Background/Purpose: Recent ACR guidelines on prevention and treatment of CS-induced osteoporosis state that women of childbearing potential who are at moderate-to-high risk of fracture should be given bisphosphonates. However, safety concerns regarding adverse outcomes restrict the prescription of the drugs in women of childbearing potential. Given that relevant human in vivo data are limited, we conducted a systematic review of available evidence to assess whether bisphosphonate use in pregnancy and preconception phase (<1 year before pregnancy) increases risk of adverse neonatal and pregnancy outcomes.

Methods: A systematic search of PubMed, Cochrane Library and Ovid was performed through December 2017 using MeSH terms and keywords maternal, pregnancy, women of childbearing potential, fetus, neonate, and bisphosphonates. Exclusion criteria included review articles, animal studies, exposure >1 year before pregnancy or post-delivery and non-English language papers. Two reviewers independently screened relevant titles and abstracts removed duplicates and selected 64 papers for full-text review. The primary outcome was all adverse outcomes including abortions, stillbirths, congenital malformations and low birth weight.

Results: 24 papers were included in the final analysis, including 15 case reports, 4 case series, 4 cohort studies and covering the impact of 120 preconception or pregnancy exposures to bisphosphonates on pregnancy or neonatal outcome. The majority of exposures were single-dose. Only 4 studies had a comparator group. Indications for bisphosphonate use were malignancy, CS-induced osteoporosis and bone-related disorders like Gaucher.

The quality of evidence in all studies (using the GRADE approach) was “low” or “very low”. Congenital malformations were reported in 7/120 pregnancies including 2 cardiac valvular defects (VSD and PDA), 1 kidney malformation and 3 bony malformative disorders (see Table 1). Rates of congenital malformation and abortion were comparable in bisphosphonate-exposed and controls in studies with a comparator group. Mean birth weight and gestational age were slightly lower than in the general population. Limiting factors include small sample size with varying bisphosphonate formulations and inclusion of case reports and case series. Few studies had a comparator group. Confounding factors include maternal underlying medical condition, concomitant use of corticosteroid, and other immunosuppression.

Conclusion: Our findings suggest that pre-conception and pregnancy exposure to bisphosphonates does not pose major teratogenic risks. These results will be useful when counselling women about risks related to pregnancy and accidental conception. However, further controlled studies are needed to fully establish safety of bisphosphonate use prior to or during pregnancy.