Loratadine during pregnancy and hypospadias.

To the Editor: In November 2001, 2780 infants exposed to loratadine in utero were identified in The Swedish Medical Birth Registry. Among those infants were 15 cases of hypospadias, compared with 5.6 cases expected (based on a population rate of 1 case per 500 in the general population). The adjusted odds ratio for hypospadias and loratadine exposure was 2.4 (95% confidence interval 1.4–3.4). Continued monitoring suggested that the association was not readily consistent with occurrence by chance. Recently, the Swedish group repeated the analysis for the period 2002–2004 and reported a prevalence ratio of 0.47 (0.06–1.65), a value considerably lower than their earlier report. This new analysis was based on 1911 infants exposed to loratadine in early pregnancy. Other attempts to study this relationship have been hampered by insufficient data and inconsistent results. To examine this association, we conducted a large nationwide case-control study in Denmark, based on administrative medical health databases and linkage to the Danish nationwide prescription database. We identified all boys with hypospadias in Denmark born in the period 1996–2004 from the nationwide Hospital Discharge Registry covering all Danish hospitals. The codes for hypospadias in ICD-10 are Q54.0 (n 640), Q54.1 (n 173), Q54.2 (n 41), Q54.3 (n 9), Q54.4 (n 48), Q54.8 (n 10), Q54.9 (n 654). Using these codes, a total of 1575 cases of hypospadias were identified anytime after delivery. For each case we randomly selected from the Danish Medical Birth Registry up to 10 controls (live male births) without a diagnosis of hypospadias, matched by birth year and mother’s residence. Through the nationwide prescription database, maintained by The Danish Medicines Agency, we identified all prescriptions to the mothers of cases and controls before the date of birth. We used conditional logistic regression to estimate prevalence ratios, controlling for potential confounding factors obtained from the databases, including maternal age, smoking status, birth order, preeclampsia, and prescriptions for ovulation-inducing drugs, antidiabetics, and antiepileptics (Table). We found a negative association between maternal exposure to loratadine and prevalence of hypospadias. Among 1575 cases of hypospadias, 7 cases (0.4%) and 88 controls (0.6%) were exposed to loratadine in the 30 days before conception and during the first trimester. The adjusted prevalence ratio for hypospadias among users of loratadine relative to nonusers was 0.6 (95% CI 0.3–1.4) and the corresponding prevalence ratio for other antihistamines was 1.3 (0.9 –1.9). The adjusted prevalence ratio for hypospadias among users of loratadine during the entire pregnancy relative to nonusers was 0.9 (0.5–1.6) and the corresponding prevalence ratio for other antihistamines was 1.0 (0.7–1.5). Thus, in this large populationbased nationwide study, we found strong evidence that maternal exposure to loratadine does not substantially increase the risk of hypospadias. Our findings do not corroborate the first Swedish study that initiated the hypospadias debate, but they are consistent with the other small studies that have reported on this topic. Several factors should be taken into account when interpreting this study. The full and independent nationwide registration of births, malformations, and prescriptions prevented several types of bias. Any noncompliance with the use of antihistamines and inaccurate data in the databases might bias the estimates of risk towards the null, since this imperfect specificity in routinely recorded data is most likely independent of prescription information.