Pregnancy outcome after first trimester exposure to corticosteroids: a prospective controlled study
Introduction
Glucocorticosteroids (GCS) are used for a variety of conditions common in women of reproductive age (i.e. allergy, asthma, collagen vascular diseases, inflammatory bowel disease, etc.). GCS cross the human placenta [1], [2]. Diffusion through the placenta is more rapid for fluorinated GCS [3]. Hydrocortisone is metabolized by 11β-ol-dehydrogenase, which is abundant in the placenta, to cortisone, while other GCS can cross the placenta unchanged (e.g. dexamethasone). Almost without exception, the GCS were potent teratogens in laboratory animals at doses that were less than or similar to those used in humans. The primary defect induced in most species was cleft palate [4]. The published animal studies raised the question of whether GCS are also human teratogens. Two case reports of neonates with isolated cleft palate after pregnancy exposure to cortisone were published in 1956 [5], [6]. Fraser and Sajoo [7] summarized 17 case series including 468 GCS exposed women in early pregnancy and concluded that the teratogenic potential of GCS was so low as to be undetectable from the data available. Prospective cohort studies in humans have not shown a teratogenic effect but had limited power (Table 1) [8], [9], [10], [11], [12], [13], [14], [15], [16], [17]. During the 1990s, several large retrospective case control studies have been published supporting the association between oral clefts and GCS in pregnancy (Table 2) [18], [19], [20], [21]. In a recent meta-analysis the Mantel–Haenszel summary odds ratio for major malformations with all cohort studies was 1.45 [95% CI, 0.80, 2.60], and 3.03 [95% CI, 1.08, 8.54] when one of the studies [11], which did not separate major and minor malformations, was removed. Summary odds ratio for case control studies examining oral clefts was significant: 3.35 [95% CI, 1.97, 5.69] [17]. With the available data, the safety of GCS in human pregnancy is controversial. The primary objective of our study was to prospectively evaluate the rate of major anomalies after in utero exposure to GCS compared to the rate in a control group of pregnant women who were counseled for non-teratogenic exposure. Secondary endpoints of interest were pregnancy outcome, rate of preterm births, birth weight and gestational age at delivery. We also recalculated a cumulative odds ratio for the published controlled cohort studies [8], [9], [11], [12], [13], [17] with our study using similar criteria as described in the previous meta-analysis [17].
Section snippets
Methods
All women who contacted (directly or through their health care providers) the Israeli Teratogen Information Service (TIS) between the years 1988 and 2001 for information about gestational systemic exposure to different GCS in the first trimester of pregnancy or to non-teratogenic agents were prospectively enrolled in the study. Details of exposure were collected during pregnancy, using a structured questionnaire. Standardized data collection forms were used to record the following information
Results
We prospectively collected and followed up 311 pregnancies exposed to systemic GCS at least in the first trimester of pregnancy. Most women were exposed only during the first trimester (65.4%), 8.4% were treated during the first and second trimesters, while 26.2% were treated throughout pregnancy. The majority of the women in our cohort were exposed to prednisone (70.0%). The distribution of the various GCS is presented in Fig. 1 and the indications for treatment in Fig. 2. The majority of
Discussion
The present study, which is the largest prospective controlled cohort on systemic GCS exposure in gestational weeks 4–13, followed-up 311 pregnancies to examine the rate of major malformations. Both the GCS exposed cases and their controls had malformation rates within the expected baseline risk for the general population. The incidence of major anomalies recognized at birth among live-born infants is 1–3% [11]. The incidence is as high as 5% if one includes malformations detected later at
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Served as partial fulfillment of the requirements for the MD degree of the Hadassah Medical School, Hebrew University.