Obstetrics and Gynecology International In most situations, infant sex is unrelated to drug exposure and is therefore not confounder, even if the sex distribution among the outcome is skewed. No adjustment for infant sex is then called for. As pointed out above, infant sex may modify the eﬀect of the drug which can be analyzed by subgroup analysis according to sex. 3.5.2. Multiple Birth. The occurrence of multiple birth may be aﬀected by drug treatments even though this situation is rare. One such example is ovulation stimulation with, for instance, clomiphene, leading to an increased rate of twin pregnancies. In most instances, drug treatment in early pregnancy does not aﬀect the rate of multiple births. An example of a possible eﬀect is exposure to SSRI (but not tricyclic antidepressants) when the twinning rate is signiﬁcantly low [2] Some evidence exists that use of folic acid may increase the twinning rate. Most of the changes in twinning rate refer to dizygotic twins. The malformation rate in twin infants diﬀers only little from that in singletons and an increased risk is mainly seen in monozygotic twins. Among dizygotic twins, some conditions associated with prematurity and perhaps with intrauterine crowding may be increased. In a situation when adjustment for twinning is needed, it should be remembered that the eﬀect of drug use on twinning rate concerns dizygotic twins, and if adjustment is made for any twinning, one will underestimate the risk for malformation after the exposure because in the reference population the percentage of monozygotic pairs will be higher than in the exposed population. This was clear in studies of twins born after in vitro fertilization (IVF)—when IVF twins were compared with spontaneously conceived twins, the former appeared to show less neonatal pathology than the latter, but when comparisons were made between unlike sexed (dizygotic) pairs the IVF twins had a worse outcome than the non-IVF twins [27]. 3.5.3. Gestational Duration, Birth Weight, and Intrauterine Growth. Infants with birth defects are sometimes born preterm with low birth weight and signs of intrauterine growth restriction. These expressions are the result of the malformations or have a common cause with the malformations, for example, placental insuﬃciency. They are thus neither intermediaries, nor confounders, and there is generally no reason to adjust for them. Only when a birth defect is studied which is the result of preterm birth, gestational duration can appear as an intermediary. This could, for instance, be the case with undescended testicle and persistent ductus arteriosus, both strongly associated with preterm birth and hardly true malformations. Birth weight strongly depends on gestational duration. If the use of a drug increases the risk of short gestational duration, it will usually also aﬀect birth weight as an intermediary between exposure and outcome and gestational duration should not be adjusted for when one is interested in the eﬀect on birth weight. If one makes such adjustments, a remaining eﬀect on birth weight will indicate that the weight of the infant at each gestational week deviates from the 11 5 4.5 )% 4 ( d em3.5 r o f la 3 M 2.5 2 2.1 2.3 2.5 2.7 2.9 3.1 3.3 3.5 3.7 3.9 With antiasthmatics (%) Figure 2: Percentage of infants with relatively severe malformations and percentage of women who used antiasthmatics in early pregnancy in 21 counties in Sweden (2000–2008). expected weight, which is reasonably an eﬀect of a disturbed intrauterine growth, resulting in small-for-gestational age (SGA) or large-for-gestational age (LGA) infants. These are often interesting outcomes but they can be studied more directly. 3.6. Geographical and Seasonal Confounding. A confounding situation can occur due to an uneven distribution of both drug use and the occurrence or completeness of registration of birth defects. Geographical confounding will be most pronounced when the studied population is distributed over a large area where variations in disease rates and/or in therapeutic traditions may occur and where also occurrence or registration of birth defects may vary. These two sources of variation are usually independent, but if they covary, a confounding can arise. Such an analysis is shown in Figure 2 which compares rates of infants with relatively severe malformations (varying between 2.25 and 3.76%) and rates of women who reported the use of antiasthmatic drugs in early pregnancy (varying between 2.20 and 4.89%) in 21 Swedish counties. A correlation analysis gives r = 0.13, P = 0.57, which suggests that the two variables do not covary signiﬁcantly. Sometimes there is a clear seasonality in drug use. A typical example is drugs for allergy which at least in Northern Europe shows a peak of use during spring. A similar peak is also seen in the use of antidepressants (Figure 3). If also the malformation studied shows a seasonality, a confounding may arise if the eﬀect of such drugs is studied. Obviously, it is not the seasonality at birth which is of interest but the sea- sonality at the formation of the malformation. An example is a possible association between use of SSRI and hypospadias [24] which could tentatively be due to the fact that use of antidepressants in early pregnancy may coincide with a peak of hypospadias in infants conceived during spring. The seasonality of hypospadias is rather weak but there is a peak among infants conceived during April and May which corresponds to the peak in antidepressant use (Figure 3). The correlation between the monthly rate of antidepressant use