Chemotherapy during the first trimester of pregnancy associated with increased risk for congenital malformations in fetus

1. Chemotherapy was associated with an increased risk of major congenital malformations in the initial 12 weeks of pregnancy.

2. These risks and the prevalence of incidental pregnancies concurrent to chemotherapeutic treatments emphasizes the importance of prenatal and perinatal counselling for women of child-bearing age with cancer.

Evidence Rating Level: 2 (Good)

Study Rundown: Although chemotherapy is a mainstay cancer treatment option that targets rapidly proliferating cells, it remains minimally selective as a therapeutic agent and can result in teratogenic effects for the developing fetus in pregnant women with cancer. In recent years, there has been a general consensus that chemotherapy initiated during the first trimester of pregnancy should be avoided, owing to risks of congenital malformations. However, the exact gestational age at which chemotherapy can be safely initiated to avoid congenital consequences remains unclear. In order to evaluate the acute teratogenic consequences of prenatal chemotherapy, this multicenter cohort study assessed the presence of major and minor congenital malformations detected during pregnancy or upon birth in offspring of patients registered in the International Network of Cancer, Infertility and Pregnancy (INCIP). In total, 755 women in the INCIP registry who underwent chemotherapy treatment during pregnancy were enrolled in the study. Of these, the risk of major congenital malformations was increased when initial exposure to chemotherapy occurred before 12 weeks gestational age (21.7% of offspring), compared to significantly lower rates in the general population when chemotherapy was initiated after 12 weeks gestational age (3.0% of offspring). These results suggest that chemotherapy initiated during the first trimester of pregnancy was associated with significantly elevated risk of congenital malformations in the developing fetus. Therefore, in patients where an aggressive cancer diagnosis in early pregnancy requires aggressive chemotherapy, patients should be counseled on the risks of congenital defects in the fetus. In addition, in patients that become pregnant while receiving chemotherapy, prenatal counselling should be offered to discuss the risks of both short- and long-term adverse effects on the fetus. Lastly, counselling regarding sufficient contraception and regular pregnancy tests should be offered to women of child-bearing age with cancer. A limitation of this study was that early miscarriages and terminations of pregnancy may have been underrepresented in the INCIP registry due to improved techniques for recognizing malformations with ultrasound in recent years. This could have resulted in a growing number of pregnancy terminations with recent advancements due to these malformations.

Click to read the study in JAMA Network Open

Relevant Reading: Use of chemotherapy during human pregnancy

In-Depth [retrospective cohort]: This multicenter cohort study assessed all pregnant women who received chemotherapy between 1977 and 2019 registered in the INCIP registry, with analysis completed through February to June 2020. In total, 755 women who underwent chemotherapy during pregnancy were included in the analysis. The median (range) age at cancer diagnosis was 33 (14-48) years. Overall among offspring, the major congenital malformation rate was 3.6% (95% Confidence Interval [CI], 2.4%-5.2%) and the minor congenital malformation rate was 1.9% (95%CI, 1.0%-3.1%). Chemotherapy exposure before 12 weeks gestation was associated with higher rates of major congenital malformations, at 21.7% (95%CI, 7.5%-43.7%; OR, 9.24 [95%CI, 3.13-27.30]) compared to 3.0% when chemotherapy was initiated after 12 weeks gestation (95%CI, 1.9%-4.6%). This rate is comparable to the expected rates of congenital malformations in the general population. Additionally, the rate for minor malformations were similar for exposures occurring before and after the first trimester (4.3% [95%CI, 0.1%-21.9%] vs 1.8% [95%CI, 1.0-3.0]; OR, 3.13 [95% CI, 0.39-25.28]). Finally, in 29 women who received chemotherapy prior to 12 weeks gestation, 17 (58.6%) were unaware of their pregnancy status, and 6 (20.7%) experienced a miscarriage (3 women [10.3%]) or decided to terminate the pregnancy (3 women [10.3%]).

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