6 is associated with an increased risk for diabetes type 2 which often goes unnoticed and undiagnosed for a long time and which seems to have a teratogenic action similar to but weaker than that of diabetes type 1 [16]. Information on the two variables which deﬁne body mass index, weight and height, should refer to the time just before pregnancy or possibly to early pregnancy while weight at delivery is aﬀected by weight changes during pregnancy which are of little interest for teratogenesis. The information can be based on anamnestic information given by the pregnant woman (with some uncertainty) or actual measurements at the ﬁrst antenatal visit if this occurs early in pregnancy. As long as the information is collected before the outcome of pregnancy is known, it will be unbiased. 3.4.5. Subfertility. The usual measure of subfertility is how many years the couple has tried to get a pregnancy before they succeeded. Clinically, a waiting time of less than one year is not regarded as indicating subfertility and the concept of subfertility should not be mixed with the concept “time to pregnancy,” which usually indicates the number of menstrual cycles which has passed before conception. It is known that a period of unwanted childlessness increases the risk for adverse pregnancy outcomes [17] including a moderately increased risk for infant congenital malformations (Table 2). This factor is of course especially important in studies of drugs or other treatment for infertility, including in vitro fertilization [18], but also the use of other drugs may be aﬀected by subfertility. In Table 2 it is seen that antidepressant use is reduced at long-standing subfertility (3 years or more), a situation where various treatments including in vitro fertilization may be considered. The same phenomenon is seen for sedatives and hypnotics [2]. Under these circumstances, the women may actively try to increase the chance for conception and a healthy pregnancy by avoiding use of these drug. Use of, for instance, antihypertensives or antiasthmatics, on the other hand, is associated with an increased occurrence of subfertility [2]. This may be due to a direct eﬀect of the underlying disease or the drug on the possibility to conceive. 3.4.6. Previous Miscarriages. A previous miscarriage may increase the risk for a congenital malformation in a newborn, and this risk may increase slightly if more than two previous miscarriages have occurred (Table 2). For some conditions, the relationship can be stronger than that. This can—like threatened abortion during an ongoing pregnancy—act as an important confounder in analyses of drugs which are used to treat these conditions. Some confounding eﬀect can also be obtained for other drugs. In Table 2, for instance, it can be seen that repeated previous miscarriages (3 or more) are associated with an increased use of antidepressants and a similar relation exists for sedatives and hypnotics [2]. 3.4.7. Previous Birth of a Malformed Infant. For many mal- formations, a genetic component is important, for example, orofacial clefts, neural tube defects, and cardiac defects. The presence of an older sibling or other close relative with such a malformation will therefore aﬀect the risk for a Obstetrics and Gynecology International malformation in a new pregnancy. This phenomenon will be a confounder in analyses of drug eﬀects only if the birth of an infant with a malformation will aﬀect the use of drugs in the following pregnancy. There is little information on this available. An ongoing study using the Medical Birth Register in Sweden indicates the complexity of this issue. The odds ratio for using (and reporting) a drug in early pregnancy is actually higher in women who had a malformed infant in a previous pregnancy compared to other women after adjustment for year of birth, maternal age, parity, smoking in early pregnancy, and BMI. The OR is only 1.14 (95% CI 1.08–1.21), and its size depends on the type of malformation that occurred: it is increased for neural tube defects and for cardiovascular defects but not for orofacial clefts, alimentary tract atresia, severe kidney malformations, hypospadias, or chromosome anomalies. The increased OR for neural tube defects is nearly exclusively explained by the use of folic acid. For cardiac defects, the main contribution is not only from insulin but also from psychopharmaca. For any relatively severe malformation, the OR varies with the drug category (Table 3). The highest OR has folic acid, insulin, psychopharmaca, thyroid drugs, and NSAID (nonsteroid anti-inﬂammatory drugs). Also for anticon- vulsants and antihypertensives ORs are high although not statistically signiﬁcant. That folic acid is used more often in the pregnancy following a birth of a malformed infant (notably neural tube defect) is reasonably the result of a therapeutic tradition, notably the recommendation of high doses of folic acid after a pregnancy complicated with a neural tube defect. A protective eﬀect of folic acid for cardiovascular defects has also been suggested even though evidence is less clear in that case. In the (rather few) instances when folic acid use is due to a previous malformation with a signiﬁcant recurrence risk, a confounding will exist. For some other drugs the explanation of an increased OR may be the following. If the woman has a chronic disease like diabetes type 1 which has a marked teratogenic eﬀect, the presence of such a defect (e.g., a cardiovascular defect) in a previous pregnancy can be due to the disease. As this is a chronic condition, any following pregnancy in such women will be characterized by maternal diabetes type 1 and use of insulin. Possibly a similar relationship is seen for hypothyreosis, epilepsy, and chronic hypertonia; all these diseases and drugs used for treating them are associated with a moderately increased risk for infant cardiovascular defects. A previous child with a malformation caused by the disease will then not act as a confounder. A third possible explanation is especially applicable to psychoactive drugs. If the burden of a handicapped or sick child increases the use of this type of drugs, women with a previous birth of a malformed infant will be more likely to use such drugs, and in this situation, the presence of a previous child with a malformation will represent a true confounder. There is little evidence that the birth of a previous mal- formed child will reduce drug use in a following pregnancy. In none of the analyses performed, an OR signiﬁcantly under 1.0 was found.