Timing of chemo during pregnancy may affect congenital malformation risk

Exposure to chemotherapy in the first 12 weeks of pregnancy may be associated with an increased risk of major congenital malformations in offspring, a recent study showed.

“We found an association between chemotherapy before 12 weeks of gestation and increased risk of congenital malformations detected during pregnancy or at birth,” noted the researchers.

Using the International Network on Cancer, Infertility and Pregnancy (INCIP) database, the researchers identified 755 pregnant women with cancer (median age at diagnosis 33 years) who received chemotherapy during pregnancy between 1977 and 2019.

A majority of women (59.3 percent) were diagnosed with cancer during their second trimester. Breast cancer was the most common diagnosis, occurring in 59.7 percent of women, followed by lymphoma (18.3 percent). Live birth occurred in 98.7 percent of women. The most common chemotherapy regimens were anthracyclines (42.4 percent), anthracyclines plus taxanes (16.2 percent), and platinum-based regimens (14.3 percent).

Major congenital malformations occurred in 3.6 percent of offspring (n=27), while minor congenital malformations occurred in 1.9 percent (n=14).

Chemotherapy exposure prior to 12 weeks gestational age was associated with an increased risk of major congenital malformations compared with chemotherapy initiation after 12 weeks gestation (21.7 percent vs 3.0 percent; odds ratio [OR], 9.24, 95 percent confidence interval [CI], 3.13–27.30). [JAMA Network Open 2021;4:e2113180]

The risk of minor congenital malformations did not differ between chemotherapy exposure prior to or after 12 weeks gestational age (4.3 percent vs 1.8 percent; OR, 3.13, 95 percent CI, 0.39–25.28), with the rates comparable to that expected in the general population.

Of the 29 women who began chemotherapy before 12 weeks gestation, 17 were unaware of their pregnancy. Three of these women experienced a miscarriage, and three opted for termination. Six of the remaining 23 neonates had congenital malformations.

“[C]hemotherapy attacks rapidly proliferating cells and is minimally selective, [and as such,] it also puts a developing foetus at risk of teratogenic effects,” the authors said.

The mechanisms behind the teratogenic effects of chemotherapy remain undetermined. “The nature of teratogenesis is extremely complex; individual genetic susceptibility, specific timing of cytotoxic exposure, and specific type of co-medication all determine the spectrum of anomalies,” they added.

The general recommendation is to hold chemotherapy until after the completion of organogenesis, approximately after the first trimester. [Int J Gynecol Cancer 2009;19(suppl 1):S1-S12] However, due to uncertainty regarding timing of conception and the fact that certain systems continue to develop following this period raises doubts on this recommendation.

“Based on our findings, we suggest that when cancer is diagnosed in early pregnancy, chemotherapy can be initiated from 12 weeks onward. The introduction of a 1-week safety period could be considered to further minimize the risk of chemotherapy-induced congenital malformations,” the authors said, highlighting the importance of accurate ultrasonographic dating to enable this. They noted that the effect of the various chemotherapy regimens on malformation risk could not be determined in this study.

The authors pointed out that 23 women in total were unaware of being pregnant at time of chemotherapy initiation. “[This underscores] the importance of adequate anticonception counselling and pregnancy testing at the start of chemotherapeutic treatment in young women with cancer,” they said.

Additionally, counselling on the potential risks of foetal malformations should be carried out in the case of diagnosis of an aggressive cancer that does not allow for treatment delay, they said.