USE OF BISPHOSPHONATES IN PREGNANCY

Bisphosphonates inhibit bone resorption by osteoclasts, as well as hydroxyapatite crystal formulation and dissolution, thereby reducing bone remodelling and turnover. They are licensed for the treatment of osteoporosis (both idiopathic and glucocorticoid-induced), Paget’s disease of the bone, and skeletal pain associated with metastatic breast cancer, and are also used off-license in children in the management of osteogenesis imperfecta. Six bisphosphonates are currently available for clinical use in the UK: alendronic acid, ibandronic acid, pamidronate disodium, risedronate sodium, sodium clodronate and zoledronic acid.

 As bisphosphonates are incorporated into bone, the terminal half-life is long (up to 10 years). Fetal exposure could therefore potentially occur in pregnant women with a history of bisphosphonate use prior to conception as a consequence of mobilisation of bisphosphonates stored in maternal bone.

 Some animal studies have demonstrated increased embryofetal resorption/decreased implantation, impaired fetal bone ossification, urinary tract anomalies and orofacial clefting following antenatal exposure to bisphosphonates at doses lower than equivalent human therapeutic doses. Impaired uterine contractility which correlated with decreased maternal calcium concentrations and resulted in obstructed labour has also been described.

 The available human exposure data are limited to a small number of uncontrolled case reports and three small cohort studies which collectively describe the outcomes of approximately 100 pregnancies with bisphosphonate exposure either prior to conception or during pregnancy. Although these data do not clearly indicate that in utero bisphosphonate exposure is directly associated with adverse fetal, pregnancy or neonatal outcomes, they are insufficient to permit an accurate assessment of the risk. Controlled studies have demonstrated possible associations between preconceptual/gestational bisphosphonate exposure and increased risk of miscarriage and neonatal complications. However, these findings may reflect methodological data limitations and/or uncontrolled data confounding. Transient disturbances in neonatal calcium levels have been reported in a small number of cases following maternal bisphosphonate use either prior to or during pregnancy. Monitoring of neonatal calcium levels could therefore be considered if an infant has been exposed in utero.

 Exposure to bisphosphonates at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy. Where exposure to bisphosphonates has occurred, either prior to or during pregnancy, skeletal development and neonatal calcium levels may be warranted. However, other risk factors may be present in individual cases. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.