Pregnancy outcome in primiparae of advanced maternal age

Objective: To investigate the impact of maternal age on singleton pregnancy outcome, taking into account intermediate and confounding factors. Study design: In this population-based retrospective cohort study, perinatal data of primiparous women aged 35 years or more ( n = 2970), giving birth to a singleton child of at least 500 g, were compared to data of primiparous women aged 25–29 years old ( n = 23,921). Univariate analysis was used to assess the effect of maternal age on pregnancy outcomes. The effects of intermediate (hypertension, diabetes and assisted conception) and confounding factors (level of education) were assessed through multivariable logistic regression analysis. Results: Older maternal age correlated, independently of confounding and intermediate factors, with very preterm birth (gestational age \u3c32 weeks) [adjusted odds ratio (AOR) 1.51, 95% confidence intervals (CI) 1.04–2.19], low birth weight (birth weight \u3c2500 g) (AOR 1.69, 95% CI 1.47–1.94) and perinatal death (AOR 1.68, 95% CI 1.06–2.65). Conclusion: Maternal age is an important and independent risk factor for adverse pregnancy outcome

Conditional generalized estimating equations for the analysis of clustered and longitudinal data

A common and important problem in clustered sampling designs is that the effect of within-cluster exposures (i.e., exposures that vary within clusters) on outcome may be confounded by both measured and unmeasured cluster-level factors (i.e., measurements that do not vary within clusters). When some of these are ill/not accounted for, estimation of this effect through population-averaged models or random-effects models may introduce bias. We accommodate this by developing a general theory for the analysis of clustered data, which enables consistent and asymptotically normal estimation of the effects of within-cluster exposures in the presence of cluster-level confounders. Semiparametric efficient estimators are obtained by solving so-called conditional generalized estimating equations. We compare this approach with a popular proposal by Neuhaus and Kalbfleisch (1998, Biometrics 54, 638-645) who separate the exposure effect into a within- and a between-cluster component within a random intercept model. We find that the latter approach yields consistent and efficient estimators when the model is linear, but is less flexible in terms of model specification. Under nonlinear models, this approach may yield inconsistent and inefficient estimators, though with little bias in most practical settings

Preterm birth in twins after subfertility treatment: population based cohort study

Objectives To assess gestational length and prevalence of preterm birth among medically and naturally conceived twins; to establish the role of zygosity and chorionicity in assessing gestational length in twins born after subfertility treatment. Design Population based cohort study. Setting Collaborative network of 19 maternity facilities in East Flanders, Belgium (East Flanders prospective twin survey). Participants 4368 twin pairs born between 1976 and 2002, including 2915 spontaneous twin pairs, 710 twin pairs born after ovarian stimulation, and 743 twin pairs born after in vitro fertilisation or intracytoplasmic sperm injection. Main outcome measures Gestational length and prevalence of preterm birth. Results Compared with naturally conceived twins, twins resulting from subfertility treatment had on average a slightly decreased gestational age at birth (mean difference 4.0 days, 95% confidence interval 2.7 to 5.2), corresponding to an odds ratio of 1.6 (1.4 to 1.8) for preterm birth, albeit confined to mild preterm birth (34-36 weeks). The adjusted odds ratios of preterm birth after subfertility treatment were 1.3 (1.1 to 1.5) when controlled for birth year, maternal age, and parity and 1.6 (1.3 to 1.8) with additional control for fetal sex, caesarean section, zygosity, and chorionicity. Although an increased risk of preterm birth was therefore seen among twins resulting from subfertility treatment, the risk was largely caused by a first birth effect among subfertile couples; conversely, the risk of prematurity was substantially levelled off by the protective effect of dizygotic twinning. Conclusions Twins resulting from subfertility treatment have an increased risk of preterm birth, but the risk is limited to mild preterm birth, primarily by virtue of dizygotic twinning

Umbilical cord anomalies are more frequent in twins after assisted reproduction

Background: The objective of this study is to analyse differences in cord characteristics between naturally conceived twins and twins born after assisted reproduction. Methods: Between 1985 and 2004, the East Flanders Prospective Twin Survey (EFPTS) registered 4159 twin pairs. We compared cord characteristics between 2119 naturally conceived dizygotic (DZ) twin members and 2243 DZ twin members originating from assisted reproductive technologies (ART). Data were adjusted for intra-twin correlation, year of birth, maternal age, gestational age, parity, sex of the child and number of placentas. Results: Marginal cord insertion, velamentous cord insertion and single umbilical artery (SUA) occur more frequently in twins following infertility treatment (P < 0.001). The incidence of velamentous cord insertion increases proportionate with 'invasiveness' of reproductive techniques: 3.6% in naturally conceived twins versus 5% in twins after artificial induction of ovulation (AIO) [ odds ratio (OR) 1.45; 95% confidence interval (CI) 0.99-2.11], 7.4% in twins after IVF (OR 1.49; 95% CI 1.26-1.77) and 10.4% in twins after ICSI (OR 1.31; 95% CI 1.14-1.51). SUA has the highest incidence in twins after AIO: 1.9% compared with 0.6% in naturally conceived twins (OR 3.19; 95% CI 1.66-6.11). Conclusions: Umbilical cords of twins born after ART have more pathologic characteristics when compared with cords of naturally conceived twins

On the Adjustment for Covariates in Genetic Association Analysis: A Novel, Simple Principle to Infer Direct Causal Effects

In genetic association studies, different complex phenotypes are often associated with the same marker. Such associations can be indicative of pleiotropy (i.e. common genetic causes), of indirect genetic effects via one of these phenotypes, or can be solely attributable to non-genetic/environmental links between the traits. To identify the phenotypes with the inducing genetic association, statistical methodology is needed that is able to distinguish between the different causes of the genetic associations. Here, we propose a simple, general adjustment principle that can be incorporated into many standard genetic association tests which are then able to infer whether an SNP has a direct biological influence on a given trait other than through the SNP's influence on another correlated phenotype. Using simulation studies, we show that, in the presence of a non-marker related link between phenotypes, standard association tests without the proposed adjustment can be biased. In contrast to that, the proposed methodology remains unbiased. Its achieved power levels are identical to those of standard adjustment methods, making the adjustment principle universally applicable in genetic association studies. The principle is illustrated by an application to three genome-wide association analyses

Perinatal outcome of twin pregnancies in women of advanced age

BACKGROUND: The aim of this study was to assess the outcome of twin pregnancies in women of advanced age (35 years) compared with women aged 25–29 years old. METHODS: This population-based retrospective study compared perinatal outcome of twin pregnancies in primiparae aged 35 or older (N 5 240) to that of twin pregnancies in primiparae aged 25–29 years (N 5 940). Observed outcomes are adjusted for intermediate (mode of conception and hypertension during pregnancy) and confounding variables (level of education). The possible effect of zygosity and chorionicity was tested in a subset of this database, recorded in the East Flanders Prospective Twin Survey (EFPTS). RESULTS: In twin pregnancies, maternal age of 35 or over is associated with a lower incidence of preterm birth [adjusted odds ratio (AOR) 0.59, 95% confidence interval (CI) 0.44–0.79] and low birthweight (AOR 0.75, 95% CI 0.58–0.98) compared with younger women. Differences in zygosity and chorionicity between both cohorts do not seem to affect the result. CONCLUSIONS: In comparison with primiparae aged 25–29 years, perinatal outcome of twin pregnancies is more favourable in primiparae aged 35 or over