The Problem of Confounding in Studies of the Effect of Maternal Drug Use on Pregnancy Outcome

In most epidemilogical studies, the problem of confounding adds to the uncertainty in conclusions drawn. This is also true for studies on the effect of maternal drug use on birth defect risks. This paper describes various types of such confounders and discusses methods to identify and adjust for them. Such confounders can be found in maternal characteristics like age, parity, smoking, use of alcohol, and body mass index, subfertility, and previous pregnancies including previous birth of a malformed child, socioeconomy, race/ethnicity, or country of birth. Confounding by concomitant maternal drug use may occur. A geographical or seasonal confounding can exist. In rare instances, infant sex and multiple birth can appear as confounders. The most difficult problem to solve is often confounding by indication. The problem of confounding is less important for congenital malformations than for many other pregnancy outcomes

No increased risk of infant hypospadias after maternal use of loratadine in early pregnancy

The original report published in 2001 on a possible association between maternal use of loratadine and an increased risk of infant hypospadias, based on data in the Swedish Medical Birth Register 1995-2001, has been followed up by continued surveillance in the same register. The original “signal” was based on 15 infants with hypospadias among 2780 loratadine-exposed infants born, representing an adjusted odd ratio of about 2.3, statistically significant. Since then another 10 cases have been identified, and 12.5 expected. For the period 2001-2004, another 1911 loratadine-exposed infants have been identified and only two had hypospadias (4 expected). Our present position is that the primary finding was a “signal” which had occurred by chance and the follow-up agrees with independent studies which indicate an absence of an association. This illustrates the care with which apparent statistically significant increases have to be handled when no prior hypothesis exists

Population-based study of antiepileptic drug exposure in utero—Influence on head circumference in newborns

AbstractPurposeTo study the effect of AED exposure on head circumference in the newborn.MethodsData on all Swedish singletons births between 1995 and 2005, over 900,000 births, were obtained from the Swedish Medical Birth Registry. The effects of AEDs on birth-weight-adjusted mean head circumference (bw-adj-HC) were estimated by comparison with data from all births in an analysis which was adjusted for year of birth, maternal age, parity, maternal smoking, and maternal body mass index.ResultsA significant reduction of mean bw-adj-HC was seen after both carbamazepine (CBZ) (standard deviation scores (SDS)=0.15, p<0.001) and valproic acid (VPA) (SDS=0.10, p=0.04) in monotherapy. No effect on mean bw-adj-HC was seen for phenytoin, clonazepam, lamotrigine and gabapentin. There was a significant increase in the occurrence of microcephaly (bw-adj-HC smaller than 2 SD below the mean) after any AED polytherapy (OR=2.85, 95% CI: 1.74–4.78) but not after AED monotherapy or monotherapy with CBZ or VPA. CBZ or VPA was taken by 71% of the pregnant mothers on AED, and the usage increased over time.ConclusionsCBZ and VPA in monotherapy during pregnancy reduce mean bw-adj-HC. AED polytherapy increases the rate of microcephaly but no significant effect is seen of AED monotherapy. The possible significance for the further development of the child is uncertain but should be explored

Optic nerve hypoplasia: Risk factors and epidemiology.

OBJECTIVES: To study the epidemiology of optic nerve hypoplasia. DESIGN AND METHODS: Children with optic nerve hypoplasia and visual impairment were identified through the Swedish Register of Visually Impaired Children. Pre- and perinatal characteristics were obtained from the Medical Birth Registry and by scrutinizing pregnancy and delivery records. Clinical characteristics of children with optic nerve hypoplasia are described. The following risk factors were studied: maternal age, parity, maternal smoking, gestational duration, birth weight, delivery method, Apgar score, maternal disease during pregnancy, drugs used in early pregnancy. RESULTS: Young maternal age, first parity, maternal smoking, preterm birth and factors associated with preterm birth were risk factors for optic nerve hypoplasia. There was an indicated association with the use of fertility drugs and antidepressant drugs. CONCLUSIONS: Optic nerve hypoplasia is apparently associated not only with other anomolies, notably of the central nervous system, but also with signs of general disturbance in fetal development

Maternal morbidity and mortality in in-vitro fertilization.

Pregnancies following in-vitro fertilization (IVF) are known to be at increased risk of a number of pregnancy- and delivery-related complications when compared with non-IVF pregnancies. Most of these complications seem to be due to underlying fertility problems. Ovarian stimulation carries a marked risk for two serious conditions - ovarian torsion and ovarian hyperstimulation syndrome - both of which are relatively rare. Although some common pregnancy complications show an up to five times increased risk over non-IVF pregnancies, the absolute frequencies are still low for most of these conditions. However, an increased risk of placenta praevia might be to some extent due to the IVF procedure. No long-terms effects on cancer risk or mortality can be linked to the IVF procedure, although follow-up time is still relatively short