Obstetrics and Gynecology International 3.7.5. Infections and Antibiotics. Most antibiotics have no apparent teratogenic eﬀects in man but in a few such asso- ciations have been suggested, either from epidemiological studies (e.g., erythromycin [33]) or from pharmacological considerations (e.g., trimethoprim which has a folic-acid antagonistic eﬀect [34]). Among infections, most interest has been shown in viral infections because of the well- known teratogenic eﬀect of rubella and some other viral infections. Viral infections are no reason for antibiotic use but undoubtedly such treatment is often given anyway. It is also possible that adequate antibiotic treatment is given for a secondary infection following a virus infection which could have increased the birth defect risk. Secondary eﬀects of the infection can also be considered, for example, the possible harmful eﬀects of high fever [35]. 3.7.6. How to Deal with the Problem of Confounding by Indication? One straight forward way is to compare women treated with drugs with women not treated with drugs but with the same disease. A classical example is anticonvulsants and epilepsy where untreated epilepsy repeatedly has been shown to have no detrimental eﬀect on the embryo [36]. Epilepsy is a heterogeneous disease with very variable severity and it is therefore likely that the disease panorama is diﬀerent among untreated and treated women. Certain other diseases are so severe that treatment is always needed, for example, diabetes type 1, and untreated patients are nearly impossible to ﬁnd. A second possibility exists when various drugs can be used at the same underlying disease. An example is the use of SSRI drugs at maternal depression. Among the four main SSRI drugs used in Sweden, a signiﬁcant diﬀerence was seen between the eﬀect of paroxetine and the other SSRI drugs on cardiovascular defects (Table 8) [24]. This approach, however, is complicated by the fact that SSRI drugs are used at many diﬀerent conditions other than depression. One such indication is anxiety and panic disorders where a special drug, for example, paroxetine, may be favoured. So there may still remain a confounding by indication. Detailed information on the indication for use may be diﬃcult to get in a study large enough for the detection of teratogenic eﬀects on speciﬁc malformations. Also given the same underlying disease, diﬀerences in severity could be related to drug selec- tion. This, for instance, could explain the diﬀerence in terato- genic eﬀects of tricyclic antidepressants and SSRI drugs [24]. Another example of the use of two alternative drugs for similar (although not quite identical) reasons is ery- thromycin and phenoxymethyl penicillin. The former drug but not the latter was associated with an increased risk for a cardiovascular defect [33]. In order to characterize disease status and severity, various clinical measurements can be used. In small studies this can be based on questionnaire or interview informa- tion aimed at such a characterization, ideally performed prospectively before the outcome of the pregnancy is known. Examples are studies based on information from teratology information services where, at the contact with the woman who seeks advice, speciﬁc questions on the reason for the Table 8: Association between maternal use of SSRI drug in early pregnancy and occurrence of cardiovascular defects in the infant [21]. Odds ratio (OR) with 95% conﬁdence intervals (95% CI) adjusted for year of birth, maternal age, parity, smoking, and BMI. The cardiovascular defect rates in the four SSRI groups diﬀer 2 signiﬁcantly: χ(3 d. f ) = 12.5, P < 0.01. SSI drug Fluoxetine Citalopram Paroxetine Sertraline Number of cardiovascular defects 21 37 24 26 OR 1.31 0.86 1.66 0.74 13 95% CI 0.85–1.02 0.62–1.20 1.09–2.53 0.50–1.09 drug use can be made and also some standardized quan- tiﬁcation of disease severity. Unfortunately such projects usually result in rather small numbers of exposed infants, and for studies of birth defect risks, they would most likely be strongly underpowered. The same is true for speciﬁc research projects based on data from one or a few clinics dealing with a speciﬁc group of diseases, for example, centres for the treatment of epilepsy. In retrospective case-control studies, a memory bias can be obtained not only on drug use, but also on disease characterization. Most studies on birth defect risks which are powered to detect moderate risk increases must utilize register informa- tion where a recording of detailed disease histories is diﬃcult. One way to solve the problem is to use a case-control design and base disease evaluations on medical records, prepared before the pregnancy outcome was known, if such records can be retrieved and are reasonably well standardized. Another possibility which has been used for instance in studies by SSRI drugs [37] is to characterize disease and disease severity by available health data, for example, number of visits to doctors for speciﬁc reasons. Based on such information a propensity score can be built for each patient which makes it possible to match or adjust for disease severity. The eﬃciency of this method depends on the selection of variables used for the propensity scoring. Often information from the time before the pregnancy is used which may not be a valid scoring for the patient in the beginning of the pregnancy when birth defects are formed. 3.8. How Eﬀective Is an Adjustment for Confounding? What- ever the technique of identiﬁcation and adjustment for confounding which has been used, the question of its eﬀectiveness remains. The situation is rather simple if an observed eﬀect disappears when a true confounder has been taken into consideration, like in the examples of smoking or drug use and the birth of an infant with Down syndrome (see the previous). It is then reasonable to conclude that no direct eﬀect of the exposure has been demonstrated. If a residual eﬀect of the exposure remains, however, this can be due to incomplete identiﬁcation or adjustment for the confounder(s). Some examples will be discussed. In most instances, the confounding eﬀect of maternal age is moderate and adjustments based on 5-year maternal