Serial examination of 20,248 newborn fetuses and infants: Correlations between drug exposure and major malformations

Abstract

Maternal medication during the first trimester of pregnancy has been discussed as a risk factor for development of birth defects. The correlation between maternal drug use and major malformations was investigated in a population‐based case‐control study in Mainz. Over a period of 5 years (1990–1994), 20,248 livebirths, stillbirths, and abortions underwent physical and sonographic examination, and anamnestic data were collected. A total of 1,472 births with congenital anomalies (cases) and 9,682 births without major and minor malformations (controls) were analyzed. We distinguished between 30 different drug categories, which were divided into medication taken continuously (before and during pregnancy; CM) and acute medication (drugs given within the first 3 months of gravidity; AM). Statistically highly‐significant results [CM: Odds Ratios (OR) 1.2, Confidence Intervals (CI) 1.1–1.4, P = 0.008; AM: OR 1.2, CI 1.1–1.3, P = 0.008] were established for maternal drug use in correlation to birth defects. For the majority of combinations between drugs and specific malformations no teratogenic risks were found. However, statistically significant associations were recorded for antiallergics and heart anomalies (CM, AM) as well as musculoskeletal anomalies (AM); for bronchodilators and heart anomalies (CM, AM); for antiepileptics and anomalies of the internal urogenital system (CM), as well as cleft palate/cleft lips (AM); for thyroid hormones and anomalies of the nervous system (CM, AM), as well as anomalies of the external urogenital system (CM, AM); for insulin and anomalies of the musculoskeletal system (CM); for digitalis and anomalies of the musculoskeletal system (AM). © 1996 Wiley‐Liss, Inc.

Use of thyroid hormones in relation to pregnancy: a Danish nationwide cohort study

“…To our knowledge there have been no previous studies that have sought a possible association between over‐use of thyroid hormones and malformations. Use of levothyroxine during pregnancy has been associated with a slightly higher risk of malformations . Also, even though most recommendations aim to facilitate the benefits of treatment with levothyroxine in pregnant women with hypothyroidism, several studies have shown that women are reluctant to use any medications during pregnancy, even those that are probably harmless and potentially necessary .…”

Maternal thyroid disease, thyroid medication use, and selected birth defects in the National Birth Defects Prevention Study

“…One large prospective study (Heinonen et al, 1977) and two large retrospective studies (Khoury et al, 1989; Queisser‐Luft et al, 1996) examined maternal thyroid disease or thyroid medication use and a variety of birth defects. All three studies reported positive associations between hyperthyroidism (Heinonen et al, 1977; Khoury et al, 1989) or thyroid hormone use (Queisser‐Luft et al, 1996) and central nervous system defects overall with ORs ranging from 2.0 to 4.1. Khoury et al (1989) noted increased ORs for hyperthyroidism and specific central nervous system defects, encephalocele, and hydrocephaly, with ORs of 5.26 (95% CI, 1.16–24.0) and 3.05 (95% CI, 1.23–7.59), respectively.…”

“…The NBDPS does not have a category for “intestinal malrotation” for comparison with the positive results from Khoury et al Our OR for thyroid disease and isolated longitudinal limb deficiencies (OR, 2.1, 95% CI, 0.8–5.2), though not significant, was similar to the estimate by Khoury et al for hypothyroidism and all limb deficiencies (OR, 1.92; 95%CI, 1.04–3.54). Queisser‐Luft et al (1996) noted an OR of 3.9 (95% CI, 1.9–8.0) for first‐trimester thyroxine use and “external genitourinary defects,” the majority of which were hypospadias (personal communication, A. Queisser‐Luft 2008). We observed an OR of 1.7 (1.0‐2.7) for periconceptional thyroxine use and hypospadias.…”

“…Other than the association with craniosynostosis, which is supported by animal studies and human case series (Akita et al, 1994; Daneman and Howard, 1980; de Lima et al, 1999), the relatively few epidemiologic studies on this topic have not provided consistent evidence for or against an association between maternal thyroid disease and birth defects (Heinonen et al, 1977; Adams et al, 1989; Khoury et al, 1989; Ferencz et al, 1997; Queisser‐Luft et al, 1996; Cedergren et al, 2002). Positive associations have been reported for thyroid disease or use of thyroid medication and selected congenital heart defects (CHDs), central nervous system defects, intestinal defects, hypospadias, and limb deficiencies (Heinonen et al, 1977; Khoury et al, 1989; Queisser‐Luft et al, 1996). However, other than associations between hyperthyroidism and central nervous system defects, none of the findings were observed in more than one study.…”

Thyroid Medication Use and Birth Defects in the National Birth Defects Prevention Study

“…A teratogenic effect of treatment with thyroid hormone is unlikely, because it is the same as thyroid hormone that is produced endogenously. Yet, some animal studies suggest that thyroid hormone supplements may be teratogenic (Giroud et al, ; Miyamoto, ; Lavado‐Autric et al, ), and epidemiologic studies have mixed results (Heinonen, ; Queisser‐Luft et al, ; Wikner et al, ; Browne et al, ; Samadi et al, ). Accumulating evidence suggests anti‐thyroid medications may have teratogenic effects, with MMI associated with more severe birth defects (Browne et al, ; Clementi et al, ; Bowman and Vaidya, ; Yoshihara et al, ; Andersen et al, , ; Andersen and Laurberg, ; Laurberg and Andersen, , ).…”