Mean Arterial Pressure and Neonatal Outcomes in Pregnancies Complicated by Mild Chronic Hypertension.

OBJECTIVE: To estimate the association between mean arterial pressure during pregnancy and neonatal outcomes in participants with chronic hypertension using data from the CHAP (Chronic Hypertension and Pregnancy) trial. METHODS: A secondary analysis of the CHAP trial, an open-label, multicenter randomized trial of antihypertensive treatment in pregnancy, was conducted. The CHAP trial enrolled participants with mild chronic hypertension (blood pressure [BP] 140-159/90-104 mm Hg) and singleton pregnancies less than 23 weeks of gestation, randomizing them to active treatment (maintained on antihypertensive therapy with a goal BP below 140/90 mm Hg) or standard treatment (control; antihypertensives withheld unless BP reached 160 mm Hg systolic BP or higher or 105 mm Hg diastolic BP or higher). We used logistic regression to measure the strength of association between mean arterial pressure (average and highest across study visits) and to select neonatal outcomes. Unadjusted and adjusted odds ratios (per 1-unit increase in millimeters of mercury) of the primary neonatal composite outcome (bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, or intraventricular hemorrhage grade 3 or 4) and individual secondary outcomes (neonatal intensive care unit admission [NICU], low birth weight [LBW] below 2,500 g, and small for gestational age [SGA]) were calculated. RESULTS: A total of 2,284 participants were included: 1,155 active and 1,129 control. Adjusted models controlling for randomization group demonstrated that increasing average mean arterial pressure per millimeter of mercury was associated with an increase in each neonatal outcome examined except NEC, specifically neonatal composite (adjusted odds ratio [aOR] 1.12, 95% CI, 1.09-1.16), NICU admission (aOR 1.07, 95% CI, 1.06-1.08), LBW (aOR 1.12, 95% CI, 1.11-1.14), SGA below the fifth percentile (aOR 1.03, 95% CI, 1.01-1.06), and SGA below the 10th percentile (aOR 1.02, 95% CI, 1.01-1.04). Models using the highest mean arterial pressure as opposed to average mean arterial pressure also demonstrated consistent associations. CONCLUSION: Increasing mean arterial pressure was positively associated with most adverse neonatal outcomes except NEC. Given that the relationship between mean arterial pressure and adverse pregnancy outcomes may not be consistent at all mean arterial pressure levels, future work should attempt to further elucidate whether there is an absolute threshold or relative change in mean arterial pressure at which fetal benefits are optimized along with maternal benefits. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT02299414.

Sodium intake and the development of hypertensive disorders of pregnancy.

BACKGROUND: In nonpregnant populations, sodium intake has been associated with the development of chronic hypertension, and sodium restriction has been identified as a strategy to reduce blood pressure. Data regarding the relationship between sodium intake and the development of hypertensive disorders of pregnancy are limited and conflicting. OBJECTIVE: This study aimed to assess the association between daily periconceptional sodium intake and the risk of hypertensive disorders of pregnancy. STUDY DESIGN: This was a secondary analysis of the prospective Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-To-Be study. Individuals with nonanomalous, singleton pregnancies who completed food frequency questionnaires with recorded sodium intake in the 3 months before pregnancy were included in the analysis. Individuals whose pregnancies did not progress beyond 20 weeks of gestation were excluded from the analysis. Sodium intake was categorized as low (<2 g per day), medium (2 to <3 g per day), or high (≥3 g per day), based on thresholds used in the nonpregnant population. The primary outcome was the development of a new-onset hypertensive disorder of pregnancy, including gestational hypertension; preeclampsia; hemolysis, elevated liver enzymes, and low platelet count syndrome; superimposed preeclampsia; or eclampsia. Bivariable analyses were performed using Kruskal-Wallis and chi-square tests. Poisson regression was used to estimate adjusted incidence risk ratios with 95% confidence intervals after controlling for potentially confounding factors. RESULTS: Among 7458 individuals included in this analysis, 2336 (31%) reported low sodium intake, 2792 (37%) reported medium sodium intake, and 2330 (31%) reported high sodium intake. Individuals with high sodium intake were more likely to have chronic hypertension, to use tobacco, and to be living with obesity. The risk of developing a hypertensive disorder of pregnancy was similar among groups (medium vs low adjusted incidence risk ratio: 1.10 [95% confidence interval, 0.94-1.28]; high vs low adjusted incidence risk ratio: 1.17 [95% confidence interval, 1.00-1.37]). There was no difference in neonatal outcomes by sodium intake, including preterm birth, small-for-gestational-age neonate, and admission to the neonatal intensive care unit. CONCLUSION: Sodium intake was not associated with the risk of developing a hypertensive disorder of pregnancy. This lack of association contrasts with that between sodium intake and hypertension in the nonpregnant state and may reflect differences in the pathophysiology underlying pregnancy- vs non-pregnancy-related hypertensive disorders.

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.

A Comparison of Vaginal and Intramuscular Progesterone for the Prevention of Recurrent Preterm Birth.

OBJECTIVE: This study aimed to examine whether vaginal progesterone is noninferior to 17-α hydroxyprogesterone caproate (17OHP-C) in the prevention of recurrent preterm birth (PTB). STUDY DESIGN: This retrospective cohort study included singleton pregnancies among women with a history of spontaneous PTB who received prenatal care at a single tertiary center from 2011 to 2016. Pregnancies were excluded if progesterone was not initiated prior to 24 weeks or the fetus had a major congenital anomaly. The primary outcome was PTB <37 weeks. A priori, noninferiority was to be established if the upper bound of the adjusted two-sided 90% confidence interval (CI) for the difference in PTB fell below 9%. Inverse probability of treatment weighting (IPTW) was used to carefully control for confounding associated with choice of treatment and PTB. Adjusted differences in PTB proportions were estimated via IPTW regression, with standard errors adjustment for multiple pregnancies per woman. Secondary outcomes included PTB <34 and <28 weeks, spontaneous PTB, neonatal intensive care unit admission, and gestational age at delivery. RESULTS: Among 858 pregnancies, 41% (n = 353) received vaginal progesterone and 59% (n = 505) were given 17OHP-C. Vaginal progesterone use was more common later in the study period, and among women who established prenatal care later, had prior PTBs at later gestational ages, and whose race/ethnicity was neither non-Hispanic white nor non-Hispanic Black. Vaginal progesterone did not meet noninferiority criteria compared with 17-OHPC in examining PTB <37 weeks, with an IPTW adjusted difference of 3.4% (90% CI: -3.5, 10.3). For secondary outcomes, IPTW adjusted differences between treatment groups were generally small and CIs were wide. CONCLUSION: We could not conclude noninferiority of vaginal progesterone to 17OHP-C; however, women and providers may be willing to accept a larger difference (>9%) when considering the cost and availability of vaginal progesterone versus 17OHP-C. A well-designed randomized trial is needed. KEY POINTS: · Vaginal progesterone is not noninferior to 17OHP-C.. · PTB risk may be 10% higher with vaginal progesterone.. · Associations did not differ based on obesity status..

Vaginal progesterone for preterm birth prevention in women with arrested preterm labor.

OBJECTIVE: We tested the hypothesis that administration of vaginal progesterone in women with arrested preterm labor would result in lower rates of preterm birth <37 weeks compared to placebo. STUDY DESIGN: We performed a randomized, placebo-controlled trial comparing vaginal progesterone to placebo in women with arrested preterm labor. Our trial included women with a singleton or twin gestation at 240/7-336/7 weeks' gestation who presented with preterm labor with cervical dilation ≥1 centimeter but remained undelivered. Participants were randomized to receive vaginal progesterone 200 mg daily or an identical placebo. The primary outcome was preterm birth <37 weeks. We performed an updated systematic review and meta-analysis of clinical trials, including our results. We searched MEDLINE, EMBASE, CINHAL, Scopus, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov using the key terms to identify relevant trials. The risk of bias was appraised using the Cochrane risk-of-bias tool. Data were synthesized using random-effects models. Heterogeneity was assessed using Higgins I2. RESULTS: The randomized trial was prematurely terminated due to slow recruitment. There were 18 women randomized to receive vaginal progesterone who had complete follow-up data and 18 women in the placebo group. The risk of preterm birth <37 weeks was not significantly different in the groups (RR 1.10, 95% CI 0.63-1.19). Secondary outcomes were also similar. Thirteen trials with 1658 women (835 in the vaginal progesterone and 823 in the control groups) were included in the meta-analysis. Risk of preterm birth <37 weeks was similar in women who received progesterone and those in the control group (pooled RR 1.06, 95% CI 0.83-1.35). Latency was significantly longer among women with arrested preterm labor who received vaginal progesterone (weighted mean difference: 9.2 d, 95% CI 3.2-15.1), but further analysis showed that prolonged latency was only observed in the subgroup of studies that were not placebo-controlled. CONCLUSIONS: This randomized controlled trial and meta-analysis do not support the use of vaginal progesterone for the prevention of preterm birth in women who present in preterm labor.

Proactive neonatal treatment at 22 weeks of gestation: a systematic review and meta-analysis.

OBJECTIVE: The objective of this study was to provide a systematic review and meta-analysis to quantify prognosis and identify factors associated with variations in reported mortality estimates among infants who were born at 22 weeks of gestation and provided proactive treatment (resuscitation and intensive care). DATA SOURCES: PubMed, Scopus, and Web of Science databases, with no language restrictions, were searched for articles published from January 2000 to February 2020. STUDY ELIGIBILITY CRITERIA: Reports on live-born infants who were delivered at 22 weeks of gestation and provided proactive care were included. The primary outcome was survival to hospital discharge; secondary outcomes included survival without major morbidity and survival without neurodevelopmental impairment. Because we expected differences across studies in the definitions for various morbidities, multiple definitions for composite outcomes of major morbidities were prespecified. Neurodevelopmental impairment was based on Bayley Scales of Infant Development II or III. Data extractions were performed independently, and outcomes agreed on a priori. STUDY APPRAISAL AND SYNTHESIS METHODS: Methodological quality was assessed using the Quality in Prognostic Studies tool. An adapted version of the Grading of Recommendations Assessment, Development and Evaluation approach for prognostic studies was used to evaluate confidence in overall estimates. Outcomes were assessed as prevalence and 95% confidence intervals. Variabilities across studies attributable to heterogeneity were estimated with the I2 statistic; publication bias was assessed with the Luis Furuya-Kanamori index. Data were pooled using the inverse variance heterogeneity model. RESULTS: Literature searches returned 21,952 articles, with 2034 considered in full; 31 studies of 2226 infants who were delivered at 22 weeks of gestation and provided proactive neonatal treatment were included. No articles were excluded for study design or risk of bias. The pooled prevalence of survival was 29.0% (95% confidence interval, 17.2-41.6; 31 studies, 2226 infants; I2=79.4%; Luis Furuya-Kanamori index=0.04). Survival among infants born to mothers receiving antenatal corticosteroids was twice the survival of infants born to mothers not receiving antenatal corticosteroids (39.0% vs 19.5%; P<.01). The overall prevalence of survival without major morbidity, using a definition that includes any bronchopulmonary dysplasia, was 11.0% (95% confidence interval, 8.0-14.3; 10 studies, 374 infants; I2=0%; Luis Furuya-Kanamori index=3.02). The overall rate of survival without moderate or severe impairment was 37.0% (95% confidence interval, 14.6-61.5; 5 studies, 39 infants; I2=45%; Luis Furuya-Kanamori index=-0.15). Based on the year of publication, survival rates increased between 2000 and 2020 (slope of the regression line=0.09; standard error=0.03; P<.01). Studies were highly diverse with regard to interventions and outcomes reported. CONCLUSION: The reported survival rates varied greatly among studies and were likely influenced by combining observational data from disparate sources, lack of individual patient-level data, and bias in the component studies from which the data were drawn. Therefore, pooled results should be interpreted with caution. To answer fundamental questions beyond the breadth of available data, multicenter, multidisciplinary collaborations, including alignment of important outcomes by stakeholders, are needed.

Prenatal cigarette smoking as a mediator between racism and depressive symptoms: The Biosocial Impact on Black Births Study.

OBJECTIVE: This study examined whether cigarette smoking mediated the association of racial discrimination with depressive symptoms among pregnant Black women. DESIGN: Cross-sectional. SAMPLE: Two hundred Black women at 8-29 weeks gestation. MEASUREMENTS: Women completed questionnaires including the Experiences of Discrimination and the Center for Epidemiologic Studies-Depression (CES-D) scales, as well as questions about sociodemographic characteristics and cigarette smoking. RESULTS: The mean age of the sample was 26.9 ± 5.7 years and the mean gestational age at data collection was 15.6 ± 5.7 weeks. Approximately 17% of women reported prenatal cigarette smoking; 27% had prenatal CES-D scores ≥23, which have been correlated with depression diagnoses; and 59% reported ever (lifetime) experiencing discrimination in at least one situation (e.g., at work). Path analysis results indicated that the standardized indirect effect of experiences of racial discrimination on CES-D scores through prenatal smoking was statistically significant (standardized indirect effect = 0.03; 95% CI: 0.001, 0.094; p = .042). CONCLUSION: Cigarette smoking during pregnancy partially mediated the association between lifetime experiences of racial discrimination and prenatal depressive symptoms among pregnant Black women. Smoking cessation programs should focus on identifying and treating depressive symptoms among pregnant Black women.

Genetic variation associated with preterm birth in African-American women.

BACKGROUND: Preterm birth is considered a multifactorial condition; however, emerging evidence suggests that genetic variation among individuals may have an important role. Prior studies have suggested that single-nucleotide polymorphisms associated with genes related to the immune system, and particularly the maternal inflammatory response, may be associated with an increased risk of preterm delivery. OBJECTIVE: The objective of the study was to identify single-nucleotide polymorphisms associated with spontaneous preterm birth <37 weeks within a cohort of African-American women. STUDY DESIGN: This is a secondary analysis of a randomized trial that evaluated periodontal disease and preterm birth. Women were enrolled between 6 and 20 weeks' gestation at 3 prenatal care clinics between 2004 and 2007. Maternal DNA samples were collected and analyzed using a custom 1536 single-nucleotide polymorphismgenotyping array designed to assess genes involved in inflammation. Women were included in this study if they self-identified as African American. We excluded women with a multiple gestation or an indicated preterm delivery. We performed allele- and genotype-based analyses to evaluate the association between spontaneous preterm birth and tag single-nucleotide polymorphisms. We used a logistic regression to adjust for prior preterm birth in our genotype-based analysis. In a subgroup analysis, we compared women who delivered at <34 weeks' gestation to women who delivered at term. Within the microarray, we identified ancestry informative markers and compared global ancestry estimates among women who delivered preterm with those who delivered at term. RESULTS: Of the 833 African-American women in the study with genotype data, 77 women (9.2%) had a spontaneous preterm birth, whereas 756 women delivered at term. In an allele-based analysis, 4 single-nucleotide polymorphisms related to the genes for protein kinase C-α (PRKCA) were associated with increased risk of spontaneous preterm birth <37 weeks, whereas a single single-nucleotide polymorphism related to fms-related tyrosine kinase 1 (FLT1) was associated with spontaneous preterm birth <34 weeks. A genotype-based analysis revealed similar associations between single-nucleotide polymorphisms related to the PRKCA genes and spontaneous premature delivery. Additionally, single-nucleotide polymorphisms related to matrix metalloproteinase-2 (MMP2), tissue inhibitor of matrix metalloproteinase-2 (TIMP2), and interleukin 16 (IL16) genes were associated with spontaneous preterm birth <37 weeks in genotype-based analysis. Genetic variants related to MMP2, matrix metalloproteinase-1 (MMP1), and leukemia inhibitory factor receptor antisense RNA 1 (LIFR-AS1) genes were associated with higher rates of preterm birth <34 weeks. Ancestry estimates were similar between the women who had a spontaneous preterm birth and those who delivered at term. CONCLUSION: We identified tag single-nucleotide polymorphisms related to 7 genes that are critical to inflammation, extracellular remodeling, and cell signaling that were associated with spontaneous preterm birth in African-American women. Specifically, we found a strong association with the PRKCA gene. Genetic variation in these regions of the genome may be important in the pathogenesis of preterm birth. Our results should be considered in the design of future genomic studies in prematurity.

Loop electrosurgical excision procedure and risk of preterm birth: a systematic review and meta-analysis.

OBJECTIVE: To assess whether loop electrosurgical excision procedure (LEEP) increases the risk for preterm birth before 37 weeks of gestation and clarify whether the increased risk for preterm birth is attributable to the procedure itself or to risk factors associated with cervical dysplasia. DATA SOURCES: Two authors performed a search of the relevant data through February 2013 using PubMed, Embase, Scopus, CENTRAL, and ClinicalTrials.gov. METHODS OF STUDY SELECTION: We included observational studies that compared rates of preterm birth in women with prior LEEP with women with no history of cervical excision. Nineteen of 559 identified studies met selection criteria. TABULATION, INTEGRATION, AND RESULTS: We compared women with a history of LEEP with two unexposed groups without a history of cervical excision: 1) women with an unknown or no history of cervical dysplasia; and 2) women with a history of cervical dysplasia but no cervical excision. The primary outcome was preterm birth before 37 weeks of gestation. Secondary outcomes were preterm birth before 34 weeks of gestation, spontaneous preterm birth, preterm premature rupture of membranes, and perinatal mortality. DerSimonian-Laird random effects models were used. We assessed heterogeneity between studies using the Q and I tests. Stratified analyses and metaregression were performed to assess confounding. Nineteen studies were included with a total of 6,589 patients with a history of LEEP and 1,415,015 without. Overall, LEEP was associated with an increased risk of preterm birth before 37 weeks of gestation (pooled relative risk 1.61, 95% confidence interval [CI] 1.35-1.92). However, no increased risk was found when women with a history of LEEP were compared with women with a history cervical dysplasia but no cervical excision (pooled relative risk 1.08, 95% CI 0.88-1.33). CONCLUSION: Women with a history of LEEP have similar risk of preterm birth when compared with women with prior dysplasia but no cervical excision. Common risk factors for both preterm birth and dysplasia likely explain findings of association between LEEP and preterm birth, but LEEP itself may not be an independent risk factor for preterm birth.

Expression of flotillins in the human placenta: potential implications for placental transcytosis.

A proteomics survey of human placental syncytiotrophoblast (ST) apical plasma membranes revealed peptides corresponding to flotillin-1 (FLOT1) and flotillin-2 (FLOT2). The flotillins belong to a class of lipid microdomain-associated integral membrane proteins that have been implicated in clathrin- and caveolar-independent endocytosis. In the present study, we characterized the expression of the flotillin proteins within the human placenta. FLOT1 and FLOT2 were coexpressed in placental lysates and BeWo human trophoblast cells. Immunofluorescence microscopy of first-trimester and term placentas revealed that both proteins were more prominent in villous endothelial cells and cytotrophoblasts (CTs) than the ST. Correspondingly, forskolin-induced fusion in BeWo cells resulted in a decrease in FLOT1 and FLOT2, suggesting that flotillin protein expression is reduced following trophoblast syncytialization. The flotillin proteins co-localized with a marker of fluid-phase pinocytosis, and knockdown of FLOT1 and/or FLOT2 expression resulted in decreased endocytosis of cholera toxin B subunit. We conclude that FLOT1 and FLOT2 are abundantly coexpressed in term villous placental CTs and endothelial cells, and in comparison, expression of these proteins in the ST is reduced. These findings suggest that flotillin-dependent endocytosis is unlikely to be a major pathway in the ST, but may be important in the CT and endothelium.

Risk of cesarean delivery after loop electrosurgical excision procedure.

OBJECTIVE: To estimate whether previous loop electrosurgical excision procedure (LEEP) affects the risk of cesarean delivery. METHODS: A secondary analysis of a multicenter retrospective cohort study was performed. Women who underwent a prior LEEP were compared with two unexposed cohorts: 1) women with prior screening cervical cytology only; and 2) women with prior cervical punch biopsy. The pregnancy evaluated in this analysis was the first pregnancy of a duration more than 20 weeks of gestation after the identifying cervical procedure. Stratified and multivariable logistic regression analyses were used to control for confounding. RESULTS: Five hundred ninety-eight women with prior LEEP, 588 women with screening cytology only, and 552 women with cervical biopsy were included in this study. After adjusting for relevant confounders, similar rates of cesarean delivery were seen in women with prior LEEP (31.6%) and women with prior cervical cytology only (29.3%, adjusted odds ratio [OR] 1.06, 95% confidence interval [CI] 0.79-1.41). Likewise, no differences were found in rates of cesarean delivery when women with prior LEEP were compared with those with a prior punch biopsy (29.0%, adjusted OR 0.99, 95% CI 0.74-1.33). Among women who had a cesarean delivery, arrest of labor was the indication for cesarean delivery in a similar proportion of women in the groups (LEEP compared with cytology only, P=.12; LEEP compared with biopsy, P=.50). Loop electrosurgical excision procedure specimen size did not vary by delivery mode. Length of time between LEEP and subsequent pregnancy also did not influence delivery mode. CONCLUSION: Loop electrosurgical excision procedure does not affect mode of delivery in the subsequent pregnancy. LEVEL OF EVIDENCE: II.