMI Z-scores compared to healthy controls.