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Medication-assisted treatment is recommended for individuals with an opioid use disorder, including pregnant women. Medication-assisted treatment during pregnancy provides benefits to the mother and fetus, including better pregnancy outcomes, reduced illicit drug use, and improved prenatal care. An alternative approach, medically supervised withdrawal (detoxification), has, in recent reports, demonstrated a low risk of fetal death and low rates of relapse and neonatal abstinence syndrome. The rates of relapse and neonatal abstinence syndrome are questioned by many who view medically supervised withdrawal as unacceptable based on the concern for the potential adverse consequences of relapse to mother and baby. The impact of opioids on the fetal brain have not been integrated into this debate. Studies in animals and human brain tissues demonstrate opioid receptors in neurons, astroglia, and oligodendrocytes. Age-specific normative data from infants, children, and adults have facilitated investigation of the impact of opioids on the human brain in vivo. Collectively, these studies in animals, human neural tissue, adult brains, and the brains of children and newborns demonstrate that opioids adversely affect the human brain, primarily the developing oligodendrocyte and the processes of myelinization (white matter microstructure), connectivity between parts of the brain, and the size of multiple brain regions, including the basal ganglia, thalamus, and cerebellar white matter. These in vivo studies across the human lifespan suggest vulnerability of specific fronto—temporal—limbic and frontal—subcortical (basal ganglia and cerebellum) pathways that are also likely vulnerable in the human fetal brain. The long-term impact of these reproducible changes in the fetal brain in vivo is unclear, but the possibility of lasting injury has been suggested. In light of the recent data on medically supervised withdrawal and the emerging evidence suggesting adverse effects of opioids on the developing fetal brain, a new paradigm of care is needed that includes the preferred option of medication-assisted treatment but also the option of medically supervised opioid withdrawal for a select group of women. Both these treatment options should offer mental health and social services support throughout pregnancy. More research on both opioid exposure on the developing human brain and the impact of medically supervised withdrawal is required to identify appropriate candidates, optimal dose reduction regimens, and gestational age timing for initiating medically supervised withdrawal.

The data available to inform pregnant and lactating women about drug safety and efficacy are woefully inadequate. This lack of information encompasses every aspect of pharmaceutics, including limited human data about the embryonic risk, limited pharmacokinetic and pharmacodynamic information during and after pregnancy to ensure proper dosing, and a dearth of new medications to treat obstetrical and lactation disorders. This state of affairs has been longstanding and can be attributed to several realities, most of which have withstood any efforts to modify them. The first reality is the disinterest of the pharmaceutical industry to undertake pregnancy and lactation studies because of the considerable disincentives to undertake such studies. The medicolegal risks and the limited opportunity for financial gain are significant barriers to their participation. The US Food and Drug Administration has not mandated that new drugs or drugs "on patent" must include studies in pregnant women. Regulatory constrains that have defined pregnant women as a vulnerable class have greatly limited pharmacologic studies. Another contributing factor to this lack of information is the lack of researchers skilled in pharmacology with an interest in the pregnant woman. In addition, although difficult to measure, there is the hesitancy of pregnant and lactating women to participate in pharmacology research either for fear of fetal risk or an inability to commit the time required for such studies. Research in obstetrical and lactation pharmacology lags far behind that of pediatric pharmacology. Through the efforts of many, research in that field is highly funded and very productive in providing new information on medications used in children who, like pregnant women, have differing pharmacologic needs based on age (chronology for children and gestational age for pregnant women). Recently, the deficiencies and possible remedies for this embarrassing state of affairs in obstetrical and lactation pharmacology have been addressed by the federal government, which led to 15 recommendations from the Task Force on Research Specific to Pregnant Women and Lactating Women. In this article, we address the challenges in providing meaningful information about specific medications used by the mother and how these problems have evolved. We also suggest specific strategies to start the process of remediation.

Understanding and improving obstetrical quality and safety is an important goal of professional societies, and many interventions such as checklists, safety bundles, educational interventions, or other culture changes have been implemented to improve the quality of care provided to obstetrical patients. Although many factors contribute to delivery decisions, a reduced workload has addressed how provider issues such as fatigue or behaviors surrounding impending shift changes may influence the delivery mode and outcomes.The objective was to assess whether intrapartum obstetrical interventions and adverse outcomes differ based on the temporal proximity of the delivery to the attending's shift change.This was a secondary analysis from a multicenter obstetrical cohort in which all patients with cephalic, singleton gestations who attempted vaginal birth were eligible for inclusion. The primary exposure used to quantify the relationship between the proximity of the provider to their shift change and a delivery intervention was the ratio of time from the most recent attending shift change to vaginal delivery or decision for cesarean delivery to the total length of the shift. Ratios were used to represent the proportion of time completed in the shift by normalizing for varying shift lengths. A sensitivity analysis restricted to patients who were delivered by physicians working 12-hour shifts was performed. Outcomes chosen included cesarean delivery, episiotomy, third- or fourth-degree perineal laceration, 5-minute Apgar score of4, and neonatal intensive care unit admission. Chi-squared tests were used to evaluate outcomes based on the proportion of the attending's shift completed. Adjusted and unadjusted logistic models fitting a cubic spline (when indicated) were used to determine whether the frequency of outcomes throughout the shift occurred in a statistically significant, nonlinear pattern RESULTS: Of the 82,851 patients eligible for inclusion, 47,262 (57%) had ratio data available and constituted the analyzable sample. Deliveries were evenly distributed throughout shifts, with 50.6% taking place in the first half of shifts. There were no statistically significant differences in the frequency of cesarean delivery, episiotomy, third- or fourth-degree perineal lacerations, or 5-minute Apgar scores of4 based on the proportion of the shift completed. The findings were unchanged when evaluated with a cubic spline in unadjusted and adjusted logistic models. Sensitivity analyses performed on the 22.2% of patients who were delivered by a physician completing a 12-hour shift showed similar findings. There was a small increase in the frequency of neonatal intensive care unit admissions with a greater proportion of the shift completed (adjusted P=.009), but the findings did not persist in the sensitivity analysis.Clinically significant differences in obstetrical interventions and outcomes do not seem to exist based on the temporal proximity to the attending physician's shift change. Future work should attempt to directly study unit culture and provider fatigue to further investigate opportunities to improve obstetrical quality of care, and additional studies are needed to corroborate these findings in community settings.

Background Preeclampsia remains a major cause of maternal and neonatal morbidity and mortality. Biologic plausibility, compelling preliminary data, and a pilot clinical trial support the safety and utility of pravastatin for the prevention of preeclampsia. Objective We previously reported the results of a phase I clinical trial using a low dose (10 mg) of pravastatin in high-risk pregnant women. Here, we report a follow-up, randomized trial of 20 mg pravastatin versus placebo among pregnant women with previous preeclampsia who required delivery before 34+6 weeks’ gestation with the objective of evaluating the safety and pharmacokinetic parameters of pravastatin. Study Design This was a pilot, multicenter, blinded, placebo-controlled, randomized trial of women with singleton, nonanomalous pregnancies at high risk for preeclampsia. Women between 12+0 and 16+6 weeks of gestation were assigned to receive a daily pravastatin dose of 20 mg or placebo orally until delivery. In addition, steady-state pravastatin pharmacokinetic studies were conducted in the second and third trimesters of pregnancy and at 4 to 6 months postpartum. Primary outcomes included maternal-fetal safety and pharmacokinetic parameters of pravastatin during pregnancy. Secondary outcomes included maternal and umbilical cord blood chemistries and maternal and neonatal outcomes, including rates of preeclampsia and preterm delivery, gestational age at delivery, and birthweight. Results Of note, 10 women assigned to receive pravastatin and 10 assigned to receive the placebo completed the trial. No significant differences were observed between the 2 groups in the rates of adverse or serious adverse events, congenital anomalies, or maternal and umbilical cord blood chemistries. Headache followed by heartburn and musculoskeletal pain were the most common side effects. We report the pravastatin pharmacokinetic parameters including pravastatin area under the curve (total drug exposure over a dosing interval), apparent oral clearance, half-life, and others during pregnancy and compare it with those values measured during the postpartum period. In the majority of the umbilical cord and maternal samples at the time of delivery, pravastatin concentrations were below the limit of quantification of the assay. The pregnancy and neonatal outcomes were more favorable in the pravastatin group. All newborns passed their brainstem auditory evoked response potential or similar hearing screening tests. The average maximum concentration and area under the curve values were more than 2-fold higher following a daily 20 mg dose compared with a 10 mg daily pravastatin dose, but the apparent oral clearance, half-life, and time to reach maximum concentration were similar, which is consistent with the previously reported linear, dose-independent pharmacokinetics of pravastatin in nonpregnant subjects. Conclusion This study confirmed the overall safety and favorable pregnancy outcomes for pravastatin in women at high risk for preeclampsia. This favorable risk-benefit analysis justifies a larger clinical trial to evaluate the efficacy of pravastatin for the prevention of preeclampsia. Until then, pravastatin use during pregnancy remains investigational.

Short cervix at midgestation, the presence of intraamniotic debris, and cervical funneling are risk factors for preterm birth; however, cervical length measurements and cutoffs are not well documented among pregnant patients of different gestational ages and self-reported races and ethnicities.This study aimed to describe the distribution of cervical length and frequency of funneling and debris at midgestation in nulliparous women by gestational age and race/ethnicity.This secondary analysis of screening data from a multicenter treatment trial of singleton nulliparous patients with short cervix was conducted at 14 geographically distributed, university-affiliated medical centers in the United States. Singleton nulliparous patients with no known risk factors for preterm birth were screened for trial participation and asked to undergo a transvaginal ultrasound to measure cervical length by a certified sonographer. The distribution of cervical length and the frequency of funneling and debris were assessed for each gestational age week (16-22 weeks) and stratified by self-reported race and ethnicity, which for this study were categorized as White, Black, Hispanic, and other. Patients enrolled in the randomized trial were excluded from this analysis.A total of 12,407 nulliparous patients were included in this analysis. The racial or ethnic distribution of the study participants was as follows: White, 41.6%; Black, 29.6%; Hispanic, 24.2%; and others, 4.6%. The 10th percentile cervical length for the entire cohort was 31.1 mm and, when stratified by race and ethnicity, 31.9 mm for White, 30.2 mm for Black, 31.4 mm for Hispanic, and 31.2 mm for patients of other race and ethnicity (P.001). At each gestational age, the cervical length corresponding to the tenth percentile was shorter in Black patients. The 25 mm value commonly used to define a short cervix and thought to represent the 10th percentile ranged from 1.3% to 5.4% across gestational age weeks and 1.0% to 3.8% across race and ethnicity groups. Black patients had the highest rate of funneling (2.6%), whereas Hispanic and Black patients had higher rates of intraamniotic debris than White and other patients (P.001).Black patients had shorter cervical length and higher rates of debris and funneling than White patients. The racial and ethnic disparities in sonographic midtrimester cervical findings may provide insight into the racial disparity in preterm birth rates in the United States.

Background Characterization of pharmacokinetics (PK) is lacking for vaginal progesterone in pregnancy. Dosing of vaginal progesterone for preterm birth prevention has been empirical. Due to pregnancy-related changes in vaginal and uterine blood flow, hepatic metabolism, renal clearance, and endogenously elevated serum progesterone, studies outside of pregnancy may not be applicable. The lack of the PK profile of vaginally administered progesterone in pregnancy limits the ability to define the exposure:response relationship needed to optimize dosing, which has implications for its use in research and clinical care regarding management of short cervix, prevention of recurrent preterm birth, and prevention of recurrent miscarriage. Objective This was a study to establish the feasibility of using serum progesterone to establish basic pharmacokinetic parameters of vaginal progesterone in pregnancy for preterm birth prevention. Study Design This is a prospective study of 6 low risk singletons 18 0/7- 23 6/7 weeks' with BMI 20-40. Exclusion criteria were current vaginitis, abnormal pap smear, prescription medication use, cervical length ≤25mm, prior preterm birth, and contraindication to progesterone. Participants received a single dose of 200mg micronized vaginal progesterone and serum progesterone levels were evaluated every two hours from 0 to 12hours and then 24 hours post-dose. Primary outcome was concentration/time profile of serum progesterone. Results Median maternal age was 27 [21.5-33.3] years, median BMI was 26.5 [23.3-29.0] kg/m 2 , and median gestational age was 22.9 [21.0-23.4] weeks.Median baseline serum progesterone was 47[40 to 52] ng/ml, median peak concentration was 54 [48 to 68]ng/ml, median time to peak was 12 [4 to 15]hours. There was a trend in rising serum progesterone over baseline with a median ΔCmax of 11ng/ml and interquartile range 2 to 22. Median percent change from baseline was an increase by 24% IQR [4% to 53%]. However, there was no clear elimination phase and the median area under the curve was 112ng*h/ml with an IQR of -43 to 239. Conclusion Unlike in non-pregnant individuals, administration of vaginal progesterone in pregnant individuals only minimally impacts systemic exposure. There is a limited trend of rising serum progesterone over baseline levels with significant inter-individual variability. Serum progesterone is unlikely to be a good candidate for establishing pharmacokinetics or dosing of vaginal progesterone in pregnancy for preterm birth prevention.

Preterm birth has staggering health implications, and yet the causes of most cases are still unknown. Placental features have been understudied as an etiology for preterm birth, and the association between placental pathologic lesions and neonatal outcomes are incompletely understood.We sought to characterize births according to placental pathology and relate these to adverse neonatal outcomes.We studied 20,091 births (15,710 term and 4381 preterm) with placental evaluations. Births were classified according to the presence or absence of placental lesions consistent with malperfusion (vasculopathy, infarct, advanced villous maturation, perivillous fibrin, fibrin deposition) and intrauterine inflammation/infection (chorioamnionitis, funisitis, vasculitis). Outcomes were gestational week of delivery, birthweight z-score, neonatal respiratory distress syndrome, and intraventricular hemorrhage.Among all preterm births, evidence of placental malperfusion was identified more often than inflammation/infection (50.6% vs 27.3%, P .0001). Placental malperfusion was associated with reduced fetal growth (adjusted birthweight z-score, -0.83, P.0001) and lesions of inflammation/infection were associated with earlier delivery (adjusted difference -2.08 weeks, P.0001) than those with no lesions. When both placental lesions were present, earlier delivery (adjusted difference -2.28 weeks, P.0001) and reduced fetal growth (adjusted birthweight z-score difference, -0.24, P = .001) were observed more often than when neither lesion was present. Findings were similar when restricted to cases of spontaneous preterm birth. Intraventricular hemorrhage was higher in preterm births with malperfusion lesions than cases with no lesions (7.6% vs 3.4%; odds ratio, 1.98; confidence interval, 1.18-3.32), accounting for gestational age and other covariates.Placental pathology provides important insight into subtypes of preterm birth with adverse neonatal outcomes. Co-occurrence of malperfusion and inflammation/infection, especially among spontaneous preterm births, may be a novel pattern of placental injury linked to severe adverse outcomes.

Background Buprenorphine is a Food and Drug Administration–approved maintenance therapy for opioid use disorders and is increasingly being used in pregnant women with opioid use disorders as an alternative to methadone. Dosing of buprenorphine in pregnant women is based on the regimen recommended for nonpregnant females and males. Limited data are available defining the pharmacokinetic properties of sublingual buprenorphine administered during pregnancy. Objective This study evaluated the impact of physiological changes associated with pregnancy on the pharmacokinetics of sublingual buprenorphine during and after pregnancy. Study Design Pregnant women (n = 13), between 18 0/7 and 37 6/7 weeks' singleton gestation, receiving sublingual buprenorphine twice daily for opioid use disorders were studied. Pharmacokinetic-2 studies were performed between 18 and 25 weeks (n = 7), pharmacokinetic-3 studies were performed between 31 and 37 weeks (n = 11), and pharmacokinetic-P was performed 4-18 weeks postpartum (n = 10). On the day of the study, blood was withdrawn prior to the daily morning dose of buprenorphine and at 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, and 12 hours after the dose. Buprenorphine plasma concentrations were analyzed by liquid chromatography tandem mass spectrometric detection. All pharmacokinetic parameters were observed or estimated using Microsoft Excel. Statistical analyses were performed to identify significant changes in study participants' buprenorphine pharmacokinetic parameter estimates over the duration of the study. Univariate linear and generalized linear mixed models were used to investigate changes in these measures over time, some of which were log transformed for normality. Results Dose-normalized (plasma concentration per dose) buprenorphine plasma concentrations were significantly lower during pregnancy (pharmacokinetic-2 plus pharmacokinetic-3) than during the postpartum period (pharmacokinetic-P). Specific pharmacokinetic parameters (and level of significance) were as follows: the area under the buprenorphine plasma concentration-time curves ( P P P P Conclusion The dose-normalized plasma concentrations during a dosing interval and the overall exposure of buprenorphine (area under the buprenorphine plasma concentration-time curves) are lower throughout pregnancy compared with the postpartum period. This indicates an increase in apparent clearance of buprenorphine during pregnancy. These data suggest that pregnant women may need a higher dose of sublingual buprenorphine compared with postpartum individuals. The dose of buprenorphine should be assessed after delivery to maintain similar buprenorphine exposure during the postpartum period.

Background Studies of early-term birth after demonstrated fetal lung maturity show that respiratory and other outcomes are worse with early-term birth (370–386 weeks) even after demonstrated fetal lung maturity when compared with full-term birth (390–406 weeks). However, these studies included medically indicated births and are therefore potentially limited by confounding by the indication for delivery. Thus, the increase in adverse outcomes might be due to the indication for early-term birth rather than the early-term birth itself. Objective We examined the prevalence and risks of adverse neonatal outcomes associated with early-term birth after confirmed fetal lung maturity as compared with full-term birth in the absence of indications for early delivery. Study Design This is a secondary analysis of an observational study of births to 115,502 women in 25 hospitals in the United States from 2008 through 2011. Singleton nonanomalous births at 37–40 weeks with no identifiable indication for delivery were included; early-term births after positive fetal lung maturity testing were compared with full-term births. The primary outcome was a composite of death, ventilator for ≥2 days, continuous positive airway pressure, proven sepsis, pneumonia or meningitis, treated hypoglycemia, hyperbilirubinemia (phototherapy), and 5-minute Apgar Results In all, 48,137 births met inclusion criteria; the prevalence of fetal lung maturity testing in the absence of medical or obstetric indications for early delivery was 0.52% (n = 249). There were 180 (0.37%) early-term births after confirmed pulmonary maturity and 47,957 full-term births. Women in the former group were more likely to be non-Hispanic white, smoke, have received antenatal steroids, have induction, and have a cesarean. Risks of the composite (16.1% vs 5.4%; adjusted odds ratio, 3.2; 95% confidence interval, 2.1–4.8 from logistic regression) were more frequent with elective early-term birth. Propensity scores matching confirmed the increased primary composite in elective early-term births: adjusted odds ratios, 4.3 (95% confidence interval, 1.8–10.5) for 1:1 and 3.5 (95% confidence interval, 1.8–6.5) for 1:2 matching. Among components of the primary outcome, CPAP use and hyperbilirubinemia requiring phototherapy were significantly increased. Transient tachypnea of the newborn, neonatal intensive care unit admission, and prolonged neonatal intensive care unit stay (>2 days) were also increased with early-term birth. Conclusion Even with confirmed pulmonary maturity, early-term birth in the absence of medical or obstetric indications is associated with worse neonatal respiratory and hepatic outcomes compared with full-term birth, suggesting relative immaturity of these organ systems in early-term births.

Background Preeclampsia complicates approximately 3–5% of pregnancies and remains a major cause of maternal and neonatal morbidity and mortality. It shares pathogenic similarities with adult cardiovascular disease as well as many risk factors. Pravastatin, a hydrophilic, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor, has been shown in preclinical studies to reverse various pathophysiological pathways associated with preeclampsia, providing biological plausibility for its use for preeclampsia prevention. However, human trials are lacking. Objective As an initial step in evaluating the utility of pravastatin in preventing preeclampsia and after consultation with the US Food and Drug Administration, we undertook a pilot randomized controlled trial with the objective to determine pravastatin safety and pharmacokinetic parameters when used in pregnant women at high risk of preeclampsia. Study Design We conducted a pilot, multicenter, double-blind, placebo-controlled, randomized trial of women with singleton, nonanomalous pregnancies at high risk for preeclampsia. Women between 12 0/7 and 16 6/7 weeks' gestation were assigned to daily pravastatin 10 mg or placebo orally until delivery. Primary outcomes were maternal-fetal safety and pharmacokinetic parameters of pravastatin during pregnancy. Secondary outcomes included rates of preeclampsia and preterm delivery, gestational age at delivery, birthweight, and maternal and cord blood lipid profile (clinicaltrials.gov identifier NCT01717586). Results Ten women assigned to pravastatin and 10 to placebo completed the trial. There were no differences between the 2 groups in rates of study drug side effects, congenital anomalies, or other adverse or serious adverse events. There was no maternal, fetal, or neonatal death. Pravastatin renal clearance was significantly higher in pregnancy compared with postpartum. Four subjects in the placebo group developed preeclampsia compared with none in the pravastatin group. Although pravastatin reduced maternal cholesterol concentrations, umbilical cord cholesterol concentrations and infant birthweight were not different between the groups. The majority of umbilical cord and maternal pravastatin plasma concentrations at the time of delivery were below the lower limit of quantification of the assay. Pravastatin use was associated with a more favorable pregnancy angiogenic profile. Conclusion This study provides preliminary safety and pharmacokinetic data regarding the use of pravastatin for preventing preeclampsia in high-risk pregnant women. Although the data are preliminary, no identifiable safety risks were associated with pravastatin use in this cohort. This favorable risk-benefit analysis justifies using pravastatin in a larger clinical trial with dose escalation.

Objective We sought to describe the prevalence of serious maternal complications following early preterm birth by gestational age (GA), delivery route, and type of cesarean incision. Study Design Trained personnel abstracted data from maternal and neonatal charts for all deliveries on randomly selected days representing one third of deliveries across 25 US hospitals over 3 years (n = 115,502). All women delivering nonanomalous singletons between 23-33 weeks' gestation were included. Women were excluded for antepartum stillbirth and highly morbid conditions for which route of delivery would not likely impact morbidity including nonreassuring fetal status, cord prolapse, placenta previa, placenta accreta, placental abruption, and severe and unstable maternal conditions (cardiopulmonary collapse, acute respiratory distress syndrome, seizures). Serious maternal complications were defined as: hemorrhage (blood loss ≥1500 mL, blood transfusion, or hysterectomy for hemorrhage), infection (endometritis, wound dehiscence, or wound infection requiring antibiotics, reopening, or unexpected procedure), intensive care unit admission, or death. Delivery route was categorized as classic cesarean delivery (CCD), low transverse cesarean delivery (LTCD), low vertical cesarean delivery (LVCD), and vaginal delivery. Association of delivery route with complications was estimated using multivariable regression models yielding adjusted relative risks (aRR) controlling for maternal age, race, body mass index, hypertension, diabetes, preterm premature rupture of membranes, preterm labor, GA, and hospital of delivery. Results Of 2659 women who met criteria for inclusion in this analysis, 8.6% of women experienced serious maternal complications. Complications were associated with GA and were highest between 23-27 weeks of gestation. The frequency of complications was associated with delivery route; compared with 3.5% of vaginal delivery, 23.0% of CCD (aRR, 3.54; 95% confidence interval (CI), 2.29–5.48), 12.1% of LTCD (aRR, 2.59; 95% CI, 1.77–3.77), and 10.3% of LVCD (aRR, 2.27; 95% CI, 0.68–7.55) experienced complications. There was no significant difference in complication rates between CCD and LTCD (aRR, 1.37; 95% CI, 0.95–1.97) or between CCD and LVCD (aRR, 1.56; 95% CI, 0.48–5.07). Conclusion The risk of maternal complications after early preterm delivery is substantial, particularly in women who undergo cesarean delivery. Obstetricians need to be prepared to manage potential hemorrhage, infection, and intensive care unit admission for early preterm births requiring cesarean delivery.

Objective This study was undertaken to compare uterine contraction frequency in twins versus singletons and to determine if contraction frequency can be an efficient predictor of spontaneous preterm birth in twin gestations. Study design Fifty-nine twin and 306 singleton gestations were enrolled between 22 and 24 weeks at 11 centers. Contraction frequency was recorded with a home uterine activity monitor (HUAM) 2 or more times per day on 2 or more days per week until delivery or 36-6/7 weeks. Masked HUAM data were interpreted according to standard protocol. Repeated measures analyses were used to determine whether mean or maximum uterine contraction frequency per hour differed between singleton and twin gestations across gestational age, by time of day, and by delivery before 35 weeks or beyond. Uterine contraction frequency was also evaluated by logistic regression and receiver operator characteristic (ROC) curves as tests to predict spontaneous preterm birth. Results There were 34,908 hours of HUAM data recorded by the 306 singleton gestations and 5,427 hours by the 59 women with twins. Uterine contraction frequency was significantly greater in twins ( P = .002) compared with singletons, regardless of gestational age. Contraction frequency in twins increased significantly with gestational age and time of day (1600-0359 hours); but was not associated with spontaneous preterm birth. Maximum uterine contraction frequency was associated with preterm birth less than 35 weeks but only in the morning (am) recording (0400-1559) and at the 29- to 30-week gestational age interval. This relationship was modest (odds ratio 1-2) and not consistent across gestational age or between the am and afternoon/evening (pm) monitoring sessions. ROC analysis revealed no contraction frequency that efficiently identified twins who delivered prematurely at any 2-week gestational age interval. Conclusion Mean uterine contraction frequency was significantly higher for twin gestations than singletons throughout the latter half of pregnancy and between 1600 and 0359 hours but was not higher among twins who delivered less than 35 weeks' gestation. Neither maximum am or pm contraction frequency predicted spontaneous preterm birth less than 35 weeks' gestation in twin pregnancies.

The purpose of this study was to determine the influence of change in infant birth weight between pregnancies on the outcome of a trial of labor for women whose first cesarean delivery was performed for dystocia.Secondary analysis of 7081 patients with 1 previous cesarean delivery and no other deliveries after 20 weeks' gestation, undergoing a trial of labor with a singleton gestation. Cases were classified as dystocia if the listed indication for the cesarean delivery in the first pregnancy was failed induction, cephalo-pelvic disproportion, failure to progress, or failed forceps or vacuum. Outcomes of the trial of labor were correlated with fetal size relative to birth weight in the initial pregnancy for those women whose initial cesarean delivery was for dystocia and those with other indications.For the cohort being studied (n = 7081), dystocia was the indication for the first cesarean delivery for 3182 (44.9%). Trial of labor resulted in vaginal delivery for 54% of patients whose first cesarean delivery was performed for dystocia, compared with 67% for those with other indications (P.01). For those whose first cesarean delivery was for dystocia, trial of labor success was correlated with birth weight differences between the pregnancies, with only 38% delivering vaginally if the trial of labor birth weight exceeded the initial pregnancy birth weight by more than 500 g. Using logistic regression and adjusting for other potential confounding factors, the odds of success decreased by 3.8% for each increase of 100 g in birth weight in the trial of labor relative to the first birth weight.For women with previous cesarean delivery for dystocia, increasing birth weight in the subsequent trial of labor relative to the first birth weight diminishes the chances of successful vaginal delivery.

Objective This study was undertaken to compare success rates of vaginal birth after cesarean (VBAC) delivery, and uterine rupture as well as maternal/perinatal outcomes between women with preterm and term pregnancies undergoing trial of labor (TOL), and to compare maternal and neonatal morbidities in those women with preterm pregnancies undergoing a TOL versus repeat cesarean delivery without labor (RCD). Study design Prospective 4-year observational study of women with a singleton gestation and a prior cesarean delivery at 19 academic centers. Clinical characteristics, maternal complications and VBAC delivery success for those with a preterm (24 0 -36 6 weeks) TOL, preterm RCD and term TOL (≥37 weeks) were analyzed. Results Among 3119 preterm pregnancies with prior cesarean delivery, 2338 (75%) underwent a TOL. 15,331 women undergoing TOL at term were also analyzed as a control group. TOL success rates for preterm and term pregnancies were similar (72.8% vs 73.3%, P = .64). Rates of uterine rupture (0.34% vs 0.74%, P = .03) and dehiscence (0.26% vs 0.67%, P = .02) were lower in preterm compared with term TOL. Thromboembolic disease, coagulopathy and transfusion were more common in women undergoing a preterm TOL than those at term. Among women undergoing a preterm TOL, rates of uterine dehiscence, coagulopathy, transfusion, and endometritis were similar to those having a preterm RCD. After controlling for gestational age at delivery and race, neonatal outcomes such as Neonatal Intensive Care Unit (NICU) admission, intraventricular hemorrhage, sepsis, and ventilatory support were similar in both groups except for a higher rate of respiratory distress syndrome in those delivered after a TOL. Conclusion The likelihood of VBAC success after TOL in preterm pregnancies is comparable to term gestations, with a lower risk of uterine rupture. Perinatal outcomes are similar with preterm TOL and RCD. TOL should be considered as an option for women undergoing preterm delivery with a history of prior cesarean delivery.

Objective The objective of the study was to estimate whether midpregnancy genitourinary tract infection with Chlamydia trachomatis is associated with an increased risk of subsequent preterm delivery. Study design Infection with C. trachomatis was determined using a ligase chain reaction assay (performed in batch after delivery) of voided urine samples collected at the randomization visit (16 0/7 to 23 6/7 weeks' gestation) and the follow-up visit (24 0/7 to 29 6/7 weeks) among 2470 gravide women with bacterial vaginosis or Trichomonas vaginalis infection enrolled in 2 multicenter randomized antibiotic treatment trials (metronidazole versus. placebo). Results The overall prevalence of genitourinary tract C. trachomatis infection at both visits was 10%. Preterm delivery less than 37 weeks' or less than 35 weeks' gestational age was not associated with the presence or absence of C. trachomatis infection at either the randomization (less than 37 weeks: 14% versus 13%, P =.58; less than 35 weeks: 6.4% versus 5.5%, P =.55) or the follow-up visit (less than 37 weeks: 13% versus 11%, P =.33; less than 35 weeks: 4.4% versus 3.7, P =.62). Treatment with an antibiotic effective against chlamydia infection was not associated with a statistically significant difference in preterm delivery. Conclusion In this secondary analysis, midtrimester chlamydia infection was not associated with an increased risk of preterm birth. Treatment of chlamydia was not associated with a decreased frequency of preterm birth.

The purpose of this study was to examine the utility of a single second-trimester plasma corticotropin-releasing hormone measurement as a marker for preterm delivery in women at high risk for preterm delivery.This is an analysis of data from a multicenter placebo-controlled trial designed to evaluate the role of 17 alpha hydroxyprogesterone caproate (17P) in the prevention of recurrent preterm birth. Women with a documented history of a previous spontaneous preterm birth at37 weeks were enrolled (16-20 wks) and randomly assigned in a 2 to 1 ratio to weekly injections of 17P or matching placebo. Blood was collected before treatment in 170 patients (113 assigned 17P and 57 placebo) who were enrolled at 11 of the 19 centers. Plasma levels of corticotropin-releasing hormone were compared between those who delivered preterm and those delivering at term. Data were analyzed using the Wilcoxon rank-sum test.The overall rates of preterm birth in this cohort of 170 patients were 35.9% at37 weeks (31.9% progesterone, 43.9% placebo), and 19.4% at35 weeks (18.6% vs 21.1%). The median levels of corticotropin-releasing hormone were similar between those delivering at37 weeks and those deliveringor = 37 weeks (0.39 ng/mL vs 0.37 ng/mL, P = .08). In addition, there were no differences in corticotropin-releasing hormone levels among those who delivered at35 weeks oror = 35 weeks (0.36 vs 0.38, P = .90). Moreover, there were no differences in corticotropin-releasing hormone levels among those in the placebo group who delivered at37 oror = 37 weeks (0.40 vs 0.41, P = .72) and at35 oror = 35 weeks (P = .64).A single measurement of corticotropin-releasing hormone at 16 to 20 weeks' gestation is not a good biomarker for recurrent preterm delivery in patients at high risk for this complication.

Objective The purpose of this study was to define independent risk factors for uterine atony after primary cesarean delivery, and to assess their overall association with atony in the study cohort. Study design This was a 13–university center prospective observational study. All women who underwent primary cesarean from January 1, 1999 to December 31, 2000 were eligible. Trained and certified research nurses performed systematic data abstraction. The definition of atony required both the clinical diagnosis and the use of methergine or a prostaglandin preparation. Risk factors for uterine atony were assessed in univariable and multivariable logistic regression analyses, and these analyses then used to inform an assessment of the association of the various risk factors with the occurrence of uterine atony in the overall cohort. Results Twenty-three thousand, three hundred and ninety pregnancies were analyzed. Uterine atony occurred in 1416 women (6%). Several variables were independently associated with atony in a multivariable model, including multiple gestation (odds ratio [OR] 2.40, 95% CI 1.95-2.93), maternal Hispanic race (2.21, 1.90-2.57), induced or augmented labor for >18 hours (2.23, 1.92-2.60), infant birth weight >4500 g (2.05, 1.53-2.69), and clinically diagnosed chorioamnionitis (1.80, 1.55-2.09). However, because the various risk factors were not very powerful, approximately half of the cases of atony were associated with the 2/3 of women lacking a given risk factor or combination of risk factors. Conclusion Although certain risk factors and uterine atony were clearly associated, the associations are of limited practical clinical use.

Objective The purpose of this study was to determine whether drug metabolism (CYP1A2, CYP2D6 and CYP3A) activity varies in the pregnant state compared with the nonpregnant state. Study design Subjects were studied at 14 to18 weeks of gestation, 24 to 28 weeks of gestation, and 36 to 40 weeks of gestation and again at 6 to 8 weeks after the delivery. Twenty-five subjects completed all 4 study periods and had evaluable data. Salivary caffeine clearance was used as a measure of CYP1A2 activity; dextromethorphan O- and N-demethylation were used to assess CYP2D6 and CYP3A activity, respectively. Results CYP1A2 activity was significantly reduced at all periods of the pregnancy as compared with the postpartum period during the first (−32.8% ± 22.8%), second (−48.1% ± 27%), and third periods (−65.2% ± 15.3%), respectively. In contrast, CYP2D6 activity was increased significantly throughout the pregnancy (25.6% ± 58.3% at 14-18 weeks of gestation, 34.8% ± 41.4% at 24-28 weeks of gestation, and 47.8% ± 24.7% at 36-40 weeks of gestation) as compared with the postpartum period. CYP3A activity was consistently, significantly increased (35%-38%) during all stages of the pregnancy. Conclusion Opposing changes in drug metabolism occur during pregnancy, with CYP1A2 activity decreased and CYP2D6 and CYP3A activities increased. The direction of dosing adjustments during pregnancy will depend on the drug and the enzyme that is responsible for its metabolism.

Objective The purpose of this study was to determine the association of vaginal pH ≥5.0 and vaginal neutrophils >5 per oil field with preterm rupture of membranes (PPROM). Study design This was a secondary analysis of the Vaginal Infections and Prematurity cohort, and was comprised of 12,734 evaluable women enrolled between 23 and 26 weeks' gestation. Women were tested for sexually transmitted infections and vaginal pH. Gram-stained smears were used for the detection of neutrophils. Results In this analysis, 5751 (41.3%) women had neutrophils >5 per oil field, and 2500 (18.0%) had pH ≥5.0. Both elevated pH and neutrophils were present in 1149 women (8.3%). The concomitant presence of both neutrophils and elevated pH was significantly associated with PPROM at 24 to 32 weeks. Conclusion Elevated vaginal pH and neutrophils are most strongly associated with early third-trimester PPROM, reflecting the importance of infection and/or inflammation in the pathogenesis of this condition.

The purpose of this study was to compare the frequency of uterine contractions in asymptomatic pregnant women with and without a short cervix (25 mm) on transvaginal ultrasound (TVU) and to determine the additive risk of contractions on the risk of preterm birth.The study involved secondary analysis of a blinded observational study of asymptomatic singleton pregnancies who were at high risk for preterm birth and who received both home uterine activity monitoring daily and transvaginal ultrasound of the cervix at 22 to 24 and 27 to 28 weeks of gestation. Thresholds for the maximum frequency of uterine contractions of 4 per hour and transvaginal ultrasound cervical length of 25 mm were used for analysis. Contraction frequency was compared in women with cervical length25 mm andor =25 mm and was correlated with the risk of spontaneous preterm birth at35 weeks of gestation.Of the 303 women whose pregnancy was evaluated at 22 to 24 weeks of gestation, the 39 women (13%) with a cervical length of25 mm had 1.6 +/- 2.7 versus 1.2 +/- 2.0 contractions per hour in the 264 women (87%) with a cervical length ofor =25 mm (P=.37). At 27 to 28 weeks of gestation (n=295 women), contraction frequency was 3.2 +/- 3.7 versus 2.8 +/- 3.1 contractions per hour in women with a cervical length of25 mm (n=59 women; 20%) versus those with a cervical length ofor =25 mm (n=236 women; 80%; P=.34). Among women with a short cervix, the relative risks for spontaneous preterm birth were 2.0 (95% CI, 0.95-4.2) and 2.1 (95% CI, 1.06-4.3) for women withor =4 contractions per hour compared with women with4 contractions per hour at 22 to 24 and 27 to 28 weeks of gestation, respectively. Results were confirmed by logistic regression analysis.The frequency of uterine contractions in asymptomatic women was not related significantly to cervical length of25 mm versusor =25 mm. Among women with a cervical length of25 mm at 22 to 24 or 27 to 28 weeks of gestation, there was a trend toward a 2-fold increased risk of spontaneous preterm birth when the maximum contraction frequency wasor =4 per hour, compared to4 per hour.

The purpose of this study was to evaluate the relationship between chorioamnionitis and its duration to adverse maternal, fetal, and neonatal outcomes.This was a 13-university center, prospective observational study. All women at term carrying a singleton gestation who underwent primary cesarean from January 1, 1999 to December 31, 2000 were eligible. Data abstraction was systematic and performed by trained research nurses. Selected adverse outcomes were compared between pregnancies with, and without, clinically diagnosed chorioamnionitis using relative risks (RRs) and 95% CIs. The duration of chorioamnionitis was stratified into 5 intervals (or=3 h,3-6 h,6-9 h,9-12 h, and12 h), and respective outcomes compared by Mantel-Haenszel test for trend. Additionally, regression analysis was used to compute odds ratios (ORs) and 95% CIs for chorioamnionitis duration length as a continuous explanatory variable.16,650 pregnancies were analyzed, 1965 (12%) with chorioamnionitis, which was associated with significantly increased risks of maternal blood transfusion, uterine atony, septic pelvic thrombophlebitis, and pelvic abscess (RR 2.3-3.7), as well as 5-minute Apgaror=3, neonatal sepsis, and seizures (RR 2.1-2.8). By test of trend, only uterine atony (P.01), maternal blood transfusion (P=.03), maternal admission to intensive care unit (P=.02), and 5-minute Apgaror=3 (P.01) were associated with duration of chorioamnionitis. By logistic analysis, only uterine atony (OR for each hour of chorioamnionitis 1.03, 95% CI 1.00-1.06), 5-minute Apgaror=3 (OR 1.09, 95% CI 1.00-1.16), and neonatal mechanical ventilation within 24 hours of birth (OR 1.07, 95% CI 1.01-1.12) were significantly associated with chorioamnionitis duration.Chorioamnionitis was associated with increased rates of morbidity after cesarean at term. The duration of chorioamnionitis, however, was not related to most measures of adverse maternal or fetal-neonatal outcome.

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 of190 mg/24 hours.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 with190 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/=500 mg protein/24 hours (n=65). The rate of preeclampsia, according to strict predefined criteria, was then determined.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 of190 mg/24 hours (16/94 women; 17%).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 of190 mg/24 hours.

Objective The purpose of this study was to determine the association of vaginal pH≥5.0 and vaginal neutrophils >5 per oil-field with early preterm birth. Study design This is a secondary analysis of the vaginal infections and prematurity cohort comprised of 13,917 women at 23 and 26 weeks of gestation. All women were tested for sexually transmitted infections and vaginal pH. Gram-stained smears were used for the detection of neutrophils. Results There were 5751 women (41.3%) with neutrophils >5 per oil-field and 2500 women (18.0%) with pH≥5.0. Both elevated pH and neutrophils were present in 1149 women (8.3%). Neutrophils and pH were each significantly associated with spontaneous preterm birth, and the point estimate of the strength of that association increased as the gestational age at delivery decreased. Conclusion Elevated vaginal pH and neutrophils are associated most strongly with the earliest preterm births.

High levels of a number of analytes are found in maternal blood; alkaline phosphatase,alpha-fetoprotein, and corticotropin-releasing hormone have been associated with spontaneous preterm birth. We investigated the relationship between 8 potential blood markers and subsequent spontaneous preterm birth in asymptomatic pregnant women.We performed a nested case control study that involved 127 women who were enrolled in the preterm prediction study and who had a singleton spontaneous preterm birth at35 weeks and 127 women who had a term birth and served as matched (age, parity, center) controls. Serum that was collected at 24 and 28 weeks was analyzed for alkaline phosphatase, alpha-fetoprotein, corticotropin-releasing hormone, and 5 other analytes.Alkaline phosphatase, alpha-fetoprotein, and corticotropin-releasing hormone, but not other analytes, were significantly elevated in pregnancies that ended in spontaneous preterm birth. For alkaline phosphatase at 24 weeks, the odds ratio for spontaneous preterm birth at32 weeks was 6.8 (range, 1.4-32.8) and for spontaneous preterm birth at35 weeks 5.1 (range, 1.7-15.6). Similar results were found at 28 weeks. For alpha-fetoprotein at 24 weeks, the odds ratio for spontaneous preterm birth at32 weeks was 8.3 (range,2.2-30.9) and for spontaneous preterm birth at35 weeks was 3.5 (range, 1.8-6.7). The levels at 28 weeks were still predictive but less so than at 24 weeks. Corticotropin-releasing hormone, at 28 weeks but not at 24 weeks, was predictive for spontaneous preterm birth at35 weeks, with an odds ratio 3.4 (range, 1.0-10.9).Elevated alkaline phosphatase and alpha-fetoprotein are associated with subsequent spontaneous preterm birth in asymptomatic pregnant women at 24 and 28 weeks. Elevated corticotropin-releasing hormone levels at 28 weeks are associated with spontaneous preterm birth at35 weeks.

OBJECTIVE: Low serum ferritin levels correlate with low iron stores, whereas high levels are associated with an acute-phase reaction. Our objective was to determine whether elevated levels of ferritin in the genital tract may be a potent marker to identify patients at risk for spontaneous preterm delivery. STUDY DESIGN: We performed a nested case-control study involving 182 women who had spontaneous preterm delivery and 182 term control subjects matched for race, parity, and recruitment center, and selected from 2929 women enrolled in the Preterm Prediction Study of the National Institute of Child Health and Development Maternal-Fetal Medicine Units Network. Cervical fluid ferritin was measured by use of radioimmunoassay. RESULTS: Cervical ferritin levels were significantly higher in women who subsequently had spontaneous early preterm delivery ( P =.002; and P =.004) than in term controls. A cervical ferritin of >75th percentile in the controls (>35.5 ng/mL) was found in 52.9% (9/17) of the women delivered CONCLUSIONS: Elevated cervical ferritin levels at 22 to 24 weeks of gestation in asymptomatic women are associated with subsequent spontaneous preterm birth. The strong correlation of cervical ferritin with other inflammatory markers provides support for the hypothesis of infection as a mediator of preterm delivery. (Am J Obstet Gynecol 2002;186:458-63.)

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

Background Opioid use disorder among pregnant women is associated with adverse perinatal outcomes and is increasing in the United States. The standard of care for pregnant women with opioid use disorder is opioid maintenance therapy including either methadone or buprenorphine, which can be initiated at any time during pregnancy. These medications are known to cross the placenta but their placental and fetal effects have not been well characterized. Delayed villous maturation, a placental finding associated with stillbirth, was observed in placentas exposed to opioid maintenance therapy. Given the association of delayed villous maturation with stillbirth, and the possible relationship between opioid maintenance therapy and delayed villous maturation, this study was undertaken to explore the association between opioid maintenance therapy and this placental finding. Delayed villous maturation was not previously reported in placentas exposed to opioids or opioid maintenance therapy. Objective This study sought to compare risk of delayed villous maturation in term placentas exposed and unexposed to opioid maintenance therapy with buprenorphine or methadone. Study Design This was a retrospective cohort study conducted between 2010 through 2012 at Magee-Womens Hospital comparing delayed villous maturation in placentas of women with opioid use disorder exposed to either buprenorphine (n = 86) or methadone (n = 268) versus women without opioid use disorder (n = 978). Potential covariates were assessed in univariate analyses with none significantly associated with delayed villous maturation. The final model used conditional logistic regression adjusting for smoking status alone. Results Among women without opioid use disorder (and therefore not exposed to opioid maintenance therapy), delayed villous maturation was identified in 5.7% of placentas while the prevalence among women treated with buprenorphine or methadone was 8.1% and 10.8%. Overall, the crude odds of being diagnosed with delayed villous maturation were significantly greater in those exposed to opioid maintenance therapy compared to those not exposed (odds ratio, 1.86; 95% confidence interval, 1.20–2.89). When considered separately, women treated with methadone had significantly greater odds of having a placenta with delayed villous maturation than women without exposure to opioid maintenance therapy (odds ratio, 2.00; 95% confidence interval, 1.52–3.20). Women treated with buprenorphine did not have significantly greater odds of this placental diagnosis when compared to the women unexposed to opioid maintenance therapy (odds ratio, 1.46; 95% confidence interval, 0.64–3.31). Results were similar after accounting for smoking. Conclusion Delayed villous maturation was more common in the placentas of women exposed to opioid maintenance therapy. Further studies are required to characterize rates and extent of delayed villous maturation in the general population as well as to differentiate between possible effects of opioid exposure (eg, heroin, illicit use of prescription opioids) vs those of opioid maintenance therapy (buprenorphine and methadone).

Objective: The Preterm Prediction Study evaluated 28 potential biologic markers for spontaneous preterm birth in asymptomatic women at 23 to 24 weeks gestational age. This analysis compares those markers individually and in combination for an association with spontaneous preterm birth at Study Design: With the use of a nested case-control design from an original cohort study of 2929 women, results of tests from 50 women with a spontaneous preterm birth at Results: In the univariate analysis, the most potent markers that are associated with spontaneous preterm birth at 90th percentiles of α-fetoprotein (odds ratio, 8.3) and alkaline phosphatase (odds ratio, 6.8), and >75th percentile of granulocyte colony-stimulating factor (odds ratio, 5.5). Results for spontaneous preterm birth at P Conclusion: Overlap among the strongest biologic markers for spontaneous preterm birth is small. This suggests that the use of tests such as maternal serum α-fetoprotein, alkaline phosphatase, and granulocyte colony-stimulating factor as a group or adding their results to fetal fibronectin test and cervical length test results may enhance our ability to predict spontaneous preterm birth and that the development of a multiple-marker test for spontaneous preterm birth is feasible. (Am J Obstet Gynecol 2001;185:643-51.)

Objective: The aim of this study was to determine whether positive results of tests for any of 5 antiphospholipid antibodies are associated with recurrent preeclampsia among women with a history of preeclampsia in a previous pregnancy. Study Design: Second-trimester serum samples were obtained from 317 women with preeclampsia in a previous pregnancy who were being followed up in a prospective treatment trial. The serum samples were measured by enzyme-linked immunoassay for immunoglobulin G and immunoglobulin M antibodies against 5 phospholipids. Positive results were analyzed with regard to preeclampsia, severe preeclampsia, intrauterine growth restriction, and preterm delivery. Results: Sixty-two of the 317 women (20%) had recurrent preeclampsia develop, 19 (6%) had severe preeclampsia, and 18 (5.8%) were delivered of infants with growth restriction. Positive results of tests for immunoglobulin G or immunoglobulin M antiphospholipid antibodies were not associated with recurrent preeclampsia. Positive results for immunoglobulin G or immunoglobulin M antibodies at the 99th percentile were also not associated with preterm delivery. Positive results at the 99th percentile for immunoglobulin G antiphosphatidylserine antibody were associated with severe preeclampsia, and positive results at the 99th percentile for immunoglobulin G anticardiolipin, antiphosphatidylinositol, and antiphosphatidylglycerol antibodies were associated with intrauterine growth restriction. The positive predictive values for these outcomes all were approximately 30%. Conclusion: Positive results of testing for antiphospholipid antibodies in the second trimester were not associated with recurrent preeclampsia among women at risk because of a history of preeclampsia. Positive results for immunoglobulin G antiphosphatidylserine antibody were associated with severe preeclampsia, and positive results for immunoglobulin G anticardiolipin, antiphosphatidylinositol, and antiphosphatidylglycerol antibodies were associated with intrauterine growth restriction. However, the positive predictive values for all these associations were modest. Testing for antiphospholipid antibodies during pregnancy is of little prognostic value in the assessment of the risk for recurrent preeclampsia among women with a history of preeclampsia. (Am J Obstet Gynecol 2001;184:825-34.)

Half of all preterm births occur in women without clinical risk factors. Our goal was to assess fetal fibronectin assay, Bishop score, and cervical ultrasonography as screening tests to predict which low-risk pregnancies will end in preterm birth.We performed a secondary analysis of data collected at 22 to 24 weeks' gestation from low-risk subjects enrolled in the Preterm Prediction Study, an observational study of risk factors for preterm birth conducted by the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Analysis was limited to primigravid women and to women who did not have a history of preterm birth or spontaneous pregnancy loss at20 weeks' gestation. Bishop score (or =4), fetal fibronectin level (or =50 ng/mL), and cervical length (or =25 mm) at 24 weeks' gestation were evaluated alone and in sequence as tests to predict spontaneous delivery before 35 weeks' gestation.Of the 2929 subjects enrolled in the original study, 2197 (1207 primigravid women and 900 low-risk multiparous women) met criteria for this analysis. There were 64 spontaneous births before 35 weeks' gestation (3.04%). All three tests were significantly related to birth before 35 weeks' gestation (high Bishop score: relative risk, 3.6; 95% confidence interval, 2.1-6.3; fetal fibronectin detection: relative risk, 8.2; 95% confidence interval, 4.8-13.9; short cervical length: relative risk, 6.9; 95% confidence interval, 4.3-11.1). However, the sensitivities of the tests alone were low (23.4% for high Bishop score, 23.4% for fetal fibronectin detection, and 39.1% for short cervix), as were the sensitivities for Bishop score followed by cervical ultrasonography (14.1%) and fetal fibronectin assay followed by cervical scan (15.6%).In the setting of low-risk pregnancy, fetal fibronectin assay and cervical ultrasonography have low sensitivity for preterm birth before 35 weeks' gestation. Sequential screening with Bishop score or fetal fibronectin assay followed by cervical ultrasonography further decreased sensitivity to only 15% among low-risk women.

Objective: The aim of this study was to determine the interrelationship between cervical concentration of interleukin 6 and detection of fetal fibronectin and other risk factors for spontaneous preterm birth. Study Design: All patients with spontaneous preterm birth at 305 and >538 pg/mL, respectively). Results: The mean (±SD) interleukin 6 concentration was significantly higher in case patients than in control subjects (212 ± 339 vs 111 ± 186 pg/mL; P =.008). With either cutoff value elevated interleukin 6 concentration was significantly associated with spontaneous preterm birth (90th percentile, 20% vs 9.6%; P =.02; 95th percentile, 12% vs 4.8%; P =.04). Cervical interleukin 6 levels were highest within 4 weeks of delivery, and the trend continued until term. Elevated interleukin 6 concentration was not significantly associated with bacterial vaginosis, maternal body mass index

Objective: A cervicovaginal fetal fibronectin value of ≥50 ng/mL has been used to define women at risk of having a preterm birth. We evaluated the relationship between quantitative fetal fibronectin values and spontaneous preterm birth. Study Design: Cervical and vaginal specimens for fetal fibronectin were obtained at 24, 26, 28, and 30 weeks' gestation from 2926 women. Quantitative fetal fibronectin values were calculated by using absorbances determined by enzyme-linked immunosorbent assay. The highest fetal fibronectin value (cervical or vaginal) for each woman at each visit was evaluated in relation to spontaneous preterm birth at Results: The risk of spontaneous preterm birth increased as a function of increasing fetal fibronectin values from approximately 20 to 300 ng/mL. Fetal fibronectin values ≥300 ng/mL were not associated with a further increase in spontaneous preterm birth. Examination of the receiver operating characteristic curve indicates that the optimal cutoff point for a positive fetal fibronectin test result at 24 to 30 weeks' gestation to predict spontaneous preterm birth at Conclusion: Increasing levels of cervicovaginal fetal fibronectin up to 300 ng/mL are associated with an increasing risk of spontaneous preterm birth. Nevertheless, at 24 to 30 weeks, the value currently used, 50 ng of fetal fibronectin per milliliter, appears to be a reasonable cutoff point for predicting spontaneous preterm birth at

Objective: The purpose of this study was to compare the rates of indicated and spontaneous preterm delivery among women with chronic hypertension or pregestational diabetes mellitus with the rates among healthy women. Study Design: This was a secondary analysis of data from healthy women with singleton gestations enrolled in a prospective observational study for prediction of preterm delivery (control group, n=2738), women with pregestational diabetes mellitus requiring insulin therapy (n = 461), and women with chronic hypertension (n = 761). The two latter groups were enrolled in a randomized multicenter trial for prevention of preeclampsia. The main outcome measures were rates of preterm delivery, either spontaneous (preterm labor or rupture of membranes) or indicated (for maternal or fetal reasons), and neonatal outcomes. Results: The overall rates of preterm delivery were significantly higher among women with diabetes mellitus (38%) and hypertension (33.1%) than among control women (13.9%). Rates were also significantly higher for delivery at Conclusion: The increased rate of preterm delivery among women with chronic hypertension relative to control women was primarily an increase in indicated preterm delivery, whereas the rates of both spontaneous and indicated preterm delivery were increased among women with pregestational diabetes mellitus. (Am J Obstet Gynecol 2000;183:1520-4.)