Triad families are routinely used to test association between genetic variants and complex diseases. Triad studies are important and popular since they are robust in terms of being less prone to false positives due to population structure. In practice, one may collect not only complete triads, but also incomplete families such as dyads (affected child with one parent) and singleton monads (affected child without parents). Since there is a lack of convenient algorithms and software to analyze the incomplete data, dyads and monads are usually discarded. This may lead to loss of power and insufficient utilization of genetic information in a study.
We develop likelihood-based statistical models and likelihood ratio tests to test for association between complex diseases and genetic markers by using combinations of full triads, parent-child dyads, and affected singleton monads for a unified analysis. A likelihood is calculated directly to facilitate the data analysis without imputation and to avoid computational complexity. This makes it easy to implement the models and to explain the results.
By simulation studies, we show that the proposed models and tests are very robust in terms of accurately controlling type I error evaluations, and are powerful by empirical power evaluations. The methods are applied to test for association between transforming growth factor alpha (TGFA) gene and cleft palate in an Irish study.
Association mapping of complex diseases; Likelihood ratio tests; Transmission disequilibrium tests
To use contemporary labor data to examine the labor patterns in a large, modern obstetric population in the United States.
Data were from the Consortium on Safe Labor, a multicenter retrospective study that abstracted detailed labor and delivery information from electronic medical records in 19 hospitals across the United States. A total of 62,415 parturients were selected who had a singleton term gestation, spontaneous onset of labor, vertex presentation, vaginal delivery, and a normal perinatal outcome. A repeated-measures analysis was used to construct average labor curves by parity. An interval-censored regression was used to estimate duration of labor stratified by cervical dilation at admission and centimeter by centimeter.
Labor may take over 6 hours to progress from 4 to 5 cm and over 3 hours to progress from 5 to 6 cm of dilation. Nulliparas and multiparas appeared to progress at a similar pace before 6 cm. However, after 6 cm labor accelerated much faster in multiparas than in nulliparas. The 95th percentile of the 2nd stage of labor in nulliparas with and without epidural analgesia was 3.6 and 2.8 hours, respectively. A partogram for nulliparas is proposed.
In a large, contemporary population, the rate of cervical dilation accelerated after 6 cm and progress from 4 to 6 cm was far slower than previously described. Allowing labor to continue for a longer period before 6 cm of cervical dilation may reduce the rate of intrapartum and subsequent repeat cesarean deliveries in the United States.
Hermansky-Pudlak syndrome (HPS) type is a rare disorder of oculocutaneous albinism, platelet dysfunction, and in some subtypes, fatal pulmonary fibrosis. There is no effective treatment for the pulmonary fibrosis except lung transplantation, but an initial trial using pirfenidone, an anti-fibrotic agent, showed promising results. The current, randomized, placebo-controlled, prospective, double-blind trial investigated the safety and efficacy of pirfenidone for mild to moderate HPS-1 and 4 pulmonary fibrosis. Subjects were evaluated every 4 months at the National Institutes of Health Clinical Center, and the primary outcome parameter was change in forced vital capacity using repeated measures analysis with random coefficients. Thirty-five subjects with HPS-1 pulmonary fibrosis were enrolled during a 4-year interval; 23 subjects received pirfenidone and 12 received placebo. Four subjects withdrew from the trial, 3 subjects died, and 10 serious adverse events were reported. Both groups experienced similar side effects, especially gastroesophageal reflux. Interim analysis of the primary outcome parameter, performed 12 months after 30 patients were enrolled, showed no statistical difference between the placebo and pirfenidone groups, and the study was stopped due to futility. There were no significant safety concerns. Other clinical trials are indicated to identify single or multiple drug regimens that may be effective in treatment for progressive HPS-1 pulmonary fibrosis.
Hermansky-Pudlak syndrome; albinism; pulmonary function tests; pulmonary fibrosis; Puerto Rico; pirfenidone
Individual studies of the genetics of neural tube defects (NTDs) contain results on a small number of genes in each report. To identify genetic risk factors for NTDs, we evaluated potentially functional single nucleotide polymorphisms (SNPs) that are biologically plausible risk factors for NTDs but that have never been investigated for an association with NTDs, examined SNPs that previously showed no association with NTDs in published studies, and tried to confirm previously reported associations in folate-related and non-folate-related genes. We investigated 64 SNPs in 34 genes for association with spina bifida in up to 558 case-families (520 cases, 507 mothers, 457 fathers) and 994 controls in Ireland. Case-control and mother-control comparisons of genotype frequencies, tests of transmission disequilibrium, and log-linear regression models were used to calculate effect estimates. Spina bifida was associated with over-transmission of the LEPR (leptin receptor) rs1805134 minor C allele (genotype relative risk (GRR): 1.5; 95% confidence interval (CI): 1.0, 2.1; P = 0.0264) and the COMT (catechol-O-methyltransferase) rs737865 major T allele (GRR: 1.4; 95% CI: 1.1, 2.0; P = 0.0206). After correcting for multiple comparisons, these individual test P-values exceeded 0.05. Consistent with previous reports, spina bifida was associated with MTHFR 677C>T, T (Brachyury) rs3127334, LEPR K109R, and PDGFRA promoter haplotype combinations. The associations between LEPR SNPs and spina bifida suggest a possible mechanism for the finding that obesity is a NTD risk factor. The association between a variant in COMT and spina bifida implicates methylation and epigenetics in NTDs.
congenital abnormalities; folic acid; neural tube defects; single nucleotide polymorphism; spina bifida
Suggestive, but not conclusive, studies implicate many genetic variants in oral cleft etiology. We used a large, ethnically homogenous study population to test whether reported associations between nonsyndromic oral clefts and 12 genes (CLPTM1, CRISPLD2, FGFR2, GABRB3, GLI2, IRF6, PTCH1, RARA, RYK, SATB2, SUMO1, TGFA) could be confirmed.
Thirty-one single nucleotide polymorphisms (SNPs) in exons, splice sites, and conserved non-coding regions were studied in 509 patients with cleft lip with or without cleft palate (CLP), 383 with cleft palate only (CP), 838 mothers and 719 fathers of patients with oral clefts, and 902 controls from Ireland. Case-control and family-based statistical tests were performed using isolated oral clefts for the main analyses.
In case-control comparisons, the minor allele of PTCH1 A562A (rs2066836) was associated with reduced odds of CLP (OR: 0.29, 95% CI: 0.13–0.64 for homozygotes) whereas the minor allele of PTCH1 L1315P (rs357564) was associated with increased odds of CLP (OR: 1.36, 95% CI: 1.07–1.74 for heterozygotes and OR: 1.56, 95% CI: 1.09–2.24 for homozygotes). The minor allele of one SUMO1 SNP, rs3769817 located in intron 2, was associated with increased odds of CP (OR: 1.45, 95% CI: 1.06–1.99 for heterozygotes). Transmission disequilibrium was observed for the minor allele of TGFA V159V (rs2166975) which was over-transmitted to CP cases (P=0.041).
For 10 of the 12 genes, this is the largest candidate gene study of nonsyndromic oral clefts to date. The findings provide further evidence that PTCH1, SUMO1, and TGFA contribute to nonsyndromic oral clefts.
cleft lip; cleft palate; congenital abnormalities
Most early-onset group B streptococcal (GBS) disease in recent years has occurred in newborns of prenatally GBS–negative mothers who missed intrapartum antibiotic prophylaxis (IAP). We aimed to assess the accuracy of prenatal culture in predicting GBS carriage during labor, the IAP use and occurrence of early-onset GBS disease.
We obtained vaginal-rectal swabs at labor for GBS culture from 5497 women of ≥32 weeks gestation and surface cultures at birth from newborns during 2/5/08–2/4/09 at three hospitals in Houston Texas and Oakland California. Prenatal cultures were performed by health care provider during routine care, and culture results obtained from medical records. The accuracy of prenatal culture in predicting intrapartum GBS carriage was assessed by positive (PPV) and negative (NPV) predictive values. Mother-to-newborn transmission of GBS was assessed. Newborns were monitored for early-onset GBS disease.
GBS carriage was 24.5% by prenatal and 18.8% by labor cultures. Comparing prenatal with labor GBS cultures of 4696 women, the PPV was 50.5% and NPV 91.7%. IAP, administered to 93.3% of prenatally GBS-positive women, was 83.7% effective in preventing newborn’s GBS colonization. Mother-to-newborn transmission of GBS occurred in 2.6% of elective Cesarean deliveries. Two newborns developed early-onset GBS disease (0.36/1000 births): one’s prenatal GBS culture was negative, the other’s unknown.
IAP was effective in interrupting mother-to-newborn transmission of GBS. However, ~10% of prenatally GBS-negative women were positive during labor and missed IAP while ~50% of prenatally GBS-positive women were negative during labor and received IAP. These findings emphasize the need for rapid diagnostics during labor.
group B streptococcus; early onset disease; predictive values; prenatal cultures; intrapartum antibiotic prophylaxis
To compare labor patterns by body mass index (BMI).
118,978 gravidas with a singleton term cephalic gestation were studied. Repeated-measures analysis constructed average labor curves by parity and BMI categories for those that reached 10cm. Interval censored regression analysis determined median traverse times adjusting for covariates in vaginal deliveries and intrapartum cesareans.
For nulliparas, the time difference to reach 10 cm was 1.2 hours from the lowest to highest BMI category. Multiparas entered active phase by 6 cm, but reaching this point took longer for BMI≥40.0 (3.4hours) compared to BMI<25.0 (2.4hours). Progression by centimeter (P<0.001) except from 7–9cm in multiparas (P>0.05), and from 4–10cm (P<0.001) increased as BMI increased for nulliparas and multiparas. Second stage length with and without an epidural was similar among BMI categories for nulliparas (P>0.05), but decreased as BMI increased for multiparas (P<0.001).
Labor proceeds more slowly as BMI increases suggesting that labor management be tailored to allow for these differences.
Body mass index; Labor curves; Obesity; Pregnancy
Neural tube defects (NTDs) are common birth defects (~1 in 1000 pregnancies in the US and Europe) that have complex origins, including environmental and genetic factors. A low level of maternal folate is one well-established risk factor, with maternal periconceptional folic acid supplementation reducing the occurrence of NTD pregnancies by 50-70%. Gene variants in the folate metabolic pathway (e.g., MTHFR rs1801133 (677 C > T) and MTHFD1 rs2236225 (R653Q)) have been found to increase NTD risk. We hypothesized that variants in additional folate/B12 pathway genes contribute to NTD risk.
A tagSNP approach was used to screen common variation in 82 candidate genes selected from the folate/B12 pathway and NTD mouse models. We initially genotyped polymorphisms in 320 Irish triads (NTD cases and their parents), including 301 cases and 341 Irish controls to perform case–control and family based association tests. Significantly associated polymorphisms were genotyped in a secondary set of 250 families that included 229 cases and 658 controls. The combined results for 1441 SNPs were used in a joint analysis to test for case and maternal effects.
Nearly 70 SNPs in 30 genes were found to be associated with NTDs at the p < 0.01 level. The ten strongest association signals (p-value range: 0.0003–0.0023) were found in nine genes (MFTC, CDKN2A, ADA, PEMT, CUBN, GART, DNMT3A, MTHFD1 and T (Brachyury)) and included the known NTD risk factor MTHFD1 R653Q (rs2236225). The single strongest signal was observed in a new candidate, MFTC rs17803441 (OR = 1.61 [1.23-2.08], p = 0.0003 for the minor allele). Though nominally significant, these associations did not remain significant after correction for multiple hypothesis testing.
To our knowledge, with respect to sample size and scope of evaluation of candidate polymorphisms, this is the largest NTD genetic association study reported to date. The scale of the study and the stringency of correction are likely to have contributed to real associations failing to survive correction. We have produced a ranked list of variants with the strongest association signals. Variants in the highest rank of associations are likely to include true associations and should be high priority candidates for further study of NTD risk.
Neural tube defects; Spina bifida; Folic acid; One-carbon metabolism; Candidate gene
Alkaptonuria is a rare, autosomal recessive disorder of tyrosine degradation due to deficiency of the third enzyme in the catabolic pathway. As a result, homogentisic acid (HGA) accumulates and is excreted in gram quantities in the urine, which turns dark upon alkalization. The first symptoms, occurring in early adulthood, involve a painful, progressively debilitating arthritis of the spine and large joints. Cardiac valvular disease and renal and prostate stones occur later. Previously suggested therapies have failed to show benefit, and management remains symptomatic. Nitisinone, a potent inhibitor of the second enzyme in the tyrosine catabolic pathway, is considered a potential therapy; proof-of-principle studies showed 95% reduction in urinary HGA. Based on those findings, a prospective, randomized clinical trial was initiated in 2005 to evaluate 40 patients over a 36-month period. The primary outcome parameter was hip total range of motion with measures of musculoskeletal function serving as secondary parameters. Biochemically, this study consistently demonstrated 95% reduction of HGA in urine and plasma over the course of 3 years. Clinically, primary and secondary parameters did not prove benefit from the medication. Side effects were infrequent. This trial illustrates the remarkable tolerability of nitisinone, its biochemical efficacy, and the need to investigate its use in younger individuals prior to development of debilitating arthritis.
Alkaptonuria; Ochronosis; Nitisinone; Homogentisic acid
Periconceptional use of folic acid prevents most neural tube defects (NTDs). Whether folic acid and/or multivitamins can prevent other congenital anomalies is not clear. This study tested whether maternal blood levels of folate and vitamin B12 in pregnancies affected by congenital malformations excluding NTDs are lower when compared to non-affected pregnancies.
We measured pregnancy red cell folate (RCF), vitamin B12, and homocysteine (tHcy) concentrations in blood samples taken at the first antenatal clinic in Dublin maternity hospitals in 1986–1990 when vitamin supplementation was rare. The cases were mothers who delivered a baby with a congenital malformation other than NTD identified by the Dublin EUROCAT Registry; controls were a systematic sample of mothers of offspring without congenital malformations from the same hospitals in the same time period.
The median maternal levels of RCF and tHcy did not differ significantly between cases and controls for any of the congenital malformation groups examined (RCF: all malformations 275.9 ug/L v controls 271.2; p=0.77; tHcy: all malformations 7.5 umol/L v controls 7.6; p=0.57). In an unadjusted analysis vitamin B12 was significantly higher in case-mothers whose babies had cleft palate only (p=0.006), musculoskeletal malformations (p=0.034) and midline defects (p=0.039) but not after adjustment for multiple testing.
Our data suggest that low maternal folate and B12 levels or high tHcy levels in early pregnancy are not associated with all congenital malformations excluding NTDs. Fortification with folic acid or B12 may not have a beneficial effect in the prevention of these anomalies.
We consider the multiple comparison problem where multiple outcomes are each compared among several different collections of groups in a multiple group setting. In this case there are several different types of hypotheses, with each specifying equality of the distributions of a single outcome over a different collection of groups. Each type of hypothesis requires a different permutational approach. We show that under a certain multivariate condition it is possible to use closure over all hypotheses, although intersection hypotheses are tested using Boole’s inequality in conjunction with permutation distributions in some cases. Shortcut tests are then found so that the resulting testing procedure is easily performed. The error rate and power of the new method is compared to existing competitors through simulation of correlated data. An example is analyzed, consisting of multiple adverse events in a clinical trial.
Adverse Events; Closed Testing; Exchangeability; Familywise Error Rate; Power
To assess the efficacy of obstetric maneuvers for resolving shoulder dystocia, and the effect that these maneuvers have on neonatal injury when shoulder dystocia occurs.
Using an electronic database encompassing 206,969 deliveries, we identified all women with a vertex fetus beyond 34 0/7 weeks of gestation who incurred a shoulder dystocia during the process of delivery. Women whose fetuses had a congenital anomaly and women with an antepartum stillbirth were excluded. Medical records of all cases were reviewed by trained abstractors. Cases involving neonatal injury (defined as brachial plexus injury, clavicular or humerus fracture, or hypoxic ischemic encephalopathy or intrapartum neonatal death attributed to the shoulder dystocia) were compared to those without injury.
Among 132,098 women who delivered a term cephalic liveborn fetus vaginally, 2,018 incurred a shoulder dystocia (1.5%), and 101 (5.2%) of these incurred a neonatal injury. Delivery of the posterior shoulder was associated with the highest rate of delivery when compared to other maneuvers (84.4% compared with 24.3% to 72.0% for other maneuvers; P<.005 to P<.001) and similar rates of neonatal injury (8.4% compared with 6.1% to 14.0%; P=.23 to P=.7). The total number of maneuvers performed significantly correlated with the rate of neonatal injury (P<.001).
Delivery of the posterior shoulder should be considered following McRoberts maneuver and suprapubic pressure in the management of shoulder dystocia. The need for additional maneuvers was associated with higher rates of neonatal injury.
Polymorphisms within the MTHFD1L gene were previously associated with risk of neural tube defects in Ireland. We sought to test the most significant MTHFD1L polymorphisms for an association with risk of cleft in an Irish cohort. This required the development of a new melting curve assay to genotype the technically challenging MTHFD1L triallelic deletion/insertion polymorphism (rs3832406).
Melting curve analysis was used to genotype the MTHFD1L triallelic deletion/insertion polymorphism (rs3832406) and a Single Nucleotide Polymorphism rs17080476 in an Irish cohort consisting of 981 Irish case-parent trios and 1,008 controls. Tests for association with nonsyndromic cleft lip with or without cleft palate and cleft palate included case/control analysis, mother/control analysis and Transmission Disequilibrium Tests of case-parent trios.
A successful melting curve genotyping assay was developed for the deletion/insertion polymorphism (rs3832406). The TDT analysis initially showed that the rs3832406 polymorphism was associated with isolated cleft lip with or without cleft palate. However, corrected p-values indicated that this association was not significant.
Melting Curve Analysis can be employed to successfully genotype challenging polymorphisms such as the MTHFD1L triallelic deletion/insertion polymorphism (DIP) reported here (rs3832406) and is a viable alternative to capillary electrophoresis. Corrected p-values indicate no association between MTHFD1L and risk of cleft in an Irish cohort.
To identify possible prepregnancy risk factors for antepartum stillbirth and determine if these factors identify women at higher risk for term stillbirth.
This retrospective cohort study of prepregnancy risk factors compared 712 singleton antepartum stillbirths to 174,097 singleton live births at or after 23 weeks of gestation. The risk of term antepartum stillbirth was then assessed in a subset of 155,629 singleton pregnancies.
In adjusted multivariable analyses, black race, Hispanic ethnicity, maternal age 35 years or older, nulliparity, prepregnancy body mass index (BMI) 30 kg/m2 or higher, preexisting diabetes, chronic hypertension, smoking, and alcohol use were independently associated with stillbirth. Prior cesarean delivery and history of preterm birth were associated with increased stillbirth risk in multiparas. The risk of a term stillbirth for women who were white, 25–29 years old, normal weight, multiparous, no chronic hypertension, and no preexisting diabetes was 0.8 per 1,000. Term stillbirth risk increased with these conditions: preexisting diabetes (3.1 per 1,000), chronic hypertension (1.7 per 1,000), black race (1.8 per 1,000), maternal age 35 years or older (1.3 per 1,000), BMI 30 kg/m2 or higher, (1/1000) and nulliparity (0.9 per 1,000).
There are multiple independent risk factors for antepartum stillbirth. However, the value of individual risk factors of race, parity, advanced maternal age (35– 39 years old) and BMI to predict term stillbirth is poor. Our results do not support routine antenatal surveillance for any of these risk factors when present in isolation.
Determination of the Bishop score is the most commonly used method to assess the readiness of the cervix for induction. However, it was created without modern statistical methods. Our objective was to determine whether a simplified score can predict vaginal delivery equally well.
Data were analyzed for 5,610 nulliparous women with singleton, uncomplicated pregnancies between 37 0/7 – 41 6/7 weeks undergoing labor induction. These women had all five components of the Bishop score recorded. Logistic regression was performed and a simplified score created with significant components. Positive and negative predictive values (PPV and NPV) and positive likelihood ratio (LR+) were calculated.
In the regression model, only dilation, station and effacement were significantly associated with vaginal delivery (P<.01). The simplified Bishop score was then devised using these 3 components (range 0 – 9) and compared to the original Bishop score (range 0 – 13) for prediction of successful induction, resulting in vaginal delivery. Compared to the original Bishop score > 8, the simplified Bishop score > 5 had a similar or better PPV (87.7% versus 87.0%), NPV (31.3% versus 29.8%), LR+ (2.34 versus 2.12) and correct classification rate (51.0% versus 47.3%). Application of the simplified Bishop score in other populations including indicated induction and spontaneous labor at term and preterm were associated with similar vaginal delivery rates compared to the original Bishop score.
The simplified Bishop score comprised of dilation, station and effacement attains a similarly high predictive ability of successful induction as the original score.
New technology for large-scale genotyping has created new challenges for statistical analysis. Correcting for multiple comparison without discarding true positive results and extending methods to triad studies are among the important problems facing statisticians. We present a one-sample permutation test for testing transmission disequilibrium hypotheses in triad studies, and show how this test can be used for multiple single nucleotide polymorphism (SNP) testing. The resulting multiple comparison procedure is shown in the case of the transmission disequilibrium test to control the familywise error. Furthermore, this procedure can handle multiple possible modes of risk inheritance per SNP. The resulting permutational procedure is shown through simulation of SNP data to be more powerful than the Bonferroni procedure when the SNPs are in linkage disequilibrium. Moreover, permutations implicitly avoid any multiple comparison correction penalties when the SNP has a rare allele. The method is illustrated by analyzing a large candidate gene study of neural tube defects and an independent study of oral clefts, where the smallest adjusted p-values using the permutation procedure are approximately half those of the Bonferroni procedure. We conclude that permutation tests are more powerful for identifying disease-associated SNPs in candidate gene studies and are useful for analysis of triad studies.
Exchangeable; familywise error rate; linkage disequilibrium; power
To study the effect of in-utero alcohol exposure on the insulin-like growth factor axis (IGF) and leptin during infancy and childhood, considering that exposed children may exhibit pre- and postnatal growth retardation.
We prospectively identified heavily drinking pregnant women who consumed on average 4 or more drinks of ethanol per day (≥48 g/day) and assessed growth in 69 of their offspring and an unexposed control group of 83 children, measuring serum IGF-I (radioimmunoassay), IGF-II (immunoradiometric assay, IRMA), insulin-like growth factor-binding protein 3 (IGFBP-3) (IRMA) and leptin (IRMA) at 1 month and 1, 2, 3, 4, and 5 years of age.
IGF-II levels increased with age in both groups, but the rate of increase was significantly higher in exposed children, and levels were significantly higher in ethanol-exposed children at 3, 4, and 5 years of age. In exposed children, IGF-I levels were higher at 3 and 4 years and leptin levels were significantly lower at 1 and 2 years. Exposed subjects showed a much lower correlation between IGF-I and growth parameters than unexposed subjects.
Exposure to ethanol during pregnancy increases IGF-I and IGF-II and decreases leptin during early childhood. The increase in serum IGF-II concentrations in ethanol-exposed children suggests that this hormone should be explored as a potential marker for prenatal alcohol exposure.
Fetal alcohol syndrome; Pregnancy; Alcohol abuse; Insulin-like growth factor I; Insulin-like growth factor II
Methods for performing multiple tests of paired proportions are described. A broadly applicable method using McNemar's exact test and the exact distributions of all test statistics is developed; the method controls the familywise error rate in the strong sense under minimal assumptions. A closed form (not simulation-based) algorithm for carrying out the method is provided. A bootstrap alternative is developed to account for correlation structures. Operating characteristics of these and other methods are evaluated via a simulation study. Applications to multiple comparisons of predictive models for disease classification and to post-market surveillance of adverse events are given.
Bonferroni-Holm; Bootstrap; Discreteness; Exact Tests; Multiple Comparisons; Post-Market Surveillance; Predictive Model
To assess ovarian follicle function in women with 46,XX spontaneous primary ovarian insufficiency
Case-control with nested prospective cohort
Clinical Research Center, National Institutes of Health
Women with primary ovarian insufficiency without estrogen replacement for two weeks (N=97) and regularly menstruating control women (N=42)
Single injection of 300 IU hrFSH
Main outcome measures
Change in serum estradiol at 24 hours
Antral follicles ≥ 3 mm were detected in 73% (69/95) of patients; both serum estradiol and progesterone levels correlated significantly with maximum follicle diameter in these women. Patients with a maximum follicle diameter ≥ 8 mm had significantly higher serum estradiol and progesterone levels and significantly lower FSH and LH levels as compared to patients without such follicles. In controls estradiol levels increased significantly after FSH administration but in patients this was not the case despite the presence of an antral follicle ≥ 8 mm.
Most women with 46,XX spontaneous primary ovarian insufficiency have antral follicles detectable by ultrasound, suggesting that down-regulation of FSH receptors is not the predominant mechanism of follicle dysfunction. Evidence of progesterone secretion by antral follicles ≥ 8 mm in these patients is consistent with prior histologic evidence that follicle luteinization is the predominant mechanism of follicle dysfunction in this condition. Prospective controlled investigation designed to improve ovulatory function and fertility in these women is indicated.
Primary ovarian insufficiency; hypergonadotropic hypogonadism; premature ovarian failure; premature menopause; lutienized Graafian follicle
To describe contemporary cesarean delivery practice in the U.S.
Consortium on Safe Labor collected detailed labor and delivery information from 228,668 electronic medical records from 19 hospitals across the U.S., 2002 – 2008.
The overall cesarean delivery rate was 30.5%. 31.2% of nulliparas were delivered by cesarean section. Prelabor repeat cesarean delivery due to a previous uterine scar contributed 30.9% of all cesarean sections. 28.8% of women with a uterine scar had a trial of labor and the success rate was 57.1%. 43.8% women attempting vaginal delivery had induction. Half of cesarean for dystocia in induced labor were performed before 6 cm of cervical dilation.
To decrease cesarean delivery rate in the U.S., reducing primary cesarean delivery is the key. Increasing VBAC rate is urgently needed. Cesarean section for dystocia should be avoided before the active phase is established, particularly in nulliparas and in induced labor.
cesarean delivery; induction; labor; VBAC
To assess body mass index (BMI) effect on cesarean risk during labor.
The Consortium on Safe Labor collected electronic data from 228,668 deliveries. Women with singletons ≥37 weeks and known BMI at labor admission were analyzed in this cohort study. Regression analysis generated relative risks for cesarean stratifying for parity and prior cesarean while controlling for covariates
Of the 124,389 women, 14.0% had cesareans. Cesareans increased with increasing BMI for nulliparas, multiparas with and without a prior cesarean. Repeat cesareans were performed in >50% of laboring women with a BMI >40kg/m2. The risk for cesarean increased as BMI increased for all subgroups, p<0.001. The risk for cesarean increased by 5%, 2%, and 5% for nulliparas, multiparas with and without a prior cesarean, respectively, for each 1kg/m2 rise in BMI.
Admission BMI is significantly associated with delivery route in term laboring women. Parity and prior cesarean are other important predictors.
Cesarean delivery; body mass index; obesity
To characterize potentially modifiable risk factors for third- or fourth-degree perineal lacerations and cervical lacerations in a contemporary U.S. obstetric practice.
The Consortium on Safe Labor collected electronic medical records from 19 hospitals within 12 institutions (228,668 deliveries from 2002 to 2008). Information on patient characteristics, prenatal complications, labor and delivery data, and maternal and neonatal outcomes were collected. Only women with successful vaginal deliveries of cephalic singletons at 34 weeks of gestation or later were included; we excluded data from sites lacking information about lacerations at delivery and deliveries complicated by shoulder dystocia; 87,267 and 71,170 women were analyzed for third- or fourth-degree and cervical lacerations, respectively. Multivariable logistic regressions were used to adjust for other factors.
Third- or fourth-degree lacerations occurred in 2,516 women (2,223 nulliparous [5.8%], 293 [0.6%] multiparous) and cervical lacerations occurred in 536 women (324 nulliparous [1.1%], 212 multiparous [0.5%]). Risks for third or fourth-degree lacerations included nulliparity (7.2-fold risk), being Asian or Pacific Islander, increasing birth weight, operative vaginal delivery, episiotomy, and longer second stage of labor. Increasing body mass index was associated with fewer lacerations. Risk factors for cervical lacerations included young maternal age, vacuum vaginal delivery, and oxytocin use among multiparous women, and cerclage regardless of parity.
Our large cohort of women with severe obstetric lacerations reflects contemporary obstetric practices. Nulliparity and episiotomy use are important risk factors for third- or fourth-degree lacerations. Cerclage increases the risk for cervical lacerations. Many identified risk factors may not be modifiable.
Resampling-based multiple testing methods that control the Familywise Error Rate in the strong sense are presented. It is shown that no assumptions whatsoever on the data-generating process are required to obtain a reasonably powerful and flexible class of multiple testing procedures. Improvements are obtained with mild assumptions. The methods are applicable to gene expression data in particular, but more generally to any multivariate, multiple group data that may be character or numeric. The role of the disputed “subset pivotality” condition is clarified.
Bootstrap; Exchangeability; Permutation; Resampling; Subset pivotality
We sought to determine maternal and neonatal outcomes by labor onset type and gestational age.
We used electronic medical records data from 10 US institutions in the Consortium on Safe Labor on 115,528 deliveries from 2002 through 2008. Deliveries were divided by labor onset type (spontaneous, elective induction, indicated induction, unlabored cesarean). Neonatal and maternal outcomes were calculated by labor onset type and gestational age.
Neonatal intensive care unit admissions and sepsis improved with each week of gestational age until 39 weeks (P < .001). After adjusting for complications, elective induction of labor was associated with a lower risk of ventilator use (odds ratio [OR], 0.38; 95% confidence interval [CI], 0.28 – 0.53), sepsis (OR, 0.36; 95% CI, 0.26 – 0.49), and neonatal intensive care unit admissions (OR, 0.52; 95% CI, 0.48 – 0.57) compared to spontaneous labor. The relative risk of hysterectomy at term was 3.21 (95% CI, 1.08 – 9.54) with elective induction, 1.16 (95% CI, 0.24 – 5.58) with indicated induction, and 6.57 (95% CI, 1.78 – 24.30) with cesarean without labor compared to spontaneous labor.
Some neonatal outcomes improved until 39 weeks. Babies born with elective induction are associated with better neonatal outcomes compared to spontaneous labor. Elective induction may be associated with an increased hysterectomy risk.
elective delivery; hysterectomy; maternal outcomes; neonatal outcomes
Polymorphisms in folate-related genes have emerged as important risk factors in a range of diseases including neural tube defects (NTDs), cancer and coronary artery disease (CAD). Having previously identified a polymorphism within the cytoplasmic folate enzyme, MTHFD1, as a maternal risk factor for NTDs; we considered the more recently identified mitochondrial paralogue, MTHFD1L as a candidate gene for NTD association. We identified a common deletion/insertion polymorphism, rs3832406, c.781-6823ATT(7-9), that influences splicing efficiency and is strongly associated with NTD risk. Three alleles of rs3832406 were detected in the Irish population with varying number of ATT repeats; Allele 1 consists of ATT7, while Alleles 2 and 3 consist of ATT8 and ATT9 respectively. Allele 2 of this triallelic polymorphism showed a decreased case risk as demonstrated by case-control logistic regression (P= 0.002) and by transmission disequilibrium test (TDT) (P= 0.001); while Allele 1 showed an increased case risk. Allele 3 showed no influence on NTD risk and represents the lowest frequency allele (0.15). Additional SNP genotyping in the same genomic region provides additional supportive evidence of an association. We demonstrate that two of the three alleles of rs3832406 are functionally different and influence the splicing efficiency of the alternate MTHFD1L mRNA transcripts.
MTHFD1L; NTD; Splicing; Polymorphism; Association; Folate; Mitochondria