Maternal vitamin D status, prolonged labor, cesarean delivery and instrumental delivery in an era with a low cesarean rate.

OBJECTIVE: To examine the association between maternal 25-hydroxyvitamin D (25(OH)D) and adverse labor and delivery outcomes. STUDY DESIGN: We measured serum 25(OH)D at ⩽ 26 weeks gestation in a random subsample of vertex, singleton pregnancies in women who labored (n=2798) from the 12-site Collaborative Perinatal Project (1959 to 1966). We used labor and delivery data to classify cases of adverse outcomes. RESULT: Twenty-four percent of women were vitamin D deficient (25(OH)D <30 nmol l(-1)), and 4.5, 3.3, 1.9 and 7.5% of women had prolonged stage 1 labor, prolonged stage 2 labor, primary cesarean delivery or indicated instrumental delivery, respectively. After adjustment for prepregnancy body mass index, race and study site, 25(OH)D concentrations were not associated with risk of prolonged stage 1 or 2, cesarean delivery or instrumental delivery. CONCLUSION: Maternal vitamin D status at ⩽ 26 weeks was not associated with risk of prolonged labor or operative delivery in an era with a low cesarean rate.

Arginase I gene single-nucleotide polymorphism is associated with decreased risk of pulmonary hypertension in bronchopulmonary dysplasia.

AIM: To test the hypothesis that there are single-nucleotide polymorphisms (SNPs) in genes of the l-arginine/nitric oxide pathway associated with pulmonary hypertension (PH) in neonates with bronchopulmonary dysplasia (BPD). METHODS: Neonates with BPD were enrolled (n = 140) and clinical characteristics compared between case (BPD + PH) and control (BPD) groups. DNA was isolated from blood leucocytes and assayed for 17 SNPs in l-arginine/nitric oxide pathway genes by Sequenom massarray. Genes included carbamoyl-phosphate synthetase, ornithine transcarbamylase, argininosuccinate synthase, nitric oxide synthase and arginase. SNPs were selected from the National Center for Biotechnology Information database for their putative functionality. Calculated minor allele frequencies (MAF) of cases and controls were compared using χ2 and logistic regression. RESULTS: Of the 140 patients with BPD, 26% had echocardiographic evidence of PH. Ventilation days were longer for cases than controls (mean 31 vs. 15 days, p < 0.05). Of the 17 SNPs, rs2781666 in arginase I gene was less common in cases (MAF = 0.23) than controls (MAF = 0.37, p = 0.04). The odds of PH decreased by 43% (p = 0.047) for each copy of the SNP minor allele in arginase I gene in patients with BPD. CONCLUSION: Arginase I SNP (rs2781666) may be associated with protection against pulmonary hypertension in preterm neonates with BPD.

Bronchopulmonary dysplasia and neurodevelopmental outcome in extremely preterm neonates.

UNLABELLED: We tested the hypothesis that the use of supplemental oxygen (sO2) at discharge from the NICU in extremely preterm neonates is associated with a greater risk of neurodevelopmental impairment (NDI) at 18 months corrected gestational age (CGA) than the risk of NDI of those neonates discharged in room air. Four hundred twenty-four charts were retrospectively reviewed from infants born at <27 weeks and transferred to Nationwide Children's Hospital from December 1, 2004 to June 14, 2010. Use of sO2 was evaluated on day of life (dol) 28, at 36 weeks post-menstrual age (PMA), and at discharge. Logistic regression was used to identify postnatal risk factors associated with sO2 at discharge and NDI. At dol 28, 96 % of surviving patients received sO2, and therefore had bronchopulmonary dysplasia (BPD) by definition from a National Institutes of Child Health and Human Development workshop. At 36 weeks PMA, 89 % continued on sO2 (moderate/severe BPD), and at discharge, 74 % continued on sO2. When factors associated with NDI were examined, the need for mechanical ventilation ≥28 days (adjOR = 3.21, p = 0.01), grade III-IV intraventricular hemorrhage (IVH) (adjOR = 4.61, p < 0.01), and discharge at >43 weeks PMA (adjOR = 2.12, p = 0.04) were the strongest predictors of NDI at 18 months CGA. There was no difference in Bayley Scales of Infant Development, third edition composite scores between patients with no/mild BPD and patients with moderate/severe BPD (cognitive p = 0.60, communication p = 0.53, motor p = 0.19) or those scores between patients on and off oxygen at discharge (cognitive p = 0.58, communication p = 0.70, motor p = 0.62). CONCLUSIONS: The need for sO2 at discharge is not associated with an increased risk of NDI in these patients. The strongest predictors of poor neurodevelopmental outcome in this population were prolonged positive pressure support, grade III-IV IVH, and discharge at >43 weeks PMA.

Vitamin D status and recurrent preterm birth: a nested case-control study in high-risk women.

OBJECTIVE: To determine whether vitamin D status is associated with recurrent preterm birth, and any interactions between vitamin D levels and fish consumption. DESIGN: A nested case-control study, using data from a randomised trial of omega-3 fatty acid supplementation to prevent recurrent preterm birth. SETTING: Fourteen academic health centres in the USA. POPULATION: Women with prior spontaneous preterm birth. METHODS: In 131 cases (preterm delivery at <35 weeks of gestation) and 134 term controls, we measured serum 25-hydroxyvitamin D [25(OH)D] concentrations by liquid chromatography-tandem mass spectrometry (LC-MS) from samples collected at baseline (16-22 weeks of gestation). Logistic regression models controlled for study centre, maternal age, race/ethnicity, number of prior preterm deliveries, smoking status, body mass index, and treatment. MAIN OUTCOME MEASURES: Recurrent preterm birth at <37 and <32 weeks of gestation. RESULTS: The median mid-gestation serum 25(OH)D concentration was 67 nmol/l, and 27% had concentrations of <50 nmol/l. Serum 25(OH)D concentration was not significantly associated with preterm birth (OR 1.33; 95% CI 0.48-3.70 for lowest versus highest quartiles). Likewise, comparing women with 25(OH)D concentrations of 50 nmol/l, or higher, with those with <50 nmol/l generated an odds ratio of 0.80 (95% CI 0.38-1.69). Contrary to our expectation, a negative correlation was observed between fish consumption and serum 25(OH)D concentration (-0.18, P < 0.01). CONCLUSIONS: In a cohort of women with a prior preterm birth, vitamin D status at mid-pregnancy was not associated with recurrent preterm birth.

Maternal hormone levels among populations at high and low risk of testicular germ cell cancer.

Ethnic differences in maternal oestrogen levels have been suggested as explaining the significantly higher risk of testicular germ cell tumours (TGCT) of white men than black men in the United States. We therefore examined levels of maternal oestrogens, as well as testosterone and alphafetoprotein (AFP), in 150 black and 150 white mothers in the Collaborative Perinatal Project. Serum levels of estradiol (total, free and bioavailable), estriol, testosterone (total, free and bioavailable), sex hormone binding globulin (SHBG), and AFP were examined during first and third trimesters. We found that the black mothers, rather than the white mothers, had significantly higher estradiol levels in first trimester (P=0.05). Black mothers also had significantly higher levels of all testosterone (P<0.001) and AFP (P<0.001) in both trimesters. In addition, the ratios of sex hormones (estradiol/testosterone) were significantly lower among black mothers. These findings provide little support to the oestrogen hypothesis, but are consistent with higher levels of testosterones and/or AFP being associated with reduced risk of TGCT; alternatively, lower oestrogen/androgen ratios may be associated with reduced risk.

Poliovirus vaccination during pregnancy, maternal seroconversion to simian virus 40, and risk of childhood cancer.

Before 1963, poliovirus vaccine produced in the United States was contaminated with simian virus 40 (SV40), which causes cancer in animals. To examine whether early-life SV40 infection can cause human cancer, the authors studied 54,796 children enrolled in the US-based Collaborative Perinatal Project (CPP) in 1959-1966, 52 of whom developed cancer by their eighth birthday. Those children whose mothers had received pre-1963 poliovirus vaccine during pregnancy (22.5% of the children) had an increased incidence of neural tumors (hazard ratio = 2.6, 95% confidence interval: 1.0, 6.7; 18 cases) and hematologic malignancies (hazard ratio = 2.8, 95% confidence interval: 1.2, 6.4; 22 cases). For 50 CPP children with cancer and 200 CPP control children, the authors tested paired maternal serum samples from pregnancy for SV40 antibodies using a virus-like particle enzyme immunoassay and a plaque neutralization assay. Overall, mothers exhibited infrequent, low-level SV40 antibody reactivity, and only six case mothers seroconverted by either assay. Using the two SV40 assays, maternal SV40 seroconversion during pregnancy was not consistently related to children's case/control status or mothers' receipt of pre-1963 vaccine. The authors conclude that an increased cancer risk in CPP children whose mothers received pre-1963 poliovirus vaccine was unlikely to have been due to SV40 infection transmitted from mothers to their children.

Maternal infections and subsequent psychosis among offspring.

BACKGROUND: We tested the hypothesis that maternal infections during pregnancy are associated with the subsequent development of schizophrenia and other psychoses in adulthood. METHODS: We conducted a nested case-control study of 27 adults with schizophrenia and other psychotic illnesses and 54 matched unaffected control subjects (matched for sex, ethnicity, and date of birth) from the Providence, RI, cohort of the Collaborative Perinatal Project. We retrieved stored blood samples that had been obtained from these mothers at the end of pregnancy. These samples were analyzed for total class-specific immunoglobulins and for specific antibodies directed at recognized perinatal pathogens capable of affecting brain development. RESULTS: Maternal levels of IgG and IgM class immunoglobulins before the mothers were delivered of their neonates were significantly elevated among the case series (t = 3.06, P =.003; t = 2.93, P =.004, respectively, for IgG and IgM immunoglobulin-albumin ratios). Secondary analyses indicated a significant association between maternal antibodies to herpes simplex virus type 2 glycoprotein gG2 and subsequent psychotic illness (matched t test = 2.43, P =.02). We did not find significant differences between case and control mothers in the serum levels of IgA class immunoglobulins, or in specific IgG antibodies to herpes simplex virus type 1, cytomegalovirus, Toxoplasma gondii, rubella virus, human parvovirus B19, Chlamydia trachomatis, or human papillomavirus type 16. CONCLUSIONS: The offspring of mothers with elevated levels of total IgG and IgM immunoglobulins and antibodies to herpes simplex virus type 2 are at increased risk for the development of schizophrenia and other psychotic illnesses in adulthood.

Ethnicity, nutrition, and birth outcomes in nulliparous women.

OBJECTIVE: Ethnic differences in birth outcomes are well established, but it is not clear whether differences in nutrition may partly explain unaccounted differences in birth outcomes. Our purpose was to evaluate the relationship of nutrition to ethnic differences in birth outcomes. STUDY DESIGN: This was a multicenter, prospective study of 4589 healthy nulliparous women who were enrolled in the Calcium for Preeclampsia Prevention trial conducted from 1992 to 1995. Main outcome measures were birth weight, gestational age at delivery, preterm birth, and small for gestational age birth after the data were controlled for maternal characteristics and intake of total calories, protein, carbohydrate, fat, and 13 vitamin and mineral constituents that were obtained from a 24-hour recall at 13 to 21 weeks' gestation. RESULTS: Black and non-Hispanic white women differed significantly in birth outcomes, with odds ratios of 2.06 (95% confidence interval, 1.48-2.86) for small for gestational age and 1.38 (95% confidence interval, 0.98-1.95) for preterm birth, after adjustment for maternal characteristics. These odds ratios were hardly changed by the further adjustment for all nutritional variables, even though there were substantial nutritional differences between black and white women. Differences in birth outcomes between Hispanic and non-Hispanic white women were small. Hispanic women who spoke only Spanish were better nourished than those Hispanic women who spoke English, but this had only a modest effect on birth outcomes. CONCLUSION: Nutritional variation among women in the United States does not appear to have a significant role in the explanation of ethnic differences in birth outcomes.

Failure of metronidazole to prevent preterm delivery among pregnant women with asymptomatic Trichomonas vaginalis infection.

BACKGROUND: Infection with Trichomonas vaginalis during pregnancy has been associated with preterm delivery. It is uncertain whether treatment of asymptomatic trichomoniasis in pregnant women reduces the occurrence of preterm delivery. METHODS: We screened pregnant women for trichomoniasis by culture of vaginal secretions. We randomly assigned 617 women with asymptomatic trichomoniasis who were 16 to 23 weeks pregnant to receive two 2-g doses of metronidazole (320 women) or placebo (297 women) 48 hours apart. We treated women again with the same two-dose regimen at 24 to 29 weeks of gestation. The primary outcome was delivery before 37 weeks of gestation. RESULTS: Between randomization and follow-up, trichomoniasis resolved in 249 of 269 women for whom follow-up cultures were available in the metronidazole group (92.6 percent) and 92 of 260 women with follow-up cultures in the placebo group (35.4 percent). Data on the time and characteristics of delivery were available for 315 women in the metronidazole group and 289 women in the placebo group. Delivery occurred before 37 weeks of gestation in 60 women in the metronidazole group (19.0 percent) and 31 women in the placebo group (10.7 percent) (relative risk, 1.8; 95 percent confidence interval, 1.2 to 2.7; P=0.004). The difference was attributable primarily to an increase in preterm delivery resulting from spontaneous preterm labor (10.2 percent vs. 3.5 percent; relative risk, 3.0; 95 percent confidence interval, 1.5 to 5.9). CONCLUSIONS: Treatment of pregnant women with asymptomatic trichomoniasis does not prevent preterm delivery. Routine screening and treatment of asymptomatic pregnant women for this condition cannot be recommended.

Does epidural analgesia prolong labor and increase risk of cesarean delivery? A natural experiment.

OBJECTIVE: More than 50% of pregnant women in the United States are using epidural analgesia for labor pain. However, whether epidural analgesia prolongs labor and increases the risk of cesarean delivery remains controversial. STUDY DESIGN: We examined this question in a community-based, tertiary military medical center where the rate of continuous epidural analgesia in labor increased from 1% to 84% in a 1-year period while other conditions remained unchanged-a natural experiment. We systematically selected 507 and 581 singleton, nulliparous, term pregnancies with spontaneous onset of labor and vertex presentation from the respective times before and after the times that epidural analgesia was available on request during labor. We compared duration of labor, rate of cesarean delivery, instrumental delivery, and oxytocin use between these two groups. RESULTS: Despite a rapid and dramatic increase in epidural analgesia during labor (from 1% to 84% in 1 year), rates of cesarean delivery overall and for dystocia remained the same (for overall cesarean delivery: adjusted relative risk, 0.8; 95% confidence interval, 0.6-1.2; for dystocia: adjusted relative risk, 1.0; 95% confidence interval, 0.7-1.6). Overall instrumental delivery did not increase (adjusted relative risk, 1.0; 95% confidence interval, 0.8-1.4), nor did the duration of the first stage and the active phase of labor (multivariate analysis; P >.1). However, the second stage of labor was significantly longer by about 25 minutes (P <.001). CONCLUSION: Epidural analgesia during labor does not increase the risk of cesarean delivery, nor does it necessarily increase oxytocin use or instrumental delivery caused by dystocia. The duration of the active phase of labor appears unchanged, but the second stage of labor is likely prolonged. (Am J Obstet Gynecol 2001;185:128-34).

Association between maternal serum concentration of the DDT metabolite DDE and preterm and small-for-gestational-age babies at birth.

BACKGROUND: DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane) is highly effective against most malaria-transmitting mosquitoes and is being widely used in malaria-endemic areas. The metabolite, DDE (1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene), has been linked to preterm birth in small studies, but these findings are inconclusive. Our aim was to investigate the association between DDE exposure and preterm birth. METHODS: Our study was based on the US Collaborative Perinatal Project (CPP). From this study we selected a subset of more than 44000 eligible children born between 1959 and 1966 and measured the DDE concentration in their mothers' serum samples stored during pregnancy. Complete data were available for 2380 children, of whom 361 were born preterm and 221 were small-for-gestational age. FINDINGS: The median maternal DDE concentration was 25 mg/L (range 3-178)-several fold higher than current US concentrations. The adjusted odds ratios (OR) of preterm birth increased steadily with increasing concentrations of serum DDE (ORs=1, 1.5, 1.6, 2.5, 3.1; trend p<0.0001). Adjusted odds of small-for-gestational-age also increased, but less consistently (ORs=1, 1.9, 1.7, 1.6, 2.6; trend p=0.04). After excluding preterm births, the association of DDE with small-for-gestational-age remained. INTERPRETATION: The findings strongly suggest that DDT use increases preterm births, which is a major contributor to infant mortality. If this association is causal, it should be included in any assessment of the costs and benefits of vector control with DDT.

Accuracy of self-reported cigarette smoking among pregnant women in the 1990s.

In large, prospective studies of pregnancy conducted in the 1960s, women reported very accurately whether or not they smoked. However, in the 1990s, pregnant women who smoke are often pressured to reduce or quit smoking, and the incentive to misreport may be greater than in the past. To assess the accuracy of reported smoking, the authors compared self-reported smoking with cotinine in the serum and/or urine of 105 women who participated in the Calcium for Pre-eclampsia Prevention pilot study in 1992. Cotinine confirmed the report of 84.6% of women who reported smoking and 94.5% of women who denied smoking. These fractions are virtually identical to those obtained in a pregnancy cohort from the 1960s. The authors conclude that in the setting of two obstetrical research studies not specifically focused on smoking, the accuracy of self-reported cigarette smoking did not change substantially from the 1960s to the 1990s.

Polychlorinated biphenyl serum levels in pregnant subjects with diabetes.

OBJECTIVE: Polychlorinated biphenyls (PCBs) are persistent pollutants that are ubiquitous in the food chain; detectable amounts are in the blood of nearly everyone. Their effect on humans at background levels of exposure is an area of active investigation. Increased blood levels of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin), a PCB-like compound, have recently been reported among subjects with diabetes, suggesting that PCB levels could be similarly elevated. To test this hypothesis, we examined a group of pregnant women whose serum PCB levels had been measured and whose diabetes status had been previously recorded. RESEARCH DESIGN AND METHODS: Using stored serum from a large birth cohort study, we conducted a cross-sectional study of 2,245 pregnant women, of whom 44 had diabetes (primarily type 1) and 2,201 were control subjects. RESULTS: The adjusted mean serum level of PCBs among the subjects with diabetes was 30% higher than in the control subjects (P = 0.0002), and the relationship of PCB level to adjusted odds of diabetes was linear. CONCLUSIONS: The possibility exists that PCBs and diabetes are causality related; alternatively, the pharmacokinetics of PCBs could be altered among patients with diabetes. At any event, if the association is replicated in other studies, increased serum levels of PCBs in subjects with diabetes or their offspring may put them at increased risk of PCB-induced changes in thyroid metabolism or neurodevelopment.

Low blood pressure during pregnancy and poor perinatal outcomes: an obstetric paradox.

Low blood pressure during pregnancy has been associated with poor perinatal outcomes. However, whether this association is causal or is due to confounding has never been carefully assessed. The authors used data from the Collaborative Perinatal Project, a large prospective cohort study in 12 hospitals in the United States from 1959 to 1966. A total of 28,095 subjects were included. At first glance, it appeared that the lower the baseline blood pressure during pregnancy, the higher the incidence of very premature birth (<34 weeks) and severe small for gestational age (<5th percentile) in a consistent dose-response pattern. However, women with low blood pressure were generally younger, shorter, lighter, leaner, poorer, and more often a minority, and they gained less weight. After the authors controlled for these factors, low blood pressure was not associated with preterm birth (adjusted relative risks ranging from 0.86 to 0.93, p > 0.05) or small for gestational age (relative risks ranging from 0.45 to 2.0). Therefore, the association between low blood pressure during pregnancy and poor perinatal outcomes is largely due to confounding by other risk factors. Low blood pressure by itself does not increase risk of poor perinatal outcomes at a population level. However, this conclusion may not apply to individual patients who also have a compromised plasma volume expansion or pathologic homeostasis.

Differences in birth weight and blood pressure at age 7 years among twins.

Blood pressure later in life has been inversely associated with birth weight. However, concerns have been raised about whether this association merely reflects common environmental risk factors for both fetal growth restriction and high blood pressure or whether there is a genetic tendency to give birth to small babies and have high blood pressure. This study examined whether difference in birth weight of twins is associated with difference in blood pressure at age 7 years. The authors used data from the Collaborative Perinatal Project, United States, 1959-1966, which included 119 pairs of monozygotic and 86 pairs of same-sex dizygotic twins. The smaller twin in each pair had an average 300-g lower birth weight and was substantially thinner than the larger twin (p < 0.001). At age 7 years, body size and blood pressure were similar. Multiple linear regression was used to examine the association between difference in birth size and difference in blood pressure, adjusting for difference in body weight at age 7 years. None of the associations was statistically significant, and the direction of the associations was inconsistent. Further analyses stratified by birth weight, race, and sex revealed a similar, inconsistent pattern. The authors' findings fail to support the hypothesis that an unfavorable intrauterine environment adversely affects blood pressure in children.

Epidural analgesia and fetal head malposition at vaginal delivery.

OBJECTIVE: To determine if nulliparas who delivered with on-demand epidural analgesia are more likely to have malpositioning of the fetal vertex at delivery than women delivered during a period of restricted epidural use. METHODS: A retrospective cohort of nulliparous women with spontaneous labor delivered during a 12-month period immediately before the availability of on-demand labor epidural analgesia was compared with a similar group of nulliparas delivered after labor epidural analgesia was available on request. The primary outcome variable was a non-occiput anterior position or malpositioned fetal head at vaginal delivery. RESULTS: The frequency of epidural use increased from 0.9% before epidural analgesia became available on demand to 82.9% afterward. Fetal head malpositioning at vaginal delivery occurred in 26 of 434 (6.0%) women delivered in the before period compared with 29 of 511 (5.7%) in the after period (relative risk 0.95, 95% confidence interval 0.6, 1.6). No statistically significant difference in the incidence of fetal head malpositioning was present after patients were stratified by mode of delivery (Mantel-Haenszel weighted relative risk 0.94, 95% confidence interval 0.6, 1.4). The study sample size provided 85% power to detect a two-fold increase in the incidence of fetal malpositioning from a baseline rate of 6% associated with on-demand epidural use. CONCLUSION: Providing on-request labor epidural analgesia to nulliparas in spontaneous labor did not result in a clinically significant increase in the frequency of fetal head malpositioning at vaginal delivery.

Prediction of adverse outcomes by common definitions of hypertension in pregnancy.

OBJECTIVE: To examine the ability of five common definitions of hypertension in pregnancy to predict adverse maternal and perinatal outcomes. METHODS: We studied 9133 singleton nulliparous pregnancies with early prenatal care from the Collaborative Perinatal Project, a large cohort study conducted between 1959 and 1965. Definitions from five different groups were evaluated. Severe maternal and perinatal morbidity and mortality were used as the outcome measurements. Sensitivity, specificity, and positive predictive value for outcomes were compared across various definitions. RESULTS: Blood pressure alone had very poor discriminatory power to predict adverse outcomes. Positive predictive values of adverse outcomes by the diagnosis of preeclampsia were 18-20% based on antepartum and intrapartum blood pressures and 22-36% based on antepartum blood pressure only. Mild hypertension occurring for the first time in labor and isolated mild systolic hypertension were not associated with adverse outcomes. Similarly, an increase in diastolic blood pressure of 15 mmHg that did not achieve an absolute value of 90 mmHg did not predict adverse outcome. CONCLUSION: Neither blood pressure nor blood pressure and proteinuria are accurate predictors of severe adverse maternal and perinatal outcomes. Mild hypertension occurring for the first time in labor and isolated mild systolic hypertension should not be considered indicators for hypertensive disorders in pregnancy in a research definition.

Bacterial vaginosis and other asymptomatic vaginal infections in pregnancy.

Preterm birth is a common cause of neonatal morbidity and mortality. Many asymptomatic genital infections have been associated with preterm birth, but attempts to determine a causal relationship between specific infections and preterm birth have been disappointing. Treatment trials of specific infections have generally failed to show a positive effect, and in some trials have shown a deleterious effect. Although there is a strong association between the presence of bacterial vaginosis and Trichomonas vaginalis in pregnancy and preterm birth, randomized treatment trials have failed to show a benefit of treatment of these organisms. Treatment of asymptomatic bacterial vaginosis or T. vaginalis to prevent preterm birth is not warranted.