LONDON – One of the largest studies of pregnancy outcomes after bisphosphonate exposure has found no evidence for major teratogenic effects in women with inflammatory diseases and glucocorticoid-induced osteoporosis and women with bone diseases.
However, the investigators for the French case-control study did find higher rates of neonatal complications and spontaneous abortion among infants of mothers with systemic inflammatory diseases and bisphosphonate use, but the results could be the result of confounding because of the severity of underlying disease and exposure to other medications.
“I think if a women is worried about bisphosphonate exposure during pregnancy, this study can bring her some reassuring news,” although it does not necessarily mean that bisphosphonates are safe during pregnancy, first author Aurélien Sokal said in an interview at the European Congress of Rheumatology. He is a medical student at Beaujon Hospital, Clichy, France, but conducted the study with colleagues during his time in training in the rheumatology department at Paris-Sud University.
“Very little is known about the effect of bisphosphonates on pregnancy outcomes and fetal development,” Mr. Sokal said, and they are feared for possible teratogenic effects in pregnancy because of their long half-life in bone – where they can be released even 1 year after their administration – as well as their ability to cross the placenta and high affinity for high-turnover bones, such as those in a growing fetus. He also noted that abnormalities in bone length, low birth weights, and bone diseases have been observed in rats exposed to bisphosphonates during gestation.
The study compared 23 patients with inflammatory diseases and bisphosphonate exposure during pregnancy against 92 controls with inflammatory diseases but no exposure, and 16 with bone diseases and exposure to bisphosphonates against 64 healthy controls with no underlying disease or bisphosphonate use. The patients came from a database assembled by the French Reference Center of Teratogenic Agents (CRAT) in Paris that has collected information since 1975 on patients referred for any drug exposure during pregnancy and followed their care through the end of pregnancy. The 39 patients who were exposed to bisphosphonates took the drugs during 1987-2014 within the 6 weeks preceding (n = 6) or during pregnancy (n = 33). They had a mean age of 33 years.
Systemic inflammatory diseases
The systemic inflammatory diseases found in women in the study included systemic lupus erythematosus (SLE), rheumatoid arthritis, antiphospholipid syndrome, systemic vasculitis, and other diseases. Of the 23 cases with systemic inflammatory diseases, 16 took risedronate, 5 took alendronate, 1 took etidronate, and the bisphosphonate was unknown in 1. Bisphosphonate exposure occurred before pregnancy in 2, during the first trimester in 21, second trimester in 4, third trimester in 4, and in all trimesters in 1.
Other types of medications were used significantly more often by patients with systemic inflammatory diseases than by controls: steroids (78% vs. 47%), methotrexate (26% vs. 5%), colchicine (17% vs. 2%), proton pump inhibitors (22% vs. 5%), and reproductive hormones (17% vs. 2%). Controls took antimalarials significantly more often (50% vs. 22%).
Voluntary abortions occurred at a similar rate in both exposed and unexposed women (12% vs. 9%), whereas significantly more therapeutic pregnancy terminations occurred among women exposed to bisphosphonates (17% vs. 1%). Live births occurred in 94% of the remaining exposed pregnant women, compared with 80% of controls.
Newborns were delivered at a mean of 38 weeks in both cases and controls, and there were no differences in birth weight, length, or rate of congenital malformation (9% vs. 2%).
The two malformations in neonates from exposed women had an uncertain link to bisphosphonates. One involved a neonate with severe malformative syndrome and advanced bone maturation who had a mother with SLE and was exposed to multiple drugs, including mycophenolate mofetil. The other neonate had ductus arteriosus, inguinal hernia, and negative otoacoustic emission; the baby’s mother had Crohn’s disease but had not taken known teratogenic drugs.
Two neonatal malformations among control women involved one neonate with severe malformative syndrome who had a mother with SLE but who was without exposure to known teratogenic drugs, and another with convulsant encephalopathy whose mother had systemic sclerosis and took pentoxifylline, cisapride, dihydroergocryptine, and colchicine.
However, cases had a 25% rate of neonatal complications, compared with a significantly lower 5% in controls. No infants had hypocalcemia.
Bone diseases
The 16 women with bone diseases included 9 with osteoporosis, 3 with malignancy, and 4 with miscellaneous bone conditions. A total of 5 received intravenous bisphosphonates and 11 received oral drugs (9 alendronate, 2 other). Most received a bisphosphonate in the first trimester (9 patients), but also 4 received it before pregnancy and 3 in the second trimester. More pregnancy terminations (voluntary or therapeutic) occurred among women with bone disease when compared with controls (19% vs. 3%), but the difference was not statistically significant. However in the remaining patients, live births occurred significantly less often in cases than in controls (69% vs. 100%). Birth weight, length, gestational age at birth, and the rates of congenital malformation and neonatal complications were otherwise similar.