12 ) ‰ ( tea 3.2 r s iad3.1 a sopp 3 y dh2.9 n a ) 2.8 % ( tsn2.7 a s sre 2.6 p e itd2.5 n A 1 2 3 4 5 6 7 8 Calendar month 9 10 11 12 Figure 3: Rates of antidepressant use (percentage, unbroken line) and of hypospadias (per thousand, broken line) for the diﬀerent calendar months. and the monthly rate of conceptions leading to hypospadias is, however, rather weak and not statistically signiﬁcant (r = 0.26, P = 0.20), and this correlation is still weaker if the formative period of hypospadias (8 weeks or more after LMP) is considered instead. 3.7. Confounding by Indication. The strongest and most dif- ﬁcult to control confounding is confounding by indication: that the disease or complaint which is the reason for drug use in itself aﬀects pregnancy outcome. The use of insulin during early pregnancy is associated with an increased risk for many types of congenital malfor- mations. As insulin is practically only used at diabetes and a pregnant woman with diabetes type 1 always gets insulin, it is theoretically impossible to separate the eﬀect of disease and treatment. As clinical experience indicates that strict blood suger control in pregnant diabetic women is important for the success of the pregnancy and also probably reduces the birth defect risk, it is generally accepted that the increased malformation risk is due to diabetes and not to insulin even if it can be debated if strict scientiﬁc evidence for this exists. In most instances, the degree of overlap between disease and drug use is not so strong but to disentangle the contribution of the drug and the underlying condition is often diﬃcult. We will take a number of examples to illustrate the dilemma. 3.7.1. Epilepsy and Anticonvulsants. The ﬁrst study that linked epilepsy with an increased risk for a birth defect concerned orofacial clefts [28] and could not distinguish between disease and treatment. Numerous studies have veri- ﬁed that the relationship between epilepsy and birth defects includes many diﬀerent malformations, for example, spina biﬁda, cardiovascular defects, orofacial clefts, hypospadias, that the eﬀects of diﬀerent anticonvulsants vary, and that untreated epilepsy seems not to be associated with an increased birth defect risk. Obstetrics and Gynecology International Anticonvulsants are also used for other medical con- ditions than epilepsy, for example, as mode stabilizers at bipolar disease and sometimes for neuropathic pain (e.g., gabapentin). No large enough studies have been published to evaluate if such use carries a similar risk as when the drugs are used at epilepsy. The general opinion is that anticonvulsant drugs per se represent a teratogenic risk, and notably for valproic acid this risk can be large why such use should be avoided during pregnancy. 3.7.2. Depression and Antidepressants. Antidepressants have in general a low teratogenic potential but some data indicate that tricyclic antidepressants (TCAs) carry a higher birth defect risk than selective serotonin reuptake inhibitors (SSRIs) do, while data for serotonin/noradrenalin inhibitors (SNRIs) are still incomplete. The teratogenicity of TCA is notably evident for cardiovascular defects—a similar eﬀect is indicated in some studies for paroxetine but may be absent for other SSRIs [29] while other studies have found also an eﬀect of ﬂuoxetine [30]. More common eﬀects are seen after antidepressant use in late pregnancy, resulting in preterm birth and increased risks for various forms of neonatal morbidity. In this situation, the importance of the eﬀect of the underlying disease, usually depression, has been much discussed. Some studies describe such eﬀects associated with maternal depression but it is not always clear if consideration has been taken to drug treatments. 3.7.3. NVP and Antihistamines. A classical example of con- founding by indication is the use of certain antihistamines for the treatment of nausea and vomiting in pregnancy (NVP). Studies of such antihistamines have shown a lower than expected rate of birth defects in the oﬀspring and also other signs of a better than expected pregnancy outcome [26]. It does not seem likely that the drugs actually prevent the occurrence of birth defects, and there is some evidence that the strength of NVP is a factor which positively correlates with pregnancy outcome. The probable mechanism is that among the factors causing NVP are hormones produced from the placenta, so a strong NVP (perhaps needing drug therapy) may indicate a well functioning placenta and thereby a decreased risk for a congenital malformation or other pregnancy complications. 3.7.4. Hypertension and Antihypertensives. Some studies have associated the use of antihypertensive drugs in early preg- nancy with an increased risk of birth defects and notably cardiovascular defects. The ﬁrst major study found such a link for ACE-inhibiting drugs [31] but a later study [32] found no diﬀerence between such drugs and other antihypertensives in the risk for birth defects. Little is known about the eﬀect of untreated essential hypertonia on birth defect risk but the possibility that the drug eﬀect is due to confounding by indication has been raised.