Anna Sara Oberg

CHRONIC HYPERTENSION IN PREGNANCY AND THE RISK OF CONGENITAL MALFORMATIONS: A COHORT STUDY

OBJECTIVE Chronic hypertension is a common medical condition in pregnancy. The purpose of the study was to examine the association between maternal chronic hypertension and the risk of congenital malformations in the offspring. STUDY DESIGN We defined a cohort of 878,126 completed pregnancies linked to infant medical records using the Medicaid Analytic Extract. The risk of congenital malformations was compared between normotensive controls and those with treated and untreated chronic hypertension. Confounding was addressed using propensity score matching. RESULTS After matching, compared with normotensive controls, pregnancies complicated by treated chronic hypertension were at increased risk of congenital malformations (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.2-1.5), as were pregnancies with untreated chronic hypertension (OR 1.2; 95% CI, 1.1-1.3). In our analysis of organ-specific malformations, both treated and untreated chronic hypertension was associated with a significant increase in the risk of cardiac malformations (OR, 1.6; 95% CI, 1.4-1.9 and OR, 1.5; 95% CI, 1.3-1.7, respectively). These associations persisted across a range of sensitivity analyses. CONCLUSION There is a similar increase in the risk of congenital malformations (particularly cardiac malformations) associated with treated and untreated chronic hypertension that is independent of measured confounders. Studies evaluating the teratogenic potential of antihypertensive medications must control for confounding by indication. Fetuses and neonates of mothers with chronic hypertension should be carefully evaluated for potential malformations, particularly cardiac defects.

Patterns of recurrence of postpartum hemorrhage in a large population-based cohort

OBJECTIVE Although a history of postpartum hemorrhage (PPH) is a recognized risk factor for PPH in subsequent pregnancies, little is known about how the risk accumulates over multiple pregnancies, how recurrence varies by PPH subtype, and whether recurrence can be explained by chronic maternal conditions. STUDY DESIGN Risks of PPH were assessed according to a history of PPH, severity, and subtype (atony, retained placenta, or lacerations) in 538,332 primiparous women whose data were included in the Swedish Medical Birth Register from 1997-2009. The role of stable maternal risk factors was evaluated in regression models that predicted probability of recurrent PPH in second and third pregnancy. RESULTS Women with a history of PPH had a 3-fold increased risk of PPH in their second pregnancy compared with unaffected women (15.0% vs 5.0%, respectively). Adjustment for stable maternal risk factors did not attenuate this risk significantly (adjusted relative risk, 3.0; 95% confidence interval, 2.9-3.1). In a third pregnancy, the risk of PPH was 26.6% after 2 previously affected pregnancies, compared with 4.4% in women with no previous PPH. A history of a specific type of PPH predicted recurrence of PPH in the second pregnancy, not only of the same type but other causes as well. CONCLUSION PPH risk is highest among women with >1 previously affected delivery and in those with a previous severe PPH. Chronic conditions that are known to be risk factors for PPH do not explain the recurrence risks. The recurrence patterns across PPH subtypes may point to shared pathologic mechanisms underlying the varying PPH causes.

Genetic contribution to postpartum haemorrhage in Swedish population: cohort study of 466 686 births

Objective To investigate the familial clustering of postpartum haemorrhage in the Swedish population, and to quantify the relative contributions of genetic and environmental effects. Design Register based cohort study. Setting Swedish population (multi-generation and medical birth registers). Main outcome measure Postpartum haemorrhage, defined as >1000 mL estimated blood loss. Participants The first two live births to individuals in Sweden in 1997-2009 contributed to clusters representing intact couples (n=366 350 births), mothers with separate partners (n=53 292), fathers with separate partners (n=47 054), sister pairs (n=97 228), brother pairs (n=91 168), and mixed sibling pairs (n=177 944). Methods Familial clustering was quantified through cluster specific tetrachoric correlation coefficients, and the influence of potential sharing of known risk factors was evaluated with alternating logistic regression. Relative contributions of genetic and environmental effects to the variation in liability for postpartum haemorrhage were quantified with generalised linear mixed models. Results The overall prevalence of postpartum haemorrhage after vaginal deliveries in our sample was 4.6%. Among vaginal deliveries, 18% (95% confidence interval 9% to 26%) of the variation in postpartum haemorrhage liability was attributed to maternal genetic factors, 10% (1% to 19%) to unique maternal environment, and 11% (0% to 26%) to fetal genetic effects. Adjustment for known risk factors only partially explained estimates of familial clustering, suggesting that the observed shared genetic and environmental effects operate in part through pathways independent of known risk factors. There were similar patterns of familial clustering for both of the main subtypes examined (atony and retained placenta), though strongest for haemorrhage after retained placenta. Conclusions There is a maternal genetic predisposition to postpartum haemorrhage, but more than half of the total variation in liability is attributable to factors that are not shared in families.

Translational Epidemiologic Approaches to Understanding the Consequences of Early-Life Exposures.

Prominent developmental theories posit a causal link between early-life exposures and later functioning. Yet, observed associations with early exposures may not reflect causal effects because of genetic and environmental confounding. The current manuscript describes how a systematic series of epidemiologic analyses that combine several genetically-informative designs and statistical approaches can help distinguish between competing theories. In particular, the manuscript details how combining the use of measured covariates with sibling-comparisons, cousin-comparisons, and additional designs can help elucidate the sources of covariation between early-life exposures and later outcomes, including the roles of (a) factors that are not shared in families, including a potential causal effect of the exposure; (b) carryover effects from the exposure of one child to the next; and (c) familial confounding. We also describe key assumptions and how they can be critically evaluated. Furthermore, we outline how subsequent analyses, including effect decomposition with respect to measured, plausible mediators, and quantitative genetic models can help further specify the underlying processes that account for the associations between early-life exposures and offspring outcomes.

Low Digit Ratio Predicts Early Age at Menarche in Colombian Schoolgirls

BACKGROUND The ratio between the lengths of the second and fourth fingers (digit ratio: 2D : 4D), a purported negative correlate of prenatal androgen exposure, has been inversely related to age at menarche. However, a recent study found high digit ratios in carriers of a single variant in the LIN28B gene, which has been linked to delayed menarche. METHODS We investigated the association of digit ratio and age at menarche in 299 pre-menarcheal girls aged 5-12 years who participated in a longitudinal cohort study in Bogotá, Colombia. Finger lengths were measured at baseline and the occurrence of menarche was periodically ascertained over a median 32 months of follow-up. We used time-to-event analysis to estimate median ages at menarche as well as hazard ratios for menarche according to tertiles of the digit ratio for each hand. RESULTS Estimated median age at menarche was lower for girls in the lowest digit ratio tertile of the right hand compared with those in the highest (12.0 vs. 12.3 years; P-value = 0.04). After adjustment for baseline age, height- and body mass index-for-age z-scores, the hazard of menarche was 86% higher in girls of the lowest digit ratio tertile (hazard ratio 1.9 [95% confidence interval 1.2, 2.9]) compared with those in the highest digit ratio tertile of the right hand. No significant associations were found with the left hand. CONCLUSIONS Digit ratio was positively associated with age at menarche in this longitudinal investigation, consistent with results from a recent gene-linkage study.

The association between caesarean section and asthma or allergic disease continues to challenge

The rate of caesarean section (CS) has increased in developed countries and is now the most common surgical procedure in women of reproductive age. According to the World Health Organization, CS is indicated in up to 15% of deliveries, yet the majority of developed countries currently exceed this recommendation (1). This suggests that the increase is due to a rise in elective, prelabour CS, without a clear medical indication, rather than the need for emergency CS. Mode of delivery may affect outcomes such as asthma and allergic disease in children many years after birth. Previous meta-analyses have reported a moderate 20% increased risk of allergic rhinitis and asthma in children delivered by CS (2), but no association with atopic dermatitis/eczema (3). More recently, studies linking the risk of asthma to mode of delivery have examined the roles of emergency CS after the onset of labour, versus elective prelabour CS (4–6), and instrumental use during vaginal delivery, involving forceps or vacuum extraction (7). Some studies have also performed sophisticated sibling analyses (5,6). Most of these aspects were reviewed by Pyrh€ onen et al. (8) in a recent issue of Acta Paediatrica, in a paper that further extends the existing literature. The authors aimed to provide further clarification of the association between CS and the occurrence of allergic manifestations – food and pollen allergies, hay fever, atopic eczema and asthma – in a group of children aged between 1 and 4 years old (8). The target population (N = 4,779) was identified from the Finnish nationwide population register, and questionnaire data on 3181 participants were merged with allergy test results from skin prick tests, IgE antibodies and open food challenges. While consistent with a null hypothesis, the authors’ negative, nonsignificant findings on the association between CS and any allergic manifestation or positive test results for food, pollen or animal allergens also need to be considered in the context of a number of factors. These are limited power from not enough participants, and methodological issues pertaining to study design and the definitions of exposures and outcomes. However, the strengths of the study included objective markers for several allergic outcomes. While the authors also emphasised the representativeness of the sample, there should be some concern about participation bias and selection for blood testing, as well as potential recall bias for perinatal data. It would also have been very interesting to see mode of delivery; vaginal delivery, emergency and elective CS and instrumental delivery, explored in greater detail. Potential shortcomings aside, it is very important that negative findings such as these are reported and published, in order to add to the growing body of literature on this far from resolved topic. The choice of birth mode of delivery is made based on maternal characteristics and anticipated paediatric outcomes. It is also related to the choice and preference of the pregnant mother or couple, as well as local clinical practice. Obstetricians assess the mode of delivery based on timing, progress and the degree of foetal distress. Normally a spontaneous vaginal delivery is considered the safest mode of delivery for both mother and child. The choice of emergency procedures, namely emergency CS or instrumental vaginal delivery, is based on many factors, such as maternal compliance, degree of foetal stress and progress of labour. If the baby needs to be delivered quickly, instrumental vaginal delivery is the best choice if the cervix is fully dilated and the foetal head is in a good position. Otherwise an emergency CS is normally the fastest and safest way of delivering the baby, when there are signs of foetal distress or when elective CS had already been agreed, but the woman has gone into labour before the planned procedure and instrumental or spontaneous vaginal delivery is not an option. An elective CS is chosen for maternal reasons, including extreme fear of labour, or a combination of maternal and foetal reasons, such as malpresentation, two or more previous CS procedures or multiple gestation. A few recent studies have distinguished between elective CS and emergency CS. Of the 37 171 children included in the Norwegian Mother and Child Cohort Study, those delivered by CS had an increased likelihood of current asthma at 36 months of age [relative risk 1.17, 95% confidence interval (CI) 1.03–1.32], with similar findings among children delivered by emergency and elective CS. Two studies based on the Swedish national health registers showed an increased risk of asthma in children born with CS, but provided different and conflicting results for emergency and elective CS (5,6). Mechanisms to explain the association between birth mode of delivery and subsequent asthma or atopy could involve confounders such as maternal smoking, socio-economic status or family history of asthma. Sibling studies therefore provide an excellent opportunity to study the association between CS and asthma independent of shared environmental and genetic factors. Full siblings share approximately half of their segregating genes, some intrauterine exposures, maternal factors and early environment. In addition, siblings may

Cancer risks in twins and singletons from twin and non-twin families.

The unique intrauterine environment has been proposed to put twins at increased risk of certain cancers compared to singletons, still large population comparisons have generally indicated lower risks in twins. To improve the understanding of potential twin influence on cancer we compared twins to their singletons siblings, to target a unique twinning influence. Singletons from twin families were contrasted to singletons from non‐twin families to further capture potential twin family influence on risk of cancer. Family relations were identified using the Swedish Multi‐Generation Register. Among individuals born between 1932 and 1958, 49,156 twins and N = 35,227 singletons were identified from 18,098 unique twin families. All incident cases of specific cancer types were identified in the National Cancer Register up to the end of 2007. Standardized survival functions were estimated using weighted Cox proportional hazard regression and the corresponding cumulative risks plotted against age. Overall, primary cancers were identified in 9% and 18% of all male and female twins, compared to 11% and 19% of their male and female singleton siblings. When specific cancer sites were compared using standardized cumulative risk plots, no consistent statistically significant differences were noted either between twins and singletons of twin families or between singletons of twin and non‐twin families. Despite a different intrauterine experience, twinning does not seem to have any greater negative influence on life‐time risks of cancer. The findings also indicate that twin family membership has no substantial influence on cancer risks.

Are Epidemiological Approaches Suitable to Study Risk/Preventive Factors for Human Birth Defects?

Birth defects are a major cause of infant morbidity and mortality and contribute substantially to long-term disability. One out of every 33 babies is born with some type of birth defect. Despite decades of research on environmental, behavioral, and genetic risk factors, the vast majority of birth defects still occur without a known cause. It is possible that birth defects are largely stochastic (and unavoidable) events, at which efforts to investigate their causes would be futile and unjustified. In this commentary, we argue for the continued research into risk/preventive factors of human birth defects, and outline why epidemiological studies are suitable for such endeavors. First, we discuss what factors to target (genetic or environmental) and how to define the pertinent research questions. Then, we present a short review of both epidemiological contributions in the past and approaches to advance the field in the future. After considering also their limitations, we conclude that modern epidemiologic approaches are invaluable to advance our understanding of risk factors for human birth defects, and that interdisciplinary collaborations will also be essential to further our knowledge.

Antiepileptic drugs in pregnancy, and duration of pregnancy, birth weight, length and head circumference:

Background: Non-inferiority trials are associated with methodological challenges. The European Medicines Agency (EMA) does not have a guideline on designing non-inferiority trials and recommend to define the non-inferiority margin based on clinical and statistical considerations. However, they do not recommend a specific method to determine the margin. Objectives: To assess the challenges in designing non-inferiority trials for drugs intended to be marketed in Europe. Methods: Using the database of the Dutch Medicines Evaluation Board (MEB), a search in recent (2014 and 2015) final EMA scientific advice letters was conducted to identify design proposals that were sent by pharmaceutical companies to the EMA about non-inferiority trials. Each scientific letter is for one drug, and it includes proposals for different aspects of the trial with a response from the EMA to each proposal. The proportion of the accepted proposals by the EMA was assessed taking into account the therapeutic class and the type of the drug application (orphan vs other drugs) using generalized estimating equations with an exchangeable correlation matrix to account for clustering of proposals within letters. Results: The EMA accepted 142 of 232 (61%) of the total proposals. Almost 65% of the proposals were for three therapeutic classes: anti-infectives (most common), drugs for endocrine disorders (mainly anti-diabetics), and oncology drugs. The EMA acceptance did not differ between proposals for endocrine drugs vs anti-infectives (OR: 1.30, 95%CI 0.52 to 3.24) and between oncology drugs vs anti-infectives (OR: 0.54, 95%CI 0.12 to 2.47). The EMA acceptance also did not differ between orphan vs other drug applications (OR: 0.47 95%CI 0.19 to 1.14). The non-inferiority margin was the main challenge, only 25 of 61 (41%) proposals for the choice of the margin were accepted. There was no common approach proposed by pharmaceutical companies to define the margin (the recommended approach by the EMA was proposed for only 18 of 61 margins) nor a common method of the recommended approach. Conclusions: There are many questions about the design of non-inferiority trials with the choice of the inferiority margin as the main challenge. We did not find that the challenge was related to one of the three most common therapeutic classes or to a type of drug applications. This study shows that more explicit guidance from the EMA on the rationale for choosing different approaches to define the margin is needed.against myocardial infarction in UK adults aged at least 65y Background A recent investigation using routinely collected health records found the influenza vaccine to be effective against heart failure. However, treatment of overt myocardial infarction (MI) events is important in preventing progression to heart failure, especially in older adults, yet evidence for the association between respiratory disease and subsequent MI is from observational data and subject to confounding bias.Background: Cough and angioedema are well-known adverse effects of angiotensin-converting enzyme (ACE) inhibitors. Some observational studies in patients using ACE inhibitors have observed that women have a higher incidence of cough and angioedema than men. Objectives: To evaluate based on randomized controlled trials (RCTs), whether the risks of developing cough and angioedema with ACE inhibitors are modified by sex. Methods: We searched PubMed and Cochrane databases for all years to August 2016. We included RCTs that contain information about the incidence of cough and angioedema in users of ACE inhibitors and controls (active/placebo) in men and women. We performed meta-analyses using the random effects model. Pooled risk ratios (RRs) for cough and angioedema associated with ACE inhibitors in women and men were estimated and tested for interaction. Results: We included four RCTs in our analysis (three studies for cough and two studies for angioedema). We found that there was no difference in the RR to develop cough or angioedema for ACE inhibitors versus controls between women and men. For cough in women, the RR was 3.70; 95% CI (2.55-5.35) and for men, 2.61; 95% CI (1.30-5.27) (P value for interaction 0.39). For angioedema, these RRs were 5.56; 95% CI (2.45-12.62) and 6.35; 95% CI (1.81-22.36), respectively (P-value for interaction 0.86). Conclusions: Our meta-analyses show that the risks of developing cough and angioedema associated with ACE inhibitors are not modified by sex. However, these findings should be interpreted cautiously due to limited number of studies involved.

Outcome-dependent associations between short interpregnancy interval and offspring psychological and educational problems : a population-based quasi-experimental study

Background Causal interpretation of associations between short interpregnancy interval (the duration from the preceeding birth to the conception of the next-born index child) and the offsprings psychological and educational problems may be influenced by a failure to account for unmeasured confounding. Methods Using population-based Swedish data from 1973-2009, we estimated the association between interpregnancy interval and outcomes [autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), severe mental illness, suicide attempt, criminality, substance-use problem and failing grades] while controlling for measured covariates. We then used cousin comparisons, post-birth intervals (the interval between the second- and third-born siblings to predict second-born outcomes) and sibling comparisons to assess the influence of unmeasured confounding. We included an exploratory analysis of long interpregnancy interval. Results Interpregnancy intervals of 0-5 and 6-11 months were associated with higher odds of outcomes in cohort analyses. Magnitudes of association were attenuated following adjustment for measured covariates. Associations were eliminated for ADHD, severe mental illness and failing grades, but maintained magnitude for ASD, suicide attempt, criminality and substance-use problem in cousin comparisons. Post-birth interpregnancy interval and sibling comparisons suggested some familial confounding. Associations did not persist across models of long interpregnancy interval. Conclusions Attenuation of the association in cousin comparisons and comparable post-birth interval associations suggests that familial genetic or environmental confounding accounts for a majority of the association for ADHD, severe mental illness and failing grades. Modest associations appear independently of covariates for ASD, suicide attempt, criminality and substance-use problem. Post-birth analyses and sibling comparisons, however, show some confounding in these associations.