Pregnancy outcome following in utero exposure to bisphosphonates
Introduction
Women of childbearing age on long-term glucocorticoid therapy are increasingly being placed on bisphosphonates for the treatment and prevention of secondary osteoporosis [1]. To date, however, data on the use of bisphosphonates in human pregnancy is limited [2], [3], [4], [5].
In two cases, pregnant women with malignant hypercalcemia were given intravenous pamidronate in the third trimester [2], [3]. In both cases, the infants' serum calcium levels decreased over the first days of life, but normalized within 5–10 days. Both infants were developing normally at 10 months and 1 year of age. In the third case report, Rugers-Verhage et al. described a 49-year-old woman treated with oral alendronate throughout her entire pregnancy [4]. The baby's weight was in the 50th percentile at birth and in the 10th percentile at 1 year of age. Bone density, psychomotor development and calcium levels were normal. Follow-up until 1 year of age did not show any abnormalities on physical exam or in psychomotor development. Recently, Ornoy et al. reported the outcome of 24 pregnancies after pre-pregnancy or early pregnancy exposure to alendronate [5]. Thirteen of them also used corticosteroids. They reported 5 spontaneous abortions and no major malformations among the offspring of the 24 women treated with alendronate.
In animal pregnancy toxicity studies with high doses of bisphosphonates, various abnormalities have been reported, including poor fetal body weight gain, delay in the descent of the testes and in the opening of the vagina [6], an increase in the amount of diaphyseal bone trabeculae with a slight shortening of the diaphysis, decreased fetal weight [7], and decrease in neonatal survival [8].
Bisphosphonates inhibit bone resorption, and non-nitrogen-containing bisphosphonates such as etidronate decrease hydroxyapatite formation as well. In addition, osteoblast and bone formation are indirectly decreased [9], [10], [11]. Although their plasma half-life is about 2 h, half-life in bone elimination is extremely long, up to 10 years in the case of alendronate [11]. Since bisphosphonates are stored in bone for long periods of time, they may be mobilized during pregnancy even if the drug has been stopped long before conception. It is, therefore, of utmost clinical importance to address the safety of bisphosphonate use prior to and during pregnancy.
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Methods
We conducted a cohort study with a comparison group to examine pregnancy outcome after bisphosphonate exposure. After the consent was obtained, the patients were recruited from the Motherisk program at the Hospital for Sick Children (Toronto, Ontario, Canada), the Korean Motherisk Program, Department of Obstetrics and Gynaecology, Cheil Hospital, Kwandong University, College of Medicine (Seoul, Korea), and the FRAME Program, Children's Hospital of Western Ontario (London, Ontario). These
Results
Between January 1998 and December 2006, we obtained neonatal outcome follow-up data from 21 infants (17 patients from the Motherisk program; 3 from the Korean Motherisk; and 1 from the FRAME Program). The average age at follow-up was 20 months. Fifteen patients in the bisphosphonate group had first-trimester exposure, and 6 patients discontinued the bisphosphonates within 3 months prior to conception. Bisphosphonates used by our cohort were as follows: alendronate (n = 12), etidronate (n = 5),
Discussion
In our small cohort of patients, we did not observe an increased risk of major birth defects from intrauterine exposure to bisphosphonates prior to conception and during the first trimester of pregnancy. There was one child in our cohort born with Apert syndrome, which has been linked to a gene mutation of the fibroblast growth factor [12]. Our patient had a positive genetic marker for the condition, and therefore, a causative link to bisphosphonate exposure is unlikely.
The mean gestational age
Acknowledgments
Supported partly by CIHR (Canadian Institute of Health Research). Dr. Taguchi was supported by the fellowship from the Research Institute, Hospital for Sick Children.
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These authors equally contributed to the work.