Deirdre J. Lyell

Temporal and spatial variation of the human microbiota during pregnancy.

Significance The human indigenous microbial communities (microbiota) play critical roles in health and may be especially important for mother and fetus during pregnancy. Using a case-control cohort of 40 women, we characterized weekly variation in the vaginal, gut, and oral microbiota during and after pregnancy. Microbiota membership remained relatively stable at each body site during pregnancy. An altered vaginal microbial community was associated with preterm birth; this finding was corroborated by an analysis of samples from an additional cohort of nine women. We also discovered an abrupt change in the vaginal microbiota at delivery that persisted in some cases for at least 1 y. Our findings suggest that pregnancy outcomes might be predicted by features of the microbiota early in gestation. Despite the critical role of the human microbiota in health, our understanding of microbiota compositional dynamics during and after pregnancy is incomplete. We conducted a case-control study of 49 pregnant women, 15 of whom delivered preterm. From 40 of these women, we analyzed bacterial taxonomic composition of 3,767 specimens collected prospectively and weekly during gestation and monthly after delivery from the vagina, distal gut, saliva, and tooth/gum. Linear mixed-effects modeling, medoid-based clustering, and Markov chain modeling were used to analyze community temporal trends, community structure, and vaginal community state transitions. Microbiota community taxonomic composition and diversity remained remarkably stable at all four body sites during pregnancy (P > 0.05 for trends over time). Prevalence of a Lactobacillus-poor vaginal community state type (CST 4) was inversely correlated with gestational age at delivery (P = 0.0039). Risk for preterm birth was more pronounced for subjects with CST 4 accompanied by elevated Gardnerella or Ureaplasma abundances. This finding was validated with a set of 246 vaginal specimens from nine women (four of whom delivered preterm). Most women experienced a postdelivery disturbance in the vaginal community characterized by a decrease in Lactobacillus species and an increase in diverse anaerobes such as Peptoniphilus, Prevotella, and Anaerococcus species. This disturbance was unrelated to gestational age at delivery and persisted for up to 1 y. These findings have important implications for predicting premature labor, a major global health problem, and for understanding the potential impact of a persistent, altered postpartum microbiota on maternal health, including outcomes of pregnancies following short interpregnancy intervals.

Developmental response to hypoxia

Molecular mechanisms underlying fetal growth restriction due to placental insufficiency and in utero hypoxia are not well understood. In the current study, time‐dependent (3 h–11 days) changes in fetal tissue gene expression in a rat model of in utero hypoxia compared with normoxic controls were investigated as an initial approach to understand molecular events underlying fetal development in response to hypoxia. Under hypoxic conditions, litter size was reduced and IGFBP‐1 was up‐regulated in maternal serum and in fetal liver and heart. Tissue‐specific, distinct regulatory patterns of gene expression were observed under acute vs. chronic hypoxic conditions. Induction of glycolytic enzymes was an early event in response to hypoxia during organ development;consis‐tently, tissue‐specific induction of calcium homeostasis‐related genes and suppression of growth‐related genes were observed, suggesting mechanisms underlying hypoxia‐related fetal growth restriction. Furthermore, induction of inflammation‐related genes in placentas exposed to long‐term hypoxia (11 days) suggests a mechanism for placental dysfunction and impaired pregnancy outcome accompanying in utero hypoxia.— Huang, S.‐T. J., Vo, K. C. T., Lyell, D. J., Faessen, G. H., Tulac, S., Tibshirani, R., Giaccia, A. J., Giudice, L. C. Developmental response to hypoxia. FASEB J. 18, 1348–1365 (2004)

Acupuncture for Depression During Pregnancy A Randomized Controlled Trial

OBJECTIVE: To estimate the efficacy of acupuncture for depression during pregnancy in a randomized controlled trial. METHODS: A total of 150 pregnant women who met Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria for major depressive disorder were randomized to receive either acupuncture specific for depression or one of two active controls: control acupuncture or massage. Treatments lasted 8 weeks (12 sessions). Junior acupuncturists, who were not told about treatment assignment, needled participants at points prescribed by senior acupuncturists. All treatments were standardized. The primary outcome was the Hamilton Rating Scale for Depression, administered by masked raters at baseline and after 4 and 8 weeks of treatment. Continuous data were analyzed using mixed effects models and by intent to treat. RESULTS: Fifty-two women were randomized to acupuncture specific for depression, 49 to control acupuncture, and 49 to massage. Women who received acupuncture specific for depression experienced a greater rate of decrease in symptom severity (P<.05) compared with the combined controls (Cohens d=0.39, 95% confidence interval [CI] 0.01–0.77) or control acupuncture alone (P<.05; Cohens d=0.46, 95% CI 0.01–0.92). They also had significantly greater response rate (63.0%) than the combined controls (44.3%; P<.05; number needed to treat, 5.3; 95% CI 2.8–75.0) and control acupuncture alone (37.5%; P<.05: number needed to treat, 3.9; 95% CI 2.2–19.8). Symptom reduction and response rates did not differ significantly between controls (control acupuncture, 37.5%; massage, 50.0%). CONCLUSION: The short acupuncture protocol demonstrated symptom reduction and a response rate comparable to those observed in standard depression treatments of similar length and could be a viable treatment option for depression during pregnancy. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, www.clinicaltrials.gov, NCT00186654. LEVEL OF EVIDENCE: I

Peritoneal closure at primary cesarean delivery and adhesions.

Objective: To evaluate the effect of parietal peritoneal closure at cesarean delivery on adhesion formation. Methods: A prospective cohort study of women undergoing first repeat cesarean delivery was designed. All surgeons were asked immediately after surgery to score the severity and location of adhesions. Patient records were then abstracted to assess prior surgical technique, including parietal peritoneal closure, other attributes of first surgery, and patient characteristics. Exclusion criteria included adhesions, other surgery, or use of permanent suture at the first cesarean, unavailable first postoperative note and course, wound infection or breakdown following first surgery, intervening pelvic surgery, insulin-dependent diabetes mellitus, and steroid-dependent disease. The &khgr;2 test and multivariable logistic regression were used for statistical comparison and analysis. A total of 128 patients was required to have 80% power to detect a 50% reduction in adhesions when the parietal peritoneum was left open. Results: One hundred seventy-three patients were enrolled. Prior parietal peritoneal closure was associated with significantly fewer dense and filmy adhesions (52% versus 73%, P = .006) and significantly fewer dense adhesions (30% versus 45%, P = .043). When controlling for potential confounding variables, including prior infection, visceral peritoneal closure, rectus muscle closure, payor status, ethnicity, maternal age, gestational diabetes, and labor, parietal peritoneal closure at primary cesarean delivery was 5-fold protective against all adhesions (odds ratio 0.20, 95% confidence interval 0.08–0.49), and 3-fold protective against dense adhesions (odds ratio 0.32, 95% confidence interval 0.13–0.79). Omental-fascial adhesions were decreased most consistently. Conclusion: Parietal peritoneal closure at primary cesarean delivery was associated with significantly fewer dense and filmy adhesions. The practice of nonclosure of the parietal peritoneum at cesarean delivery should be questioned. Level of Evidence: II-2

Peritoneal Closure at Primary Cesarean Delivery and Adhesions

OBJECTIVE To evaluate the effect of parietal peritoneal closure at cesarean delivery on adhesion formation. METHODS A prospective cohort study of women undergoing first repeat cesarean delivery was designed. All surgeons were asked immediately after surgery to score the severity and location of adhesions. Patient records were then abstracted to assess prior surgical technique, including parietal peritoneal closure, other attributes of first surgery, and patient characteristics. Exclusion criteria included adhesions, other surgery, or use of permanent suture at the first cesarean, unavailable first postoperative note and course, wound infection or breakdown following first surgery, intervening pelvic surgery, insulin-dependent diabetes mellitus, and steroid-dependent disease. The chi2 test and multivariable logistic regression were used for statistical comparison and analysis. A total of 128 patients was required to have 80% power to detect a 50% reduction in adhesions when the parietal peritoneum was left open. RESULTS One hundred seventy-three patients were enrolled. Prior parietal peritoneal closure was associated with significantly fewer dense and filmy adhesions (52% versus 73%, P = .006) and significantly fewer dense adhesions (30% versus 45%, P = .043). When controlling for potential confounding variables, including prior infection, visceral peritoneal closure, rectus muscle closure, payor status, ethnicity, maternal age, gestational diabetes, and labor, parietal peritoneal closure at primary cesarean delivery was 5-fold protective against all adhesions (odds ratio 0.20, 95% confidence interval 0.08-0.49), and 3-fold protective against dense adhesions (odds ratio 0.32, 95% confidence interval 0.13-0.79). Omental-fascial adhesions were decreased most consistently. CONCLUSION Parietal peritoneal closure at primary cesarean delivery was associated with significantly fewer dense and filmy adhesions. The practice of nonclosure of the parietal peritoneum at cesarean delivery should be questioned.

Maternal prepregnancy body mass index and risk of spontaneous preterm birth.

BACKGROUND Findings from studies examining risk of preterm birth associated with elevated prepregnancy body mass index (BMI) have been inconsistent. METHODS Within a large population-based cohort, we explored associations between prepregnancy BMI and spontaneous preterm birth across a spectrum of BMI, gestational age, and racial/ethnic categories. We analysed data for 989,687 singleton births in California, 2007-09. Preterm birth was grouped as 20-23, 24-27, 28-31, or 32-36 weeks gestation (compared with 37-41 weeks). BMI was categorised as <18.5 (underweight); 18.5-24.9 (normal); 25.0-29.9 (overweight); 30.0-34.9 (obese I); 35.0-39.9 (obese II); and ≥ 40.0 (obese III). We assessed associations between BMI and spontaneous preterm birth of varying severity among non-Hispanic White, Hispanic, and non-Hispanic Black women. RESULTS Analyses of mothers without hypertension and diabetes, adjusted for age, education, height, and prenatal care initiation, showed obesity categories I-III to be associated with increased risk of spontaneous preterm birth at 20-23 and 24-27 weeks among those of parity 1 in each race/ethnic group. Relative risks for obese III and preterm birth at 20-23 weeks were 6.29 [95% confidence interval (CI) 3.06, 12.9], 4.34 [95% CI 2.30, 8.16], and 4.45 [95% CI 2.53, 7.82] for non-Hispanic Whites, non-Hispanic Blacks, and Hispanics, respectively. A similar, but lower risk, pattern was observed for women of parity ≥ 2 and preterm birth at 20-23 weeks. Underweight was associated with modest risks for preterm birth at ≥ 24 weeks among women in each racial/ethnic group regardless of parity. CONCLUSIONS The association between womens prepregnancy BMI and risk of spontaneous preterm birth is complex and is influenced by race/ethnicity, gestational age, and parity.

Interpregnancy interval and obstetrical complications.

Obstetricians are often presented with questions regarding the optimal interpregnancy interval (IPI). Short IPI has been associated with adverse perinatal and maternal outcomes, ranging from preterm birth and low birth weight to neonatal and maternal morbidity and mortality. Long IPI has in turn been associated with increased risk for preeclampsia and labor dystocia. In this review, we discuss the data regarding these associations along with recent studies revealing associations of short IPI with birth defects, schizophrenia, and autism. The optimal IPI may vary for different subgroups. We discuss the consequences of short IPI in women with a prior cesarean section, in particular the increased risk for uterine rupture and the considerations regarding a trial of labor in this subgroup. We review studies examining the interaction between short IPI and advanced maternal age and discuss the risk-benefit assessment for these women. Finally, we turn our attention to women after a stillbirth or an abortion, who often desire to conceive again with minimal delay. We discuss studies speaking in favor of a shorter IPI in this group. The accumulated data allow for the reevaluation of current IPI recommendations and management guidelines for women in general and among subpopulations with special circumstances. In particular, we suggest lowering the current minimal IPI recommendation to only 18 months (vs 24 months according to the latest World Health Organization recommendations), with even shorter recommended minimal IPI for women of advanced age and those who conceive after a spontaneous or induced abortion.

Magnesium sulfate compared with nifedipine for acute tocolysis of preterm labor: a randomized controlled trial.

OBJECTIVE: To compare the efficacy and side effects of intravenous magnesium to oral nifedipine for acute tocolysis of preterm labor. METHODS: A multicenter randomized trial was performed. Patients in active preterm labor who were at 24 to 33 weeks and 6 days of gestation were randomly assigned to receive magnesium sulfate or nifedipine. The primary outcome was arrest of preterm labor, defined as prevention of delivery for 48 hours with uterine quiescence. RESULTS: One hundred ninety-two patients were enrolled. More patients assigned to magnesium sulfate achieved the primary outcome (87% compared with 72%, P=.01). There were no differences in delivery within 48 hours (7.6% magnesium sulfate compared with 8.0% nifedipine, P=.92), gestational age at delivery (35.8 compared with 36.0 weeks, P=.61), birth before 37 and 32 weeks (57% compared with 57%, P=.97, and 11% compared with 8%, P=.39), and episodes of recurrent preterm labor. Mild and severe maternal adverse effects were significantly more frequent with magnesium sulfate. Birth weight, birth weight less than 2,500 g, and neonatal morbidities were similar between groups, but newborns in the magnesium sulfate group spent longer in the neonatal intensive care unit (8.8±17.7 compared with 4.2±8.2 days, P=.007). CONCLUSION: Patients who received magnesium sulfate achieved the primary outcome more frequently. However, delay of delivery, gestational age at delivery, and neonatal outcomes were similar between groups. Nifedipine was associated with fewer maternal adverse effects. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00185900 LEVEL OF EVIDENCE: I

Adhesions and perioperative complications of repeat cesarean delivery

The unprecedented high rate of cesarean delivery and the declining rate of vaginal birth after cesarean delivery make necessary awareness of the potential complications that are associated with repeat cesarean delivery. This article reviews the epidemiologic features of cesarean delivery and the perioperative risks that are associated with repeat cesarean delivery. These risks include increased adhesions, infections and wound complications, bleeding, bowel injury and obstruction, hysterectomy, operative time, hospital stay, and delays in delivery.

Maintenance nifedipine tocolysis compared with placebo: a randomized controlled trial.

OBJECTIVE: To estimate whether maintenance nifedipine tocolysis after arrested preterm labor prolongs pregnancy and improves neonatal outcomes. METHODS: A prospective, randomized double-blind, multicenter study was conducted. After successful tocolysis, patients were randomly assigned to receive 20 mg nifedipine or an identical-appearing placebo every 4–6 hours until 37 weeks of gestation. The primary outcome was attainment of 37 weeks of gestation. Patients were enrolled between 24 weeks and 34 weeks if they had six or fewer contractions per hour, intact membranes, and less than 4 cm cervical dilation. Exclusion criteria were placental abruption or previa, fetal anomaly incompatible with life, or maternal medical contraindication to tocolysis. Sixty-six patients were required for 80% power to detect a 50% reduction in birth before 37 weeks, with a two-tailed alpha of 0.05. Data were analyzed by intent to treat. RESULTS: Seventy-one patients were randomly assigned. Two patients were excluded after randomization and one was lost to follow-up. Thirty-five patients received placebo, and 33 received nifedipine. There were no maternal demographic differences between groups; the placebo group was significantly more dilated and effaced at study entry. There was no difference in attainment of 37 weeks (39% nifedipine compared with 37% placebo, P>.91), mean delay of delivery (33.5±19.9 days nifedipine compared with 32.6±21.4 days placebo, P=.81) or delay of delivery for greater than 48 hours or 1, 2, 3, or 4 weeks. Neonatal outcomes were similar between groups. CONCLUSION: When compared with placebo, maintenance nifedipine tocolysis did not confer a large reduction in preterm birth or improvement in neonatal outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00185952 LEVEL OF EVIDENCE: I