more_vert
Researchers have looked at mothers’ medication use before and during pregnancy to see whether babies conceived with assisted reproductive technology (ART) are more likely to be exposed to potentially teratogenic medicines than non-ART babies.
One in every 16 babies born in Australia is conceived using assisted reproductive technology (ART). ART babies are known to have higher rates of birth defects than non-ART babies but it has proven difficult to disentangle the reason for this.
Birth defects may be more common in ART babies due to one or more elements of ART treatment itself, the underlying subfertility of parents, other pre-existing parental medical conditions, greater parental age, or some combination of these. For this reason, researchers have begun splitting “non-ART” conceptions into more informative comparison groups including subfertile conceptions (achieved without ART but after a history of ART or subfertility investigation/treatment) and fertile conceptions (achieved without ART and no known history of ART or subfertility investigations/treatment).
One factor that has not been considered for women undergoing ART is the role of teratogenic medicines — medications known or suspected to cause fetal harm — particularly when taken during the first trimester. Previous studies estimate that 2–3% of all pregnancies in Australia are exposed to teratogenic medicines, but we don’t have data for ART babies specifically.
Our research
We looked at individual-level, routinely collected records for all livebirths and stillbirths in Western Australia over 18 months; (N=57 681). These records were linked to reproductive technology, hospital, and Pharmaceutical Benefits Scheme (PBS) records; allowing identification of conceptions achieved with ART or ovulation induction, or to subfertile untreated or fertile parents. We looked at PBS medicines dispensed in the year before, and during, each pregnancy to see how many had been exposed to medicines classified as D or X medicines by the Therapeutic Goods Administration (TGA). Category D medicines are those suspected to cause fetal harm, but where the risk may be outweighed by the therapeutic benefit in individual cases (for example, anti-epileptics), while Category X medicines are absolutely contraindicated during pregnancy due to the high risk of fetal harm (eg, isotretinoin).
Reassuringly, we found that exposure to Category X medicines during pregnancy was rare across all conception groups (<0.5%). Similarly, we found that less than 1% of all pregnancies were exposed to Category D medicines in the first trimester. However, pregnancies achieved with ART or ovulation induction were significantly more likely to have a first trimester exposure to Category D medicines: 4.9% for ART conceptions and 2.0% for ovulation induction conceptions, compared with 0.6% for fertile and 1.3% for subfertile conceptions. The specific Category D medicines most likely to be used in the first trimester by the ART and ovulation induction groups were medroxyprogesterone acetate and immunomodulators (eg, azathioprine). We noted that immunomodulators were not more commonly used by these groups in the year before pregnancy, indicating that they were not being used for treatment of a pre-existing chronic condition.
Our study has limitations. Obtaining linked, whole-population data for this project involved a lengthy approval, linkage, extraction, and validation process. Consequently, these data are now more than a decade old. More recent data are needed to better understand current practice. Our study did not include miscarriages or terminations before 20 weeks gestational age, some of which may have been teratogen-induced. This means we may have underestimated early-pregnancy exposure to Category D/X medicines. There are also limitations to the TGA risk classification system for medicines during pregnancy. However, we consider it to be the most useful available tool for identifying potential “red flag” medicine exposures during pregnancy, and to allow comparability with previous research.
Implications/next steps
While we found that overall exposure to teratogenic medicines is low, exposure was highest in pregnancies arising from ART. We think that the higher exposure we saw in ART (and ovulation induction) pregnancies is likely fertility treatment-related rather than reflecting underlying chronic conditions. Medroxyprogesterone may have been used to treat threatened or recurrent miscarriage, and immunomodulators are reportedly used during ART to manage repeated implantation failure. More research is needed to examine whether use of these medicines is linked to specific birth defects. For example, medroxyprogesterone acetate exposure in pregnancy has been linked to genital defects in girls and hypospadias in boys. It is possible that use of these medicines may be a modest contributor to the higher rate of birth defects previously observed in ART babies.
Going forward, the challenge for clinicians is to balance the potential risks and benefits of all medicines during pregnancy, including those for fertility treatment. The vast majority of ART babies are healthy, and ART pregnancies are not inherently unsafe; however, this research does underscore the importance of personalised medical care for women undergoing fertility treatment and close monitoring for women in early pregnancy.
Dr Anna Kemp-Casey is a research fellow with the Quality Use of Medicines and Pharmacy Research Centre at the University of South Australia.
Professor Roger Hart is the Medical Director of Fertility Specialists of Western Australia, National Medical Director of City Clinic, and Professor of Obstetrics and Gynaecology at The University of Western Australia.
Dr Michele Hansen is a research fellow with The Kids Research Institute Australia and the Centre for Child Health Research at the University of Western Australia.
Conflict of interest statement: Professor Hart is a shareholder in CHA SMG; he has received educational sponsorship from MSD, Merck-Serono, Origio, Igenomix and Ferring Pharmaceuticals. The other authors have no competing interests to declare.
The statements or opinions expressed in this article reflect the views of the authors and do not necessarily represent the official policy of the AMA, the MJA or InSight+ unless so stated.
Subscribe to the free InSight+ weekly newsletter here. It is available to all readers, not just registered medical practitioners.
If you would like to submit an article for consideration, send a Word version to mjainsight-editor@ampco.com.au.