Ronald J. Wapner

The relationship of the factor V Leiden mutation and pregnancy outcomes for mother and fetus.

Objective: We sought to estimate the frequency of pregnancy-related thromboembolic events among carriers of the factor V Leiden (FVL) mutation without a personal history of thromboembolism, and to evaluate the impact of maternal and fetal FVL mutation carriage or other thrombophilias on the risk of adverse outcomes. Methods: Women with a singleton pregnancy and no history of thromboembolism were recruited at 13 clinical centers before 14 weeks of gestation from April 2000 to August 2001. Each was tested for the FVL mutation, as was the resultant conceptus after delivery or after miscarriage, when available. The incidence of thromboembolism (primary outcome), and of other adverse outcomes, was compared between FVL mutation carriers and noncarriers. We also compared adverse outcomes in a secondary nested carrier-control analysis of FVL mutation and other coagulation abnormalities. In this secondary analysis, we defined carriers as women having one or more of the following traits: carrier for FVL mutation, protein C deficiency, protein S deficiency, antithrombin III deficiency, activated protein C resistance, or lupus anticoagulant-positive, heterozygous for prothrombin G20210A or homozygous for the 5,10 methylenetetrahydrofolate reductase mutations. Carriers of the FVL mutation alone (with or without activated protein C resistance) were compared with those having one or more other coagulation abnormalities and with controls with no coagulation abnormality. Results: One hundred thirty-four FVL mutation carriers were identified among 4,885 gravidas (2.7%), with both FVL mutation status and pregnancy outcomes available. No thromboembolic events occurred among the FVL mutation carriers (0%, 95% confidence interval 0–2.7%). Three pulmonary emboli and one deep venous thrombosis occurred (0.08%, 95% confidence interval 0.02–0.21%), all occurring in FVL mutation noncarriers. In the nested carrier-control analysis (n = 339), no differences in adverse pregnancy outcomes were observed between FVL mutation carriers, carriers of other coagulation disorders, and controls. Maternal FVL mutation carriage was not associated with increased pregnancy loss, preeclampsia, placental abruption, or small for gestational age births. However, fetal FVL mutation carriage was associated with more frequent preeclampsia among African-American (15.0%) and Hispanic (12.5%) women than white women (2.6%, P = .04), adjusted odds ratio 2.4 (95% confidence interval 1.0–5.2, P = .05). Conclusion: Among women with no history of thromboembolism, maternal heterozygous carriage of the FVL mutation is associated with a low risk of venous thromboembolism in pregnancy. Neither universal screening for the FVL mutation, nor treatment of low-risk carriers during pregnancy is indicated. Level of Evidence: II-2

Pregnancy outcomes with weight gain above or below the 2009 institute of medicine guidelines

OBJECTIVE: To evaluate pregnancy outcomes according to 2009 Institute of Medicine (IOM) gestational weight gain guidelines. METHODS: This study is a secondary analysis of a preeclampsia prevention trial among nulliparas carrying singletons. Odds ratios and 95% confidence intervals (adjusted for maternal age, race, smoking, and treatment group) were calculated based on total weight gain below or above the IOM guidelines stratified by prepregnancy body mass index (BMI). The referent group was weight gain within the guidelines. RESULTS: Of 8,293 pregnancies, 9.5% had weight gain below, 17.5% within, and 73% above IOM guidelines. With excess weight gain, all BMI categories had an increased risk of hypertensive disorders; normal weight and overweight women also had increased risk of cesarean delivery and neonatal birth weight at or above the 90th centile but a decreased risk of weight below the 10th centile. There were no consistent associations with insufficient weight gain and adverse outcomes. CONCLUSION: Excess weight gain was prevalent and associated with an increased risk of hypertensive disorders, cesarean delivery, and large-for-gestational-age neonates.

The relationship between maternal glycemia and perinatal outcome.

OBJECTIVE: To examine the relationship between varying degrees of maternal hyperglycemia and pregnancy outcomes. METHODS: This was a secondary analysis of a treatment trial for mild gestational diabetes including four cohorts: 1) 473 women with untreated mild gestational diabetes; 2) 256 women with a positive 50-g screen and one abnormal oral glucose tolerance test (OGTT) value; 3) 675 women with a positive screen and no abnormal OGTT values; and 4) 437 women with a normal 50-g screen. Groups were compared by test of trend for a composite perinatal outcome (neonatal hypoglycemia, hyperbilirubinemia, elevated cord C-peptide level, and perinatal trauma or death), frequency of large for gestational age neonates, shoulder dystocia, and pregnancy-related hypertension. Three-hour OGTT levels (fasting, 1-, 2-, and 3-hour) levels were divided into categories and analyzed for their relationship to perinatal and maternal outcomes. RESULTS: There were significant trends by glycemic status among the four cohorts for the composite and all other outcomes (P<.001). Analysis for trend according to OGTT categories showed an increasing relationship between fasting and all postload levels and the various outcomes (P<.05). Fasting glucose 90 mg/dL or greater and 1 hour 165 mg/dL or greater were associated with an increased risk for the composite outcome (odds ratios and 95% confidence intervals of 2.0 [1.03–4.15] and 1.46 [1.02–2.11] to 1.52 [1.08–2.15] for the fasting and 1 hour, respectively). A 1 hour glucose 150 mg/dL or greater was associated with an increased risk for large for gestational age (odds ratios, 1.8 [1.02–3.18] to 2.35 [1.35–4.14]); however, 2- and 3-hour glucose levels did not increase the risk for the composite or large for gestational age until well beyond current gestational diabetes diagnostic thresholds. CONCLUSION: A monotonic relationship exists between increasing maternal glycemia and perinatal morbidity. Current OGTT criteria require reevaluation in determining thresholds for the diagnosis and treatment of gestational diabetes. LEVEL OF EVIDENCE: II

Timing of Elective Repeat Cesarean Delivery at Term and Maternal Perioperative Outcomes

OBJECTIVE: Elective repeat cesarean delivery at 37 or 38 weeks compared with 39 completed weeks of gestation is associated with adverse neonatal outcomes. We assessed whether delivery before 39 weeks is justifiable on the basis of decreased adverse maternal outcomes. METHODS: We conducted a cohort study of women with live singleton pregnancies delivered by prelabor elective repeat cesarean delivery from 1999 through 2002 at 19 U.S. academic centers. Gestational age was examined by completed weeks (eg, 37 completed weeks=37 0/7–37 6/7 weeks). Maternal outcomes included a primary composite of death, hysterectomy, uterine rupture or dehiscence, blood transfusion, uterine atony, thromboembolic complications, anesthetic complications, surgical injury or need for arterial ligation, intensive care unit admission, wound complications, or endometritis. RESULTS: Of 13,258 elective repeat cesareans performed at 37 weeks of gestation or later, 11,255 (84.9%) were between 37 0/7 and 39 6/7 weeks (6.3% at 37, 29.5% at 38, and 49.1% at 39 completed weeks), and 15.1% were at 40 0/7 weeks or more. The primary outcome occurred in 7.43% at 37 weeks, 7.47% at 38 weeks and 6.56% at 39 weeks (P for trend test=.09). Delivery before 39 weeks was not associated with a decrease in the primary outcome when compared with delivery at 39 weeks (adjusted odds ratio 1.16; 95% confidence interval 1.00–1.34). Early delivery was associated with increased maternal hospitalization of 5 days or more [1.96 (1.54, 2.49)] but not with a composite of death or hysterectomy or with individual maternal morbidities. CONCLUSION: Elective repeat cesarean delivery at 37 or 38 weeks is not associated with decreased maternal morbidity. LEVEL OF EVIDENCE: II

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

Risk of uterine rupture and placenta accreta with prior uterine surgery outside of the lower segment

OBJECTIVE: Women with a prior myomectomy or prior classical cesarean delivery often have early delivery by cesarean because of concern for uterine rupture. Although theoretically at increased risk for placenta accreta, this risk has not been well-quantified. Our objective was to estimate and compare the risks of uterine rupture and placenta accreta in women with prior uterine surgery. METHODS: Women with prior myomectomy or prior classical cesarean delivery were compared with women with a prior low-segment transverse cesarean delivery to estimate rates of both uterine rupture and placenta accreta. RESULTS: One hundred seventy-six women with a prior myomectomy, 455 with a prior classical cesarean delivery, and 13,273 women with a prior low-segment transverse cesarean delivery were evaluated. Mean gestational age at delivery differed by group (P<.001), prior myomectomy (37.3 weeks), prior classical cesarean delivery (35.8 weeks), and low-segment transverse cesarean delivery (38.6 weeks). The frequency of uterine rupture in the prior myomectomy group (P-MMX group) was 0% (95% confidence interval [CI] 0–1.98%). The frequency of uterine rupture in the low-segment transverse cesarean delivery group (LTC group) (0.41%) was not statistically different from the risk in the P-MMX group (P>.99) or in the prior classical cesarean delivery group (PC group) (0.88%; P=.13). Placenta accreta occurred in 0% (95% CI 0–1.98%) of the P-MMX group compared with 0.19% in the LTC group (P>.99) and 0.88% in the PC group (P=.01 relative to the LTC group). The adjusted odds ratio for the PC group (relative to LTC group) was 3.23 (95% CI 1.11–9.39) for uterine rupture and 2.09 (95% CI 0.69–6.33) for accreta. The frequency of accreta for those with previa was 11.1% for the PC group and 13.6% for the LTC group (P>.99). CONCLUSION: A prior myomectomy is not associated with higher risks of either uterine rupture or placenta accreta. The absolute risks of uterine rupture and accreta after prior myomectomy are low.

Influenza-like illness in hospitalized pregnant and postpartum women during the 2009-2010 H1N1 pandemic

OBJECTIVE: To estimate characteristics and outcomes of pregnant and immediately postpartum women hospitalized with influenza-like illness during the 2009–2010 influenza pandemic and the factors associated with more severe illness. METHODS: An observational cohort in 28 hospitals of pregnant and postpartum (within 2 weeks of delivery) women hospitalized with influenza-like illness. Influenza-like illness was defined as clinical suspicion of influenza and either meeting the Centers for Disease Control and Prevention definition of influenza-like illness (fever 100.0°F or higher, cough, sore throat) or a positive influenza test. RESULTS: Of 356 women meeting eligibility criteria, 35 (9.8%) were admitted to the intensive care unit (ICU) and four (1.1%) died. Two hundred eighteen women (61.2%) were in the third trimester and 10 (2.8%) were postpartum. More than half (55.3%) were admitted in October and 25.0% in November with rapidly decreasing numbers thereafter. Antiviral therapy was administered to 10.1% of the women before hospitalization and to 88.5% during hospitalization. Factors associated with an increased likelihood of ICU admission included cigarette smoking (29.4% compared with 13.4%; odds ratio [OR] 2.77, 95% confidence interval [CI] 1.19–6.45) and chronic hypertension (17.1% compared with 3.1%; OR 6.86, 95% CI 2.19–21.51). Antiviral treatment within 2 days of symptom onset decreased the likelihood of ICU admission (31.4% compared with 56.6%, OR 0.36, 95% CI 0.16–0.77). CONCLUSION: Comorbidities, including chronic hypertension and smoking in pregnancy, increase the likelihood of ICU admission in influenza-like illness hospitalizations, whereas early antiviral treatment may reduce its frequency. LEVEL OF EVIDENCE: II

Avascular Villi, Increased Syncytial Knots, and Hypervascular Villi Are Associated with Pregnancies Complicated by Factor V Leiden Mutation

There is controversy about whether pathologic abnormalities are associated with pregnancies complicated by factor V Leiden (FVL) mutation. The purpose of this study was to evaluate 105 placentas delivered to mothers heterozygous for FVL mutation to determine if there are pathologic changes suggestive of hypoxia or thrombosis, which correlate with mutation status. We examined placentas obtained as part of a prospective study of 5188 pregnancies analyzed for the presence of FVL mutation in either the mother or the infant. One hundred five placentas from mothers heterozygous for the mutation were compared with 225 controls matched for maternal age, race, and geographic site. Of the 330 pregnancies, 50 infants were FVL mutation heterozygotes. Maternal FVL heterozygote status was associated with more frequent increased numbers of syncytial knots (13% vs 4%); the difference remained significant after controlling for hypertension, preeclampsia, small-for-gestational-age infants, and delivery prior to 35 weeks of gestation (odds ratio 3.6, 95% confidence interval 1.5−8.7, P = 0.004). Maternal FVL heterozygotes had more hypervascular villi (10% vs 3%), with significance retained controlling for delivery route (odds ratio 3.4, 95% confidence ratio 1.2–9.4, P = 0.018). Placentas from infants heterozygous for FVL mutation had more avascular villi than controls (odds ratio 2.9, 95% confidence interval 1.5–5.6, P = 0.001). Fetal or maternal FVL heterozygosity was not associated with infarcts, small-for-gestational-age placentas, or fetal thrombotic vasculopathy. This analysis demonstrates that pathologic findings associated with placental hypoxia, specifically focal avascular villi, increased numbers of syncytial knots, and hypervascular villi, also correlate with FVL heterozygosity in infants or mothers.

Relationship between 1-hour glucose challenge test results and perinatal outcomes

OBJECTIVE: To estimate the relationship between 1-hour 50 g glucose challenge test values and perinatal outcomes. METHODS: This was a secondary analysis of data from a multicenter treatment trial of mild gestational diabetes mellitus. Women with glucose challenge test values of 135–199 mg/dL completed a 3-hour oral glucose tolerance test. Mild gestational diabetes mellitus was defined as fasting glucose less than 95 mg/dL and two or more abnormal oral glucose tolerance test values: 1-hour 180 mg/dL or more; 2-hour 155 mg/dL or more; and 3-hour 140 mg/dL or more. Our study included untreated women with glucose challenge test values of 135–139 mg/dL and 140–199 mg/dL and a comparison group with values less than 120 mg/dL. Primary outcomes included a perinatal composite (stillbirth, neonatal death, hypoglycemia, hyperbilirubinemia, neonatal hyperinsulinemia, and birth trauma), large for gestational age (LGA, birth weight above the 90th percentile based on sex-specific and race-specific norms), and macrosomia (greater than 4,000 g). RESULTS: There were 436 women with glucose challenge test values less than 120 mg/dL and 1,403 with values of 135 mg/dL or more (135–139, n=135; 140–199, n=1,268). The composite perinatal outcome occurred in 25.6% of those with glucose challenge test values less than 120 mg/dL compared with 21.1% for values of 135–139 mg/dL and 35.3% for values of 140–199 mg/dL. Rates of LGA by group were 6.6%, 6.8%, and 12.4%, respectively. Rates of macrosomia by group were 7.8%, 6.1%, and 12.1%, respectively. Compared with glucose challenge test values less than 120 mg/dL, the adjusted odds ratios (ORs) (95% confidence intervals [CIs]) for values of 140–199 mg/dL were 1.48 (1.14–1.93) for the composite outcome, 1.97 (1.29–3.11) for LGA, and 1.61 (1.07–2.49) for macrosomia. For glucose challenge test values of 135–139 mg/dL, adjusted ORs and 95% CIs were 0.75 (0.45–1.21), 1.04 (0.44–2.24), and 0.75 (0.30–1.66), respectively. The subcategories with glucose challenge test values of 140–144 mg/dL and 145–149 mg/dL also were associated with an increase in selected outcomes when compared with those with values less than 120 mg/dL. CONCLUSIONS: Glucose challenge test values of 135–139 mg/dL were not associated with adverse outcomes compared with values less than 120 mg/dL; however, glucose challenge test values of 140 mg/dL or more were associated with an increase in odds of the composite perinatal outcome, LGA, and macrosomia. LEVEL OF EVIDENCE: II

Change in mononuclear leukocyte responsiveness in midpregnancy and subsequent preterm birth

OBJECTIVE: To estimate the associations of change in immune response with preterm delivery, omega-3 supplementation, and fish diet. METHODS: This was an ancillary study to a randomized trial of omega-3 fatty acid supplementation for the prevention of recurrent preterm birth. In vitro maternal peripheral blood mononuclear leukocyte production of the anti-inflammatory cytokine, interleukin-10, and the proinflammatory cytokine, tumor necrosis factor-&agr;, in response to stimulation with lipopolysaccharide, was measured at 16–22 weeks of gestation (baseline) and again at 25–28 weeks of gestation (follow-up) among women with prior spontaneous preterm birth. Changes in concentrations from baseline to follow-up ([INCREMENT]) were compared separately among groups defined by gestational age category at delivery, fish diet history, and omega-3 compared with placebo treatment assignment with Kruskal-Wallis tests. RESULTS: Interleukin-10 [INCREMENT] differed by gestational age category among 292 women with paired assays. Concentrations increased less in women delivering between 35 and 36 6/7 weeks of gestation (48.9 pg/mL) compared with women delivering at term (159.3 pg/mL) and decreased by 65.2 pg/mL in women delivering before 35 weeks of gestation (P=.01). Tumor necrosis factor-&agr; &Dgr; also differed by gestational age category among 319 women, but the pattern was inconsistent. Those delivering between 35 and 36 6/7 weeks of gestation exhibited decreased concentrations of tumor necrosis factor-&agr; at follow-up compared with baseline (−356.0 pg/mL); concentrations increased among women delivering before 35 weeks of gestation and those delivering at term, 132.1 and 86.9 pg/mL (P=.03). Interleukin-10 &Dgr; and tumor necrosis factor-&agr; &Dgr; were unaffected by either omega-3 supplementation or fish diet. CONCLUSION: Recurrent preterm birth was associated with decreased peripheral blood mononuclear leukocyte production of interleukin-10 in response to a stimulus during the second trimester. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00135902. LEVEL OF EVIDENCE: II