Jay D. Iams

Frequency of and factors associated with severe maternal morbidity

OBJECTIVE: To estimate the frequency of severe maternal morbidity, assess its underlying etiologies, and develop a scoring system to predict its occurrence. Supplemental Digital Content is Available in the Text. METHODS: This was a secondary analysis of a Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network cohort of 115,502 women and their neonates born in 25 hospitals across the United States over a 3-year period. Women were classified as having severe maternal morbidity according to a scoring system that takes into account the occurrence of red blood cell transfusion (more than three units), intubation, unanticipated surgical intervention, organ failure, and intensive care unit admission. The frequency of severe maternal morbidity was calculated and the underlying etiologies determined. Multivariable analysis identified patient factors present on admission that were independently associated with severe maternal morbidity; these were used to develop a prediction model for severe maternal morbidity. RESULTS: Among 115,502 women who delivered during the study period, 332 (2.9/1,000 births, 95% confidence interval 2.6–3.2) experienced severe maternal morbidity. Postpartum hemorrhage was responsible for approximately half of severe maternal morbidity. Multiple patient factors were found to be independently associated with severe maternal morbidity and were used to develop a predictive model with an area under the receiver operating characteristic curve of 0.80. CONCLUSION: Severe maternal morbidity occurs in approximately 2.9 per 1,000 births, is most commonly the result of postpartum hemorrhage, and occurs more commonly in association with several identifiable patient characteristics. LEVEL OF EVIDENCE: II

Neonatal outcomes in twin pregnancies delivered moderately preterm, late preterm, and term

We compared neonatal outcomes in twin pregnancies following moderately preterm birth (MPTB), late preterm birth (LPTB), and term birth. A secondary analysis of a multicenter, randomized controlled trial of multiple gestations was conducted. MPTB was defined as delivery between 32 (0)/(7) and 33 (6)/(7) weeks and LPTB between 34 (0)/(7) and 36 (6)/(7) weeks. Primary outcome was a neonatal outcome composite consisting of one or more of the following: neonatal death, respiratory distress syndrome, early onset culture-proven sepsis, stage 2 or 3 necrotizing enterocolitis, bronchopulmonary dysplasia, grade 3 or 4 intraventricular hemorrhage, periventricular leukomalacia, pneumonia, or severe retinopathy of prematurity. Among 552 twin pregnancies, the MPTB rate was 14.5%, LPTB 49.8%, and term birth rate 35.7%. The rate of the primary outcome was different between groups: 30.0% for MPTB, 12.8% for LPTB, 0.5% for term birth ( P < 0.001). Compared with term neonates, the primary neonatal outcome composite was increased following MPTB (relative risk [RR] 58.5; 95% confidence interval [CI] 11.3 to 1693.0) and LPTB (RR 24.9; 95% CI 4.8 to 732.2). Twin pregnancies born moderately and late preterm encounter higher rates of neonatal morbidities compared with twins born at term.

Failed Labor Induction Toward an Objective Diagnosis

OBJECTIVE: To evaluate maternal and perinatal outcomes in women undergoing labor induction with an unfavorable cervix according to duration of oxytocin administration in the latent phase of labor after ruptured membranes. METHODS: This was a secondary analysis of a randomized multicenter trial in which all cervical examinations from admission were recorded. Inclusion criteria: nulliparas at or beyond 36 weeks of gestation undergoing induction with a cervix of 2 cm or less dilated and less than completely effaced. The latent phase of labor was defined as ending at a cervical dilation of 4 cm and effacement of at least 90%, or at a cervical dilation of 5 cm regardless of effacement. RESULTS: A total of 1,347 women were analyzed. The overall vaginal delivery rate was 63.2%. Most women had exited the latent phase after 6 hours of oxytocin and membrane rupture (n=939; 69.7%); only 5% remained in the latent phase after 12 hours. The longer the latent phase, the lower the vaginal delivery rate. Even so, 39.4% of the 71 women who remained in the latent phase after 12 hours of oxytocin and membrane rupture were delivered vaginally. Chorioamnionitis, endometritis, or both, and uterine atony were the only maternal adverse outcomes related to latent-phase duration: adjusted odds ratios (95% confidence intervals) of 1.12 (1.07, 1.17) and 1.13 (1.06, 1.19), respectively, for each additional hour. Neonatal outcomes were not related to latent-phase duration. CONCLUSION: Almost 40% of the women who remained in the latent phase after 12 hours of oxytocin and membrane rupture were delivered vaginally. Therefore, it is reasonable to avoid deeming labor induction a failure in the latent phase until oxytocin has been administered for at least 12 hours after membrane rupture. LEVEL OF EVIDENCE: III

Preterm Prediction Study: Comparison of the Cervical Score and Bishop Score for Prediction of Spontaneous Preterm Delivery

OBJECTIVE: To prospectively compare digital cervical score with Bishop score as a predictor of spontaneous preterm delivery before 35 weeks of gestation. METHODS: Data from a cohort of 2,916 singleton pregnancies enrolled in a multicenter preterm prediction study were available. Patients underwent digital cervical examinations at 22–24 and 26–29 weeks of gestation for calculation of Bishop score and cervical score. Relationships between Bishop score, cervical score, and spontaneous preterm delivery were assessed with multivariable logistic regression analysis, McNemar test, and receiver operating characteristic (ROC) curves to identify appropriate diagnostic thresholds and predictive capability. RESULTS: One hundred twenty-seven of 2,916 patients (4.4%) undergoing cervical examination at 22–24 weeks had a spontaneous preterm delivery before 35 weeks. Eighty-four of the 2,538 (3.3%) reexamined at 26–29 weeks also had spontaneous preterm delivery. Receiver operating characteristic curves indicated that optimal diagnostic thresholds for Bishop score were at least 4 at 22–24 weeks, at least 5 at 26–29 weeks, and less than 1.5 at both examinations for cervical score. At 22–24 weeks, areas under the ROC curve favored Bishop score. At 26–29 weeks, there was no significant difference in areas under the ROC curve; however, a cervical score less than 1.5 (sensitivity 35.7%, false positive rate 4.8%) was superior to a Bishop score of 5 or more (P<.001). CONCLUSION: Both cervical evaluations are associated with spontaneous preterm delivery in a singleton population; however, predictive capabilities for spontaneous preterm delivery were modest among women with low event prevalence. Although Bishop score performed better in the mid trimester, by 26–29 weeks a cervical score less than 1.5 was a better predictor of spontaneous preterm delivery before 35 weeks than a Bishop score of at least 5. LEVEL OF EVIDENCE: II

Activity restriction among women with a short cervix.

OBJECTIVE: To estimate determinants of and outcomes associated with activity restriction among women with a short cervix. METHODS: This was a secondary analysis of a randomized trial of 17-&agr; hydroxyprogesterone caproate for prevention of preterm birth among nulliparous women with singleton gestations and cervices less than 30 mm by midtrimester ultrasonography. Women were asked weekly whether they had been placed on pelvic, work, or nonwork rest. “Any activity restriction” was defined as being placed on any type of rest. Factors associated with any activity restriction were determined and the association between preterm birth and activity restriction was estimated with multivariable logistic regression. RESULTS: Of the 657 women in the trial, 646 (98%) responded to questions regarding activity restriction. Two hundred fifty-two (39.0%) were placed on any activity restriction at a median of 23.9 weeks (interquartile range 22.6–27.9 weeks). Women on activity restriction were older, more likely to have private insurance, less likely to be Hispanic, had a shorter cervical length, and were more likely to have funneling and intra-amniotic debris. Preterm birth at less than 37 weeks of gestation was more common among women placed on activity restriction (37% compared with 17%, P<.001). After controlling for potential confounding factors, preterm birth remained more common among those placed on activity restriction (adjusted odds ratio 2.37, 95% confidence interval 1.60–3.53). Results were similar for preterm birth at less than 34 weeks of gestation. CONCLUSION: Activity restriction did not reduce the rate of preterm birth in asymptomatic nulliparous women with a short cervix. LEVEL OF EVIDENCE: II

Maternal 25-Hydroxyvitamin D and Preterm Birth in Twin Gestations

OBJECTIVE: To assess whether there was an independent association between maternal 25-hydroxyvitamin D concentrations at 24–28 weeks of gestation and preterm birth in a multicenter U.S. cohort of twin pregnancies. METHODS: Serum samples from women who participated in a clinical trial of 17 &agr;-hydroxyprogesterone caproate for the prevention of preterm birth in twin gestations (2004–2006) were assayed for 25-hydroxyvitamin D concentrations using liquid chromatography tandem mass spectrometry (n=211). Gestational age was determined early in pregnancy using a rigorous algorithm. Preterm birth was defined as delivery of the first twin or death of either twin at less than 35 weeks of gestation. RESULTS: The mean serum 25-hydroxyvitamin D concentration was 82.7 nmol/L (standard deviation 31.5); 40.3% of women had concentrations less than 75 nmol/L. Preterm birth at less than 35 weeks of gestation occurred in 49.4% of women with 25-hydroxyvitamin D concentrations less than 75 nmol/L compared with 26.2% among those with concentrations of 75 nmol/L or more (P<.001). After adjustment for maternal race and ethnicity, study site, parity, prepregnancy body mass index, season, marital status, education, gestational age at blood sampling, smoking status, and 17 &agr;-hydroxyprogesterone caproate treatment, maternal 25-hydroxyvitamin D concentration of 75 nmol/L or more was associated with a 60% reduction in the odds of preterm birth compared with concentrations less than 75 nmol/L (adjusted odds ratio [OR] 0.4, 95% confidence interval [CI] 0.2–0.8). A similar protective association was observed when studying preterm birth at less than 32 weeks of gestation (OR 0.2, 95% CI 0.1–0.6) and after confounder adjustment. CONCLUSIONS: Late second-trimester maternal 25-hydroxyvitamin D concentrations less than 75 nmol/L are associated with an increase in the risk of preterm birth in this cohort of twin pregnancies. LEVEL OF EVIDENCE: II

Use and attitudes of obstetricians toward 3 high-risk interventions in MFMU Network hospitals.

OBJECTIVE We sought to evaluate the frequency of, and factors associated with, the use of 3 evidence-based interventions: antenatal corticosteroids for fetal lung maturity, progesterone for prevention of recurrent preterm birth, and magnesium sulfate for fetal neuroprotection. STUDY DESIGN A self-administered survey was conducted from January through May 2011 among obstetricians from 21 hospitals that included 30 questions regarding their knowledge, attitudes, and practice of the 3 evidence-based interventions and the 14-item short version of the Team Climate for Innovation survey. Frequency of use of each intervention was ascertained from an obstetrical cohort of women between January 2010 and February 2011. RESULTS A total of 329 obstetricians (74% response rate) who managed 16,946 deliveries within the obstetrical cohort participated in the survey. More than 90% of obstetricians reported that they incorporated each intervention into routine practice. Actual frequency of administration in women eligible for the treatments was 93% for corticosteroids, 39% for progesterone, and 71% for magnesium sulfate. Provider satisfaction with quality of treatment evidence was 97% for corticosteroids, 82% for progesterone, and 57% for magnesium sulfate. Obstetricians perceived that barriers to treatment were most frequent for progesterone (76%), 30% for magnesium sulfate, and 17% for corticosteroids. Progesterone use was more frequent among patients whose provider reported the quality of the evidence was above average to excellent compared with poor to average (42% vs 25%, respectively; P < .001), and they were satisfied with their knowledge of the intervention (41% vs 28%; P = .02), and was less common among patients whose provider reported barriers to hospital or pharmacy drug delivery (31% vs 42%; P = .01). Corticosteroid administration was more common among patients who delivered at hospitals with 24 hours a day-7 days a week maternal-fetal medicine specialist coverage (93% vs 84%; P = .046), CONCLUSION: Obstetricians in Maternal-Fetal Medicine Units Network hospitals frequently use these evidence-based interventions; however, progesterone use was found to be related to their assessment of evidence quality. Neither progesterone nor the other interventions were associated with overall climate of innovation within a hospital as measured by the Team Climate for Innovation. National Institutes of Health Consensus Conference Statements may also have an impact on use; there is such a statement for antenatal corticosteroids but not for progesterone for preterm prevention or magnesium sulfate for fetal neuroprotection.

Absence of Mitochondrial Progesterone Receptor Polymorphisms in Women With Spontaneous Preterm Birth

Objective: The truncated mitochondrial progesterone receptor (PR-M) is homologous to nuclear PRs with the exception of an amino terminus hydrophobic membrane localization sequence, which localizes PR-M to mitochondria. Given the matrilineal inheritance of both spontaneous preterm birth (SPTB) and the mitochondrial genome, we hypothesized that (a) PR-M is polymorphic and (b) PR-M localization sequence polymorphisms could result in variable progesterone-mitochondrial effects and variable responsiveness to progesterone prophylaxis. Methods: Secondary analysis of DNA from women enrolled in a multicenter, prospective, study of 17 alpha-hydroxyprogesterone caproate (17OHPC) versus placebo for the prevention of recurrent SPTB. DNA was extracted from stored saliva. Results: The PR-M localization sequence was sequenced on 344 patients. Sequences were compared with the previously published 48 base-pair sequence, and all were identical. Conclusions: We did not detect genetic variation in the mitochondrial localization sequence of the truncated PR-M in a group of women at high risk for SPTB.

Association of Cervical Effacement With the Rate of Cervical Change in Labor Among Nulliparous Women.

OBJECTIVE: To assess the association of cervical effacement with the rate of intrapartum cervical change among nulliparous women. METHODS: We conducted a secondary analysis of a prospective trial of intrapartum fetal pulse oximetry. For women who had vaginal deliveries, interval-censored regression was used to estimate the time to dilate at 1-cm intervals. For each given centimeter of progressive cervical dilation, women were divided into those who had achieved 100% cervical effacement and those who had not. The analysis was performed separately for women in spontaneous labor and those who were given oxytocin. RESULTS: A total of 3,902 women were included in this analysis, 1,466 (38%) who underwent labor induction, 1,948 (50%) who underwent labor augmentation (combined for the analysis), and 488 (13%) who labored spontaneously. For women in spontaneous labor, the time to dilate 1 cm was shorter for those who were 100% effaced starting at 4 cm of cervical dilation (P=.01 to <.001). For women who received oxytocin, the time to dilate 1 cm was shorter for those who were 100% effaced throughout labor (P<.001). CONCLUSION: The rate of cervical dilation among nulliparous women is associated with not only the degree of cervical dilation, but also with cervical effacement. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00098709.

Activity restriction among women with a short cervix

Preterm birth remains a leading cause of perinatal morbidity and mortality, and prophylactic and therapeutic strategies have not reduced its frequency. Activity restriction specifically has not been beneficial and is associated with adverse social, economic, and health outcomes. This present secondary analysis of data from the Short Cervix and Nulliparity Trial was designed to estimate the determinants and outcomes of activity restriction in parturients with a short cervix. In the original randomized placebo-controlled trial, asymptomatic nulliparous women with singleton gestations and cervices of less than 30 mm received either weekly intramuscular 17-α hydroxyprogesterone caproate or placebo. During the weekly study visits, participants were asked whether pelvic rest (no sexual activity), reduction of work activity, or reduction of nonwork activity had been recommended. Women who had reductions in either pelvic, work, or nonwork activity were considered as having had “any” activity restriction. The association between activity restriction and preterm birth was determined at less than 37 and less than 34 weeks’ gestation. Multivariable analyses were performed with multiple logistic regression with odds ratios (ORs), adjusted ORs (aORs), and 95% confidence intervals (CIs) reported. All tests were 2 tailed, and P < 0.05 defined statistical significance. All analyses were performed with SAS version 9.2. Of the 657 women in the randomized trial, 646 (98%) responded to questions regarding activity restriction. Nearly 40% of women with a short cervix were placed on some activity restriction, usually in the midsecond to early third trimester, soon after the diagnosis of a short cervix was made. In 171 (68%) of 252 patients, all 3 types of activity restriction were combined. Compared with women without activity restriction, women who received recommendations for activity restriction were older (P < 0.001), more likely to have private insurance (P = 0.01), and less likely to be Hispanic white (P < 0.001); they also had shorter cervical lengths and were more likely to have cervical funneling or intra-amniotic debris. Preterm birth at less than 37 weeks’ gestation was significantly more common among women placed on any activity restriction (37% vs 17%, P < 0.001; OR, 2.91; 95% CI, 2.0–4.21). No significant interactions were found between activity restriction and treatment with 17-α hydroxyprogesterone caproate, cervical length of less than 15 mm, or gestational age at screening. After controlling for treatment group and demographic and ultrasonographic differences among those with and without activity restriction, preterm birth at less than 37 or less than 34 weeks’ gestation remained significantly more common among those placed on any activity restriction (aOR, 2.37; 95% CI 1.60–3.53 and aOR, 2.28, 95% CI, 1.36–3.80, respectively). Results were similar when only women prescribed limitation of work and nonwork activities were included in the restriction group (<37 weeks’ gestation: aOR, 2.44; 95% CI, 1.63–3.65; <34 weeks gestation: aOR, 2.70; 95% CI, 1.62–4.52). Some form of activity restriction was prescribed for more than 1 in every 3 nulliparous women with a short cervix. Activity restriction affected patients’ work and home life, and yet, they were still significantly more likely to deliver preterm. Activity restriction has been associated with increased stress and anxiety and increased chances of venous thromboembolism, bone loss, deconditioning, and financial difficulties. These complications and risk of preterm birth suggest that this intervention should be proven beneficial before it is used routinely for preterm birth prophylaxis.