Richard K. Silver

Multicenter randomized trial of cerclage for preterm birth prevention in high-risk women with shortened midtrimester cervical length

OBJECTIVE The objective of the study was to assess cerclage to prevent recurrent preterm birth in women with short cervix. STUDY DESIGN Women with prior spontaneous preterm birth less than 34 weeks were screened for short cervix and randomly assigned to cerclage if cervical length was less than 25 mm. RESULTS Of 1014 women screened, 302 were randomized; 42% of women not assigned and 32% of those assigned to cerclage delivered less than 35 weeks (P = .09). In planned analyses, birth less than 24 weeks (P = .03) and perinatal mortality (P = .046) were less frequent in the cerclage group. There was a significant interaction between cervical length and cerclage. Birth less than 35 weeks (P = .006) was reduced in the less than 15 mm stratum with a null effect in the 15-24 mm stratum. CONCLUSION In women with a prior spontaneous preterm birth less than 34 weeks and cervical length less than 25 mm, cerclage reduced previable birth and perinatal mortality but did not prevent birth less than 35 weeks, unless cervical length was less than 15 mm.

Comparative trial of prednisone plus aspirin versus aspirin alone in the treatment of anticardiolipin antibody-positive obstetric patients

OBJECTIVE We compared the use of aspirin alone with combined therapy (prednisone plus aspirin) in antiphospholipid antibody-positive obstetric patients with prior adverse pregnancy outcome. STUDY DESIGN Thirty-nine patients meeting specific laboratory and clinical inclusion criteria were randomized to receive either combined therapy (prednisone plus low-dose aspirin, n = 17) or aspirin alone (n = 22). The daily aspirin dose was 81 mg; prednisone was begun at 20 mg/day and increased or decreased on the basis of observed changes in serial antibody levels. Perinatal outcomes were compared between groups. Evaluation of treatment-related maternal complications and serial antibody titers was also accomplished. RESULTS Thirty-four randomized subjects were evaluable (prednisone plus low-dose aspirin, n = 12 vs aspirin only, n = 22); no perinatal losses were observed in the study cohort. Preterm delivery was experienced by significantly more patients receiving prednisone plus low-dose aspirin than aspirin only (8/12 vs 3/22, respectively; p = 0.003), and prednisone exposure appeared to be an independent risk factor for preterm birth. CONCLUSIONS The use of prednisone therapy in conjunction with low-dose aspirin does not appear to improve outcome and may provoke obstetric complications in antiphospholipid antibody-positive patients.

Immunologic studies in presumed amniotic fluid embolism

Objective To evaluate the potential role of immunologic mechanisms that involve mast cell degranulation (anaphylaxis) or complement activation in the mechanism of amniotic fluid embolism. Methods This study was a case series of nine women with presumed amniotic fluid embolism and a control group of 22 women who had normal labor. Women were from community and tertiary referral hospitals in Japan and the United States. Main outcome measures were maternal peripartum complement levels (C3 and C4), serum levels of tryptase, urinary histamine concentrations, and serum levels of a fetal antigen (sialyl Tn). Results Serum tryptase and urinary histamine measurements were negative in women with amniotic fluid embolism; seven of nine had elevated levels of fetal antigen. All eight who had serum available for testing had abnormally low levels of complement. Mean C3 level of 44.0 mg/dL and C4 level of 10.7 mg/dL were significantly lower than corresponding postpartum control values of 117.3 mg/dL and 29.4 mg/dL (P = .018 for C3, P = .012 for C4). Postpartum C3 and C4 levels decreased by 8% and 5%, respectively, compared with intrapartum values (P = .003 for C3, P = .021 for C4) but were still within normal range. Conclusion Serologic findings suggest a role for complement activation in the mechanism of amniotic fluid embolism. Laboratory data from this series did not implicate mast cell degranulation (anaphylaxis) in the pathophysiology of the disease.

Interlaboratory variation in antiphospholipid antibody testing

OBJECTIVE Because of the widespread use of antiphospholipid antibody testing in the evaluation of patients with recurrent pregnancy loss, we evaluated the consistency of results among laboratories testing for anticardiolipin antibody and the lupus anticoagulant. STUDY DESIGN A questionnaire regarding methods used and samples of blood from 20 patients were sent to five university-based and five commercial facilities for antiphospholipid antibody testing. RESULTS The responses of the participating laboratories to the questionnaires revealed significant differences in methods, standardization, and units of reporting. For anticardiolipin antibody, the number of specimens found to be positive for any isotype (immunoglobulin G, M, or A) varied considerably among laboratories, with a range of 5 to 13. All laboratories were in agreement (i.e., at least one isotype was present or all were absent) for only 5 of 20 specimens (25%). In contrast, lupus anticoagulant results were more reproducible, although one facility reported results markedly discordant from the other four laboratories. CONCLUSION These observations suggest that significant interlaboratory variation exists in antiphospholipid antibody, and particularly anticardiolipin antibody, testing and might lead to unnecessary therapeutic interventions.

Evaluation of nitric oxide as a mediator of severe preeclampsia

OBJECTIVE Our purpose was to determine whether a reduction in nitric oxide synthesis occurs in women with severe preeclampsia as a consequence of soluble serum factors. STUDY DESIGN Circulating nitrate and nitrite levels were compared between women who met standard clinical criteria for severe preeclampsia (n = 21) and maternal or gestational age-matched, normotensive, primagravid control subjects (n = 21). End-products of nitric oxide synthesis were measured from venous blood samples using nitrate reduction and chemiluminescence. To detect in vitro suppression of nitric oxide synthesis, human umbilical vein endothelial cell monolayers were grown to confluence and exposed to culture media containing 20% severe preeclamptic or control sera. Nitrate and nitrite production were compared in duplicate monolayers for each experimental condition, expressed as means +/- SEM in picomoles per 10(6) cells. Data were compared by Students t or Mann-Whitney U tests, when appropriate, along with Spearman correlations for comparisons of laboratory and clinical data. RESULTS Circulating nitrate and nitrite levels were similar in normotensive and preeclamptic cohorts (976 +/- 88 vs 1009 +/- 41 pmol/ml, respectively; p = 0.22), and no correlations between blood pressure and nitric oxide metabolite levels were observed for the control or severely preeclamptic subsets. Similar patterns of in vitro endothelial nitrite production were observed after 1-, 12-, and 24-hour incubations with 20% control or preeclamptic sera. CONCLUSIONS Circulating nitrate and nitrite levels are not reduced in patients with severe preeclampsia compared with normotensive controls, and sera from these women do not suppress endothelial cell nitric oxide synthesis in vitro.

Sequential pathways of testing after first-trimester screening for trisomy 21

OBJECTIVE: To evaluate the performance and use of second-trimester multiple-marker maternal serum screening for trisomy 21 by women who had previously undergone first-trimester combined screening (nuchal translucency, pregnancy-associated plasma protein A, and free β-hCG), with disclosure of risk estimates. METHODS: In a multicenter, first-trimester screening study sponsored by the National Institute of Child Health and Human Development, multiple-marker maternal serum screening with alpha-fetoprotein, unconjugated estriol, and total hCG was performed in 4,145 (7 with trisomy 21) of 7,392 (9 with trisomy 21) women who were first-trimester screen-negative and 180 (7 with trisomy 21) of 813 (52 with trisomy 21) who were first-trimester screen-positive. Second-trimester risks were calculated using multiples of the median and a standardized risk algorithm with a cutoff risk of 1:270. RESULTS: Among the first-trimester screen-negative cohort, 6 of 7 (86%) trisomy 21 cases were detected by second-trimester multiple-marker maternal serum screening with a false-positive rate of 8.9%. Among the first-trimester screen-positive cohort, all 7 trisomy 21 cases were also detected in the second trimester, albeit with a 38.7% false-positive rate. CONCLUSION: Our data demonstrate that a sequential screening program that provides patients with first-trimester results and offers the option for early invasive testing or additional serum screening in the second trimester can detect 98% of trisomy 21–affected pregnancies. However, such an approach will result in 17% of patients being considered at risk and, hence, potentially having an invasive test. LEVEL OF EVIDENCE: II-2

Late First-Trimester Invasive Prenatal Diagnosis: Results of an International Randomized Trial

OBJECTIVE: To assess, in a randomized trial, the safety and accuracy of amniocentesis and transabdominal chorionic villus sampling (CVS) performed at 11–14 weeks of gestation, given that this time frame is increasingly relevant to early trisomy screening. METHODS: We compared amniocentesis with CVS from 77 to 104 days of gestation in a randomized trial in a predominantly advanced maternal age population. Before randomization, the feasibility of both procedures was confirmed by ultrasonography, and experienced operators performed sampling under ultrasound guidance; conventional cytogenetic analysis was employed. The primary outcome measure was a composite of fetal loss plus preterm delivery before 28 weeks of gestation in cytogenetically normal pregnancies. RESULTS: We randomized 3,775 women into 2 groups (1,914 to CVS; 1,861 to amniocentesis), which were comparable at baseline. More than 99.6% had the assigned procedure, and 99.9% were followed through delivery. In contrast to previous thinking, in the cytogenetically normal cohort (n = 3,698), no difference in primary study outcome was observed: 2.1% (95% confidence interval 1.5, 2.8) for CVS and 2.3% (95% confidence interval, 1.7, 3.1) for amniocentesis. However, spontaneous losses before 20 weeks and procedure-related, indicated terminations combined were increased in the amniocentesis group (P = .07, relative risk 1.74). We found a 4-fold increase in the rate of talipes equinovarus after amniocentesis (P = .02) overall and in week 13 (P = .03, relative risk = 4.65), but data were insufficient to determine this risk in week 14. CONCLUSION: Amniocentesis at 13 weeks carries a significantly increased risk of talipes equinovarus compared with CVS and also suggests an increase in early, unintended pregnancy loss. LEVEL OF EVIDENCE: I

Pregnancy-associated Plasma Protein A, Free β-hcg, Nuchal Translucency, and Risk of Pregnancy Loss

OBJECTIVE: To estimate the likelihood of clinical early and late pregnancy loss as a function of first-trimester maternal serum analytes and fetal nuchal translucency measurements. METHODS: Study subjects were recruited for a National Institute of Child Health and Human Development–sponsored multicenter cohort study initially designed to study the detection of Down syndrome during the first trimester of pregnancy. The cohort consisted of women who had a live fetus between 10 and 14 weeks of gestation and had no significant vaginal bleeding. Women with prior fetal trisomy (T21/18) and those with structural or chromosomal abnormalities in the index pregnancy were excluded. First-trimester screening consisted of pregnancy-associated plasma protein A (PAPP-A), free β-hCG, and nuchal translucency. Pregnancy loss rates in women with various levels of PAPP-A, free β-hCG, or nuchal translucency (less than 1st, less than 5th, more than 95th, and more than 99th percentile) were compared with losses in women with normal values (5th to 95th percentile). RESULTS: The mean gestational age at screening of 7,932 women meeting study criteria was 12.1 weeks. Loss rates were only 0.36% at less than 20 weeks after normal free β-hCG, PAPP-A, and nuchal translucency. Conversely, low levels of PAPP-A and free β-hCG as well as increased nuchal translucency were individually associated with increased early loss. These associations persisted after controlling for maternal age and race using logistic regression analysis. CONCLUSION: Normal values of PAPP-A, free β-hCG, and nuchal translucency are associated with a very low risk of pregnancy loss at less than 20 weeks. LEVEL OF EVIDENCE: II-2

Lamellar body counts compared with traditional phospholipid analysis as an assay for evaluating fetal lung maturity

Objective To compare lamellar body counts with the lecithin/sphingomyelin ratio and phosphatidylglycerol analysis in terms of assessment of risk of respiratory distress syndrome (RDS). Methods Lamellar body counts, lecithin-sphingomyelin ratios (L/Ss), and phosphatidylglycerol levels were assessed in 1611 amniotic fluid samples obtained at four clinical sites from pregnant women whose fetuses were at risk for RDS. Cases in which delivery occurred within 72 hours of sample collection (n = 833) were analyzed. Specific cutoffs for predicting the likelihood of RDS for both the lamellar body count and the L/S had been derived previously at each of the clinical sites based on receiver operating characteristic curves using unrelated samples, whereas phosphatidylglycerol was reported as either mature (present) or immature (absent). Standard clinical and radiographic criteria were used to diagnose RDS, and the diagnosis was confirmed by review of newborn records. Results One hundred (12.0%) of the 833 infants delivered within 72 hours of sample collection developed RDS. The negative predictive value of the lamellar body count (97.7%) was similar to that of the L/S (96.8%) and slightly better than that of phosphatidylglycerol analysis (94.7%) (P = .048). The lamellar body count performed as well as phospholipid analysis irrespective of gestational age or patient population. Conclusion The lamellar body count compares favorably with traditional phospholipid analysis as an assay for assessment of fetal lung maturity. Lamellar body counts are preferable because they are faster, more objective, less labor intensive, less technique dependent, and less expensive and because they can be performed with equipment available in every hospital laboratory.

Universal perinatal depression screening in an Academic Medical Center.

OBJECTIVE: To develop a department-based program to identify and treat women at risk for perinatal depression. METHODS: Private and employed physician groups were engaged to conduct antepartum maternal depression screening using the Edinburgh Postnatal Depression Scale. A comprehensive program was established to ensure that patients identified as being at risk would receive appropriate care. The program 1) developed a network of existing community mental health providers to accommodate screen-positive referrals, 2) created a 24/7 hotline staffed by mental health workers to respond to urgent/emergent patient needs, 3) provided nursing and physician education via a comprehensive curriculum on perinatal depression, and 4) facilitated outpatient depression screening that included a centralized scoring and referral system. RESULTS: A total of 4,322 women completed 4,558 screens during the initial 24 months (June 2003–May 2005). Although initial uptake of the screening program was gradual, all 20 departmental obstetric practices were screening their patients at the end of the first year. Depression screening was accomplished between 28–32 weeks of gestation, and postpartum screening (during the 6-week postpartum visit) was subsequently added. Overall, 11.1% of women screened positive in the antenatal period, and 7.3% screened positive in the postnatal period. Three hundred three women were referred for evaluation and care. CONCLUSION: Department-based, perinatal depression screening was feasible when individual physician practices were not required to develop the infrastructure necessary to respond to at-risk patients. We believe that the provision of clinical safety nets (mental health provider network and the hotline) were essential to the universal acceptance of this program by practitioners. LEVEL OF EVIDENCE: III