Objective: To evaluate whether breastfeeding and its duration are associated with a reduced risk of low intelligence quotient (IQ) scores or other neurodevelopmental problems. Methods: We conducted a secondary analysis of two parallel multicenter, double-blinded randomized controlled trials in which participants with a singleton pregnancy and either subclinical hypothyroidism or hypothyroxinemia were treated with thyroxine or placebo. Our primary outcome was low IQ score (<85 at age 5 by Wechsler Preschool and Primary Scale of Intelligence III). Secondary outcomes included performance measures on other validated neurodevelopmental tests. Univariable and multivariable analyses were performed to evaluate the association between breastfeeding and neurodevelopmental outcomes. Step-wise backward proceeding linear and logistic regression models were used to develop the final adjusted models. Results: Of the 772 participants studied, 614 (80%) reported breastfeeding. Of these, 31% reported breastfeeding for <4 months, 19% for 4–6 months, 11% for 7–9 months, 15% for 10–12 *Other members of the NICHD MFMU Network are listed in Appendix 1, available online at http://links.lww.com/xxx. Corresponding author: Beth A. Plunkett, MD, MPH, 2650 Ridge Avenue, Walgreen’s Building Suite 1570, Evanston, IL 60201, Tel 847-570-4038, Cell 773-263-4334, Fax 847-570-1846, bplunkett@northshore.org. Financial Disclosure The authors did not report any potential conflicts of interest. Each author has confirmed compliance with the journal’s requirements for authorship. HHS Public Access Author manuscript Obstet Gynecol. Author manuscript; available in PMC 2022 April 01. Published in final edited form as: Obstet Gynecol. 2021 April 01; 137(4): 561–570. doi:10.1097/AOG.0000000000004314. A uhor M anscript

Objective To assess the risk of ischemic placental disease (IPD) including preeclampsia, small for gestational age (SGA), and abruption, in relation to preeclampsia in maternal grandmother, mother, and sister(s). Study Design We performed a secondary analysis of data from a randomized trial of vitamins C and E for preeclampsia prevention. Data on family history of preeclampsia were based on recall by the proband. The associations between family history of preeclampsia and the odds of IPD were evaluated from alternating logistic regressions. Results Of the 9,686 women who delivered nonmalformed, singleton live births, 17.1% had IPD. Probands provided data on preeclampsia in 55.5% ( n =5,374) on all three family members, 26.5% ( n =2,562) in mother and sister(s) only, and 11.6% ( n =1,125) in sister(s) only. The pairwise odds ratio (pOR) of IPD was 1.16 (95% confidence interval [CI]: 1.00-1.36) if one or more of the female relatives had preeclampsia. The pORs of preeclampsia were 1.54 (95% CI: 1.12-2.13) and 1.35 (95% CI: 1.03-1.77) if the proband's mother or sister(s) had a preeclamptic pregnancy, respectively, but no associations were seen for SGA infant or abruption. Conclusion This study suggests that IPD may share a predisposition with preeclampsia, suggesting a familial inheritance.

Objective To examine the relation between maternal vitamin D status and risk of pre‐eclampsia and preterm birth in women at high risk for pre‐eclampsia. Design Analysis of prospectively collected data and blood samples from a trial of prenatal low‐dose aspirin. Setting Thirteen sites across the USA . Population Women at high risk for pre‐eclampsia. Methods We measured 25‐hydroxyvitamin D [25( OH )D] concentrations in stored maternal serum samples drawn at 12–26 weeks’ gestation ( n = 822). We used mixed effects models to examine the association between 25( OH )D and risk of pre‐eclampsia and preterm birth, controlling for confounders including prepregnancy BMI and race. Main outcome measures Pre‐eclampsia and preterm birth. Results Twelve percent of women were vitamin D deficient [25( OH )D <30 nmol/l]. Women with 25( OH )D <30 versus ≥75 nmol/l had a 2.4‐fold (95% CI 1.0–5.6) higher risk of early‐onset pre‐eclampsia (<35 weeks’ gestation) after confounder adjustment. Women with 25( OH )D <50 nmol/l had a 1.8‐fold (95% CI 1.0–3.2) increased risk of preterm birth at <35 weeks compared with women who had 25( OH )D ≥75 nmol/l, which was driven by indicated preterm births at <35 weeks’ gestation [25( OH )D <50 versus ≥75 nmol/l adjusted RR 2.5 (95% CI 1.1–5.8)]. There was no association between vitamin D status and pre‐eclampsia or preterm birth at <37 weeks. Conclusion Maternal vitamin D status in the second trimester was inversely associated with risk of early‐onset pre‐eclampsia and preterm birth at <35 weeks in women at high risk for pre‐eclampsia. Tweetable abstract Vitamin D is inversely related to risk of pre‐eclampsia and preterm birth at <35 weeks in high‐risk pregnancies.

Depression affects an estimated 18.4% of all pregnancies with major depressive disorder occurring in up to 12.7% (Gavin et al. Obstet Gynecol 2005;106:1071–83). It is well understood that untreated depression is harmful to both mother and infant. Selective serotonin reuptake inhibitors (SSRIs) are commonly used as first-line treatment in this population. However, the fetal risks associated with this class of medication in pregnancy are highly debated. In the current study, Handal et al. used the Norwegian Mother and Child Cohort to conduct a population-based prospective study of the association between SSRI use before and during pregnancy and childhood motor skill development at age 3 years. They reported lower fine and gross motor development in children born to women reporting ‘prolonged’ SSRI use compared with women with no reported exposure or with no anxiety/depression before or throughout pregnancy (adjusted odds ratio 1.47, 95% CI 1.12–1.94) and adjusted odds ratio 1.64, 95% CI 1.15–2.34, respectively). Although associations were statistically significant, the estimated number needed to harm indicates little clinically meaningful difference between groups. Findings represent only seven children with impaired fine motor skills and 11 with gross motor skill impairment in women who reported taking ‘prolonged’ SSRIs. A major limitation of previous studies is a lack of separating effects of treatment for depression from effects of depressive symptoms. Indeed, many women who are treated with SSRIs remain symptomatic. Handal et al. recognised this and accounted for direct effects of depression/anxiety both before and throughout pregnancy by creating six groups of exposure based on SSRI use, length of SSRI use, and symptoms of depression/anxiety then performing several stratified sensitivity analyses adjusting for confounders. Despite conducting a very thorough analysis accounting for confounding by indication, the issue of confounding by severity remained. Authors duly acknowledged that their findings may indicate that depression before pregnancy is a marker of more severe disease. The effects attributed to SSRIs may actually be associated with the severity of the depression and not with the medication used to treat it. Future studies will need to address the limitations of small sample sizes, inadequate accounting for confounding by indication and severity, inadequate consideration of prenatal and intrapartum effects, limited length of follow up of exposed children, and lack of information on drug type, dose, frequency and gestational timing of treatment. These limitations are shared by the majority of the literature on this topic. Ultimately these study limitations impact the translation of findings into clinical practice. It is biologically plausible that SSRIs impact motor skill development because these medications cross the placenta and therefore have the potential to alter fetal development (Rampono et al. Pharmacopsychiatry 2009;42:95–100). There is no doubt that great caution should be exercised before initiating or continuing pharmacotherapy in a pregnant woman. Current literature generally supports the use of SSRIs in pregnancy, as any minimal risks associated with treatment are typically outweighed by the potential effects of untreated depression. With regards to motor skill development in the child, the results of this well-performed study do not provide sufficient evidence to incite a change in current practice. None declared. Completed disclosure of interests form available to view online as supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

According to the March of Dimes, one in eight births in the United States is a preterm birth.Preterm birth, defined as childbirth occurring at < 37 weeks of gestational age, is the leading cause of neonatal morbidity and mortality.Based on the promising effects seen in clinical trials [1,2] in reducing the risk of preterm birth, intramuscular injection of 17 alpha hydroxyprogesterone caproate (17-OHPC) has recently become the only Food and Drug Administration (FDA)-approved therapy labeled for reducing the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth.In addition to the FDA-approved product (Makena®), compounded 17-OHPC prepared by licensed compounding pharmacies is also available for women with risk of preterm delivery.

The placebo effect has not been characterised in pregnant women suffering from nausea and vomiting of pregnancy (NVP). Our aim was to characterise determinants of the placebo effect in women treated with placebo for NVP. We analysed data from a multicentre, double blind randomised controlled trial of Diclectin (R) (delayed release doxylamine and pyridoxine) vs placebo for the treatment of NVP. A total of 127 women in the placebo arm and 130 in the active arm provided evaluable data for this analysis. Women who chose to continue placebo on a compassionate basis (n = 41) had significantly better improvement in symptoms of NVP and higher Wellbeing scores than those who did not ask to continue compassionate use. Results were similar in the active drug arm. The request to continue compassionate use of either placebo or active drug could be predicted by greater improvement in symptoms of NVP during the trial period.

The rationale for using tocolytics in preterm labour is to enable transfer of the mother to a tertiary centre and to prolong pregnancy sufficiently so that glucocorticoids can be administered to the mother. There is little question that these short term objectives can be achieved with contemporary tocolytics. Whether tocolytics can maintain pregnancy for sufficient periods to enable in utero maturation to occur remains an unresolved question. When a decision is made to use tocolytics, the clinician is faced with a multitude of choices with side effects, efficacy and ease of administration generally being the most important considerations. Placebo-controlled studies suggest that the beta-agonists, prostaglandin inhibitors and atosiban are effective in prolonging pregnancy for 24-48 hours. Of these three agents, atosiban has the best safety profile. There are no placebo-controlled studies with calcium channel blockers or nitric oxide donors. However, because of their ease of use and efficacy compared with the beta-agonists, calcium channel blockers are widely used. Calcium channel blockers appear to have a better safety profile than the beta-agonists, but there are still significant cardiovascular side effects associated with their use. Indomethacin, although proven to be efficacious, has a safety profile that limits its utility for other than short courses. Magnesium sulphate is the most commonly used tocolytic in the United States, despite a lack of evidence for its efficacy. Although magnesium sulphate appears to have a good safety profile, serious side effects have been reported with its use. The choice of tocolytics is commonly based on personal preference. Whichever tocolytic is chosen, the fundamental parturitional process is not reversed by contemporary treatment, rather a reduction in uterine response to a stimulant; thus, the expectations of tocolytic treatment need to be reconsidered.

Bacterial vaginosis (BV) is known to alter many aspects of reproductive immunity. The production and activity of anti-inflammatory cytokines are thought to be a critical element of the lower genital tract innate immune defense with respect to STDs and infection-related spontaneous preterm birth. We sought to ascertain the impact of BV among pregnant women on the production of the three most important anti-inflammatory cytokines (IL-4, IL-10, and IL-13) in the cervix. In this cohort study, ninety-eight gravid women from 4 to 16 weeks´ gestation (median 8.4 weeks´) without N gonorrhoeae, C trachomatis, or T vaginalis were queried regarding clinical and demographic history and underwent pelvic examination for collection of vaginal swabs for Gram stain and cervical swabs for STDs and cytokines. BV was defined as a Nugent score of ≥7. Concentrations of cytokines were determined in duplicate using Luminex multiplex assay. Race and smoking status was determined by self-report. Statistical analyses were performed using Stata 8.0. BV was present in 30 (30.6%) women. The median cervical concentrations of IL-4, 10, and 13 were all significantly lower among women with BV than women without BV (P = .02, .03, .006, respectively). Even after adjustment for African-American race and cigarette smoking, women with BV had increased odds of having anti-inflammatory cytokine concentrations in the lowest quartile compared with women who did not have BV(see Table). BV in pregnancy is associated with an alteration of cervical innate immunity, as represented by a decreased concentration of the three most important anti-inflammatory cytokines. This may have an important impact upon the host response to immune challenges, such as STDs or infection-related preterm birth.Tabled 1Relationship of BV with anti-inflammatory cytokine concentrations in lowest quartileAdjusted odds ratio for IL-4 < 25th %ileAdjusted odds ratio for IL-10 < 25th %ileAdjusted odds ratio for IL-13 < 25th %ileBV + vs BV −4.4(1.5-12.8)10.4(3.0-36.1)5.2(1.8-15.0) Open table in a new tab

Objective: The purpose of this study was to determine whether the rate of preeclampsia in pregnant diabetic women is increased in those women with early-pregnancy proteinuria of 190 to 499 mg/24 hours compared with women with proteinuria of < 190 mg/24 hours.Study design: Secondary analysis was performed with relevant data from 194 pregnant women with type 1 and type 2 diabetes mellitus whose condition required insulin and who were enrolled previously in a multicenter trial of low-dose aspirin for the prevention of preeclampsia. The women Were assigned to 1 of 3 groups, based on the level of proteinuria at enrollment (13-26 weeks of gestation). Group 1 comprised women with < 190 mg protein/24 hours (n = 94); group 2 comprised women with 190 to 499 mg protein/24 hours (n = 35); and group 3 comprised women with greater than or equal to 500 mg protein/24 hours (n = 65). The rate of preeclampsia, according to strict predefined criteria, was then determined.Results: The rate of preeclampsia, was not increased statistically significantly in patients with early-pregnancy proteinuria of 190 to 499 mg/24 hours (7/35 women; 20%) when compared with women with proteinuria, of < 190 mg/24 hours (16/94 women; 17%).Conclusion: We did not find an increased rate of preeclampsia in women with pregestational diabetes mellitus with early-pregnancy proteinuria of 190 to 499 mg/24 hours when compared with women with pregestational diabetes mellitus with proteinuria of < 190 mg/24 hours. (C) 2004 Elsevier Inc. All rights reserved.

Preterm premature rupture of membranes (PPROM) occurs in 3% of pregnancies and is responsible for one third of all preterm births. In part I of this series, the definition, pathophysiology, and diagnosis of PPROM was reviewed. In this part, treatment is discussed. Adjunctive antibiotic and corticosteroid therapy has the strongest evidence for improving neonatal outcome. Treatment is gestational age-dependent and will be influenced by local neonatal intensive-care unit (NICU) survival statistics. This review presents the available evidence and grades it according to the U.S. Preventative Task Force recommendations. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader should be able to summarize the data on the use of labor inhibition in the setting of PPROM, list potential antibiotics regimens that are recommended for prophylaxis in patients with PPROM, to describe the benefits of corticosteroid administration in patients with PPROM, and to outline potential management strategies for patients with PPROM based on gestational age.

We have previously demonstrated a relationship between the concomitant presence of vaginal pH ≥5.0 & vaginal polymorphonuclear leukocytes (PMNs) >5 and early spontaneous preterm birth after preterm labor with intact membranes. The purpose of this investigation is to determine the association of these markers with preterm premature rupture of membranes (PPROM). This is a secondary analysis of a seven-center cohort originally studied from 11/84 to 3/89. The cohort for this analysis is comprised of 13,917 women enrolled between 23 and 26 weeks' gestation. All women had history; cervical swabs obtained for Neisseria gonorrhoeae (NG), Chlamydia trachomatis (CT), Trichomonas vaginalis (TV); & had vaginal swabs obtained for pH and Gram stain for diagnosis of PMNs and bacterial vaginosis (BV) using bacterial morphotypes evaluated by the Nugent 10 point scoring system. The association between vaginal pH ≥5.0 & vaginal PMNs >5 per oil-field with PPROM overall & in two gestational age strata was determined using logistic regression. Variables considered as possible confounders or effect modifiers include BV score, TV, NG, CT, race, age, recent antibiotic use, smoking, & obstetric history. In this cohort of 13,917 women, 169 (1.2%) had PPROM from 24 to 26 weeks', 5,751 (41.3%) had vaginal PMNs >5 per oil-field, and 2500 (18.0%) had vaginal pH ≥5.0. Both elevated vaginal pH & vaginal PMNs were present in 1149 women (8.3%). The Table below depicts the strength of the relationship between both markers together & PPROM overall & in both gestational age strata. The concomitant presence of both elevated vaginal pH & vaginal neutrophils is associated with PPROM from 24 to 32 weeks'. These two markers are most strongly associated with the earliest PPROM that is most likely related to infection.Tabled 1Association of pH ≥5 and PMN >5 with PPROMAdj OR (95% CI)PPROM unstratified1.54 (0.99-2.39)PPROM 24-32 weeks2.21 (1.02-4.76)PPROM 32-36 weeks1.29 (0.75-2.20) Open table in a new tab

Preeclampsia is a multisystem disorder that complicates 6% to 8% of pregnancies, with higher rates in women with preexisting hypertension, diabetes mellitus, or previous history of preeclampsia. Recent large randomized trials, including two large trials conducted by members of the Maternal-Fetal Medicine Network, have not shown a benefit in reducing the rate of preeclampsia or perinatal outcome from the use of low-dose aspirin. Secondary analysis from these trials revealed that the onset of mild gestational hypertension or mild preeclampsia at or near term was associated with minimal to low neonatal and maternal morbidities. During review of the medical records we found considerable differences among the various centers regarding the definitions of both mild and severe preeclampsia. These differences were more prevalent in those women with pre-existing hypertension or diabetes mellitus. The majority of adverse pregnancy outcomes occurred in women who developed severe gestational hypertension-preeclampsia prior to 35 weeks' gestation and in those women with previous preeclampsia and/or pre-existing vascular disease. We also found that epidural anesthesia is safe in parturients receiving low-dose aspirin in pregnancy and in women with severe preeclampsia.

OBJECTIVE To compare the rates and perinatal outcome in women who experienced preeclampsia in a previous pregnancy to those in women who developed preeclampsia as nulliparas. STUDY DESIGN This is a secondary analysis of data from 2 separate multi-center trials of aspirin for prevention of preeclampsia. Women who had preeclampsia in a previous pregnancy (n = 598) were compared with nulliparous women (n = 2934). Outcome variables were rates of preeclampsia, preterm delivery at <37 and <35 weeks of gestation, small-for-gestational-age infant, abruptio placentae, and perinatal death. Data were compared by using chi-square analysis and Wilcoxon rank sum test. RESULTS The rates of preeclampsia and of severe preeclampsia were significantly higher in the previous preeclamptic group as compared to the nulliparous group (17.9% vs 5.3%, P <.0001, and 7.5% vs. 2.4%, P <.0001, respectively). Women who had recurrent preeclampsia experienced more preterm deliveries before 37 and 35 weeks of gestation than nulliparous women who developed preeclampsia. In addition, among women who developed severe preeclampsia, those with recurrent preeclampsia had higher rates of preterm delivery both before 37 weeks (67% vs 33%, P =.0004) and before 35 weeks of gestation (36% vs 19%, P =.041), and higher rates of abruptio placentae (6.7% vs 1.5%) and fetal death (6.7% vs 1.4%) than did nulliparous women. CONCLUSION Compared to nulliparous women, women with preeclampsia in a previous pregnancy had significantly higher rates of preeclampsia and adverse perinatal outcomes associated with preterm delivery as a result of preeclampsia.

OBJECTIVE The current literature emphasizes increased risk of adverse outcomes in the presence of proteinuria and hypertension. The objective of this study was to compare the frequency of adverse fetal outcomes in women who developed hypertensive disorders with or without proteinuria. STUDY DESIGN The study design was a secondary analysis of data from women who had preeclampsia in a previous pregnancy (n = 598) who were enrolled in a multicenter trial of aspirin for the prevention of preeclampsia. The women had no history of chronic hypertension or renal disease and were normotensive at study inclusion. The maternal and perinatal outcome variables assessed were preterm delivery at <37 and <35 weeks of gestation, rate of small-for-gestational-age infants, and abruptio placenta. Data were analyzed by using the chi-square test, and women who remained normotensive or who had mild gestational hypertension were considered as a single group because they had similar outcomes. RESULTS As compared to mild preeclampsia, women who developed severe gestational hypertension (without proteinuria) had higher rates of both preterm delivery at <37 weeks of gestation and small-for-gestational-age infants. In addition, when compared to women with mild preeclampsia, for women with severe gestational hypertension, gestational age and birth weight were significantly lower at delivery (P <.003 for both age and birth weight). Moreover, women who developed severe gestational hypertension had higher rates of preterm delivery at <37 weeks of gestation (54.2% vs 17.8%, P =.001) and at <35 weeks of gestation (25.0% vs 8.4%, P =.0161), and delivery of small-for-gestational-age infants (20.8% vs 6.5%, P =.024) when compared to women who remained normotensive or those who developed mild gestational hypertension. There were no statistically significant differences in perinatal outcomes between the normotensive/mild gestational hypertension and the mild preeclampsia groups. Overall, women who had severe gestational hypertension had increased rates of preterm delivery and delivery of small-for-gestational-age infants than women with mild gestational hypertension or mild preeclampsia. In the presence of severe hypertension, proteinuria did not increase the rates of preterm delivery or delivery of small-for-gestational-age infants. CONCLUSIONS In women who have gestational hypertension or preeclampsia, increased rates of preterm delivery and delivery of small-for-gestational-age infants are present only in those with severe hypertension. In these women, the presence of proteinuria does not influence perinatal outcome.

OBJECTIVES:This study was undertaken to determine the frequencies of preeclampsia and adverse neonatal outcomes among women with pregestational diabetes.STUDY DESIGN:This was a prospective observation of pregnancy outcomes among 462 women with pregestational diabetes mellitus (White classes B-F) and singleton pregnancies who were enrolled in a multicenter trial to compare low-dose aspirin with placebo for preeclampsia prevention. The main outcome measures were preeclampsia and neonatal outcomes.RESULTS:Among 462 women with pregestational diabetes, 92 (20%) had preeclampsia. Preeclampsia frequency rose significantly with increasing severity of diabetes according to White classification (class B, 11%; class C, 22%; class D, 21%; class R plus class F, 36%; P <.0001). Preeclampsia was also more common among women who had proteinuria at baseline (28% vs 18%; odds ratio, 1.75; 95% confidence interval, 1.02-3.01). Frequency of preterm delivery at <35 weeks' gestation rose greatly with increasing severity of diabetes (P =.0002). Women with proteinuria at baseline were significantly more likely to be delivered at <35 weeks' gestation (29% vs 13%; odds ratio, 2.6; 95% confidence interval, 1.5-4.6) and to have small-for-gestational-age infants (14% vs 3%; odds ratio, 5. 4; 95% confidence interval, 2.7-17.7), and they were less likely to have large-for-gestational-age infants (14% vs 40%; odds ratio, 0.2; 95% confidence interval, 0.1-0.5).CONCLUSION:Among women with pregestational diabetes mellitus, the frequency of preeclampsia rose with increasing severity of diabetes. Proteinuria early in pregnancy was associated with marked increases in adverse neonatal outcomes independent of preeclampsia development.