In a recent study, researchers have unveiled concerning findings regarding the use of anti-ERBB2 inhibitors during pregnancy, which include trastuzumab, pertuzumab, and lapatinib. These drugs, employed to combat cancers, have been associated with substantial and specific risks to both pregnancy and the developing fetus.
Trastuzumab, for instance, is currently contraindicated during pregnancy due to its high risk of causing oligohydramnios and anhydramnios, coupled with a lack of data regarding other potential fetal outcomes. Similar restrictions extend to other anti-ERBB2 agents due to insufficient evidence demonstrating their safety during pregnancy.
These drugs are historically employed in cases of ERBB2-positive and hormone receptor-negative breast tumors due to their efficacy. However, their usage during pregnancy is often contingent on the expectation of greater maternal benefit compared to potential fetal harm. This necessitates in-depth studies to ascertain their safety under these circumstances.
The study, as published in JAMA Network Open, relied on the World Health Organization (WHO) VigiBase, a repository of adverse drug reaction case reports spanning from 1967, to gather information on maternal and fetal outcomes following exposure to drugs contraindicated in pregnancy, including anti-cancer drugs.
The research aimed to establish the probability of maternal or fetal complications with ERBB2 inhibitors when compared to other antineoplastic agents.
Key Findings
The researchers conducted a case-control study involving over 3,500 cases of pregnant individuals with cancer who received treatment during pregnancy. These cases were categorized into anti-ERBB2 recipients and those who received other drugs, with approximately 330 and 3,200 cases in each group, respectively.
In the anti-ERBB2 group, the average participant age was around 31 years, with nearly half of the patients originating from the United States. The majority of these cases were related to breast cancer. Trastuzumab was the most commonly administered drug, with some patients receiving trastuzumab-emtansine or lapatinib, and 55 patients on pertuzumab.
Over 50% of exposures in the anti-ERBB2 group involved anti-ERBB2 monotherapy, with most patients using drugs in this category. The remaining 50% were prescribed molecular-targeted therapies.
Chronic myeloid leukemia (CML) was slightly more prevalent than breast cancer at 30% and 23%, respectively. Approximately one in seven reports on the use of anti-ERBB2 drugs during pregnancy dated to 2009 or earlier, in contrast to about 10% for other anti-cancer drugs.
The majority of reports in both groups contained information on adverse pregnancy outcomes, as well as fetal or newborn outcomes, with 61% and 56% in the anti-ERBB2 and other drug categories, respectively. This aligns with previous research findings.
Oligohydramnios was reported in roughly 25% of exposures, while preterm birth was reported in over one in seven cases. Intrauterine growth restriction (IUGR) was reported in 10% of cases.
Respiratory disorders in newborns and spontaneous miscarriages accounted for approximately 7% of exposures, with only a single complication reported in each case, except for five cases.
The study revealed that the likelihood of oligohydramnios in the anti-ERBB2 group was approximately 18 times higher than in recipients of other drugs. A similar trend was observed, to a lesser extent, for respiratory tract disorders at birth or kidney failure during the newborn period, both of which were increased by nine-fold in children born to anti-ERBB2 recipients compared to those on other drugs.
These findings underscore the role of ERBB2 in the development of the lung, skin, intestine, and kidneys during intrauterine life.
For the trastuzumab-emtansine combination alone, the likelihood of cardiovascular defects was five times higher, while fetuses exposed to lapatinib were at an eight-fold increased risk of IUGR.
Implications and Recommendations
The use of anti-ERBB2 agents during pregnancy has been associated with significant adverse outcomes for both pregnancy and the fetus, including congenital disabilities and IUGR, compared to the use of other anti-cancer drugs. Due to the association of lapatinib and trastuzumab-emtansine with teratogenicity, contraindicating their use during pregnancy is recommended.
When oligohydramnios is identified during anti-ERBB2 therapy in pregnancy, careful monitoring and withdrawal of these agents are advised, despite their valuable role in treating hormone receptor-negative breast cancers in pregnant women. This approach necessitates thorough investigation to confirm its safety, emphasizing the need for dedicated research in this regard.
Additional studies are needed to corroborate these findings, as VigiBase data quality can vary due to multiple sources contributing to the database.
