The incidence of cancer during pregnancy is estimated to be in 1 in 1000 pregnancies.¹ The delivery of anti-cancer therapies during pregnancy poses a number of physiological, safety and ethical challenges; one must balance best maternal care with safety to the fetus. There is established evidence that some chemotherapies can be safely delivered from the second trimester of pregnancy, for example, anthracycline-containing regimens platinum agents and taxanes used in breast and gynaecological cancers.² However, in the era of targeted and immunological treatments, optimal cancer care is no longer limited to chemotherapy-based regimens alone. Commonly used novel biologic agents for cancers that affect women of childbearing age, such as melanoma, breast cancer and lymphoma have limited safety data in pregnancy. Here, we review the current safety evidence for a number of commonly used agents (Table 1).

Table 1. Biologic agents in pregnancy

Monoclonal antibodies (mAbs)

Most therapeutic mAbs are IgG, which can be actively transported across the human placenta. Unlike chemotherapy, mAbs are generally considered to be safest during the first trimester of pregnancy because transplacental transport occurs in the second and third trimesters, following the development of placental transporting systems at approximately 14 weeks gestation.³

Rituximab is a mAb against the CD20 antigen and is commonly used in B-cell lymphomas and chronic lymphocytic leukaemia, as well as other immune-mediated conditions. In a meta-analysis of 102 pregnancies in which rituximab was used for multiple sclerosis or neuromyelitis optica spectrum disorders within six months of conception, 78 live births and 12 spontaneous abortions were reported. Myelosuppression and CD19+ lymphopenia occurred in 39% of neonates, all of which normalised within six months post-delivery.⁴ The current recommendation for rituximab is to use with caution, preferably in the first and early second trimesters.^{2 3}

Conversely, there are a number of mAbs that are contraindicated in pregnancy.^{2 3} Anti-angiogenesis agents such as bevacizumab, which are commonly used in gynaecological and colorectal cancers, are absolutely contraindicated in pregnancy. Aside from the theoretical risk of pre-eclampsia due to concurrent risk of hypertension and proteinuria, there is evidence from animal models demonstrating their harmful effects on embryogenesis and placental development resulting in decreased fetal body weight and fetal death.³ Likewise, human epidermal growth factor receptor 2 (HER2) targeted therapies, such as trastuzumab and pertuzumab (used predominately in breast and gastric cancers) can also be detrimental to embryonic development. Trastuzumab has been the most widely studied in pregnancy. A study of 18 cases demonstrated it carries a high risk of severe oligohydramnios, especially when given in the second or third trimester, with 73% of pregnancies thus affected.⁵ However, a case series of 61 patients who continued pregnancy after prior exposure to trastuzumab (16 cases during and up to 3 months after trastuzumab exposure, and 45 cases >3 months after trastuzumab exposure) did not demonstrate adverse short-term fetal outcomes.⁶ Therefore, HER2-targeted agents are contraindicated in pregnancy; however, women who become accidentally pregnant during trastuzumab administration can be counselled regarding the possibility of ceasing trastuzumab and continuing their pregnancy.^{2 3}

Immune checkpoint inhibitors (ICIs)

ICIs have revolutionised the treatment of many malignancies over the last decade. Commonly used ICIs are immunoglobulin G4 (IgG4) antibodies which inhibit programmed death-1 (PD-1), PD-ligand 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA4). These play a key role in switching off inhibitory immune regulation, thereby activating the immune system. Immune regulation is imperative for maternal tolerance in pregnancy, and IgG4 antibodies can be transferred across the placenta. Thus, ICIs are likely to have an effect on pregnancy.^{1 3}

A case series of seven women with metastatic melanoma who were administered ICI during pregnancy, reported increased pregnancy complications including miscarriages, prematurity (mean gestational age at delivery was 30.4 weeks) and lower birth weight (mean weight of neonates at delivery was 1267g).¹ Fetal immune-related adverse effects (such as congenital hypothyroidism) have also been observed due to maternal exposure to ICI.^{1 3} Therefore, ICIs are currently not recommended in pregnancy.

Tyrosine kinase inhibitors (TKIs)

In contrast to mAbs, which require a transporting system for transplacental passage, TKIs are able to easily cross the placenta. The various molecular pathways that are targeted by many TKIs are often also implicated in physiological fetal development, and therefore use of TKIs in pregnancy may result in developmental abnormalities.

BRAF and MEK inhibitors, such as dabrafenib and trametinib, are used in BRAF V600E-mutated melanoma and other malignancies. The evidence for their use in pregnancy is limited to isolated case reports, two of which reported healthy neonates, one reported fetal growth restriction and emergency delivery at 30 weeks, and another resulted in early preterm delivery due to significant maternal adverse events.³ As these agents have not been studied sufficiently to provide a clear recommendation, they are currently not recommended in pregnancy.^{2 3}

EGFR inhibitors are standard of care for lung cancers with activating EGFR mutations. In animal models, use of erlotinib resulted in embryo death. However, three cases of live birth with no fetal anomalies have been reported after use of erlotinib during pregnancy and two cases after use of gefitinib.² There have also been five reported cases of ALK inhibitors (alectinib, crioztinib and ceritinib) used in women with non-small cell lung cancer during pregnancy without any newborn malformations or developmental abnormalities (at 30 months of follow up).⁷ However, as these agents have not been studied sufficiently during pregnancy , they are not currently recommended in pregnancy.²

Imatinib is a multitargeted TKI towards BCR-ABL, c-Kit and platelet-derived growth factor (PDGF) used in chronic myeloid leukaemia. When given in the first trimester, it has been associated with a high rate of complex fetal malformations (approximately 10% in a case series of 125 pregnancies).⁸ However, a small study of seven women who ceased imatinib prior to conception then restarted after the first trimester resulted in only one spontaneous abortion.⁹ Therefore, imatinib is contraindicated in the first trimester; there are limited data for its use after the first trimester.^{2 3}

Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, used in BRCA-mutated breast and ovarian cancers, has no human data in pregnancy. Animal studies of olaparib in pregnancy caused teratogenicity and embryo-fetal toxicity. It is therefore also contraindicated in pregnancy.

Conclusion

As standard-of-care cancer treatment continues to evolve to include novel biologic agents including mAbs, TKIs and ICIs, information about the safety of these agents during pregnancy is crucially needed. Use of biologic anti-cancer agents should be carefully considered with respect to both the safety and interest of the mother and child.

Our feature articles represent the views of our authors and do not necessarily represent the views of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG), who publish O&G Magazine. While we make every effort to ensure that the information we share is accurate, we welcome any comments, suggestions or correction of errors in our comments section below, or by emailing the editor at [email protected].

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