Table 2.
Targeted therapies during pregnancy.
| Targeted Therapy | Mode of Action | Placental Passage in Humans | Physiological Role of Target in Human Embryonal and Fetal Development | Exposure in 1st Trimester in Humans | Exposure in 2nd and 3rd Trimester in Humans | Evidence Level |
|---|---|---|---|---|---|---|
| Trastuzumab | Monoclonal IgG1 antibody against human epidermal growth factor (HER2) receptors [47] | -low during 1. Trimester -increasing during second and third trimester [46] |
Implantation Cardiac and neural development [46,47] |
25% spontaneous abortion - No congenital malformations [47] No mandatory pregnancy interruption when exposed during the first trimester [46] |
Oligohydramnios (68.1%) (reversible) Fetal renal failure Fetal death due to multiorgan failure due to prematurity, anhydramnios or oligohydramnios (17.3%) [5,46] |
34 cases (Case reports) [5,47] |
| Other anti-Her-2 agents (lapatinib, pertuzumab and T-DM1) | - | No data | Implantation Cardiac and neural development [47] |
Lapatinib: three cases with no congenital malformation [47,49] | No data | Three cases (lapatinib) [49] |
| Bevacizumab | VEGF-specific mAb | No data | Vasculogenesis and angiogenesis of the placenta and in normal fetal development [47] | No data regarding systemic exposure [47] Intravitreal exposure followed by abortion in some cases [47] |
No data regarding systemic exposure [47] Intravitreal injection with no adverse effects [47] |
No reports for systemic application in pregnancy [46,47] |
| Rituximab | mAb IgG targeting the surface antigen CD 20 | transplacental passage increases with gestational age, reaching the maximum during the last 4 weeks of gestation. [46] | Hematopoiesis (lymphocytes) [51] | No congenital malformations [50] Miscarriage rate 21% [51] |
Cytopenia (63% of neonates at full term) -complete neonate recovery from hematotox within 6 months [50] |
A total of 253 pregnancies were reported, but pregnancy outcome was available for 153 pregnancies only [46,50] |
| Imatinib | TKI targeting the bcr-abl tyrosine kinase [47] | Placental transfer documented [47] | -fetal organogenesis [47] | -Major malformations 11% [47] -spontaneous abortion 12.1% [47] |
-no major or minor malformations [47] | Case reports (n > 180) [47] |
| EGFR inhibitors (erlotinib, gefitinib, afatinib and cetuximab) | EGF receptor | Placental transfer documented [47] | Conception Implantation Embryonic development |
No congenital malformation [47] | No congenital malformation [47] | Sparse to no data [47] |
| ATRA (tretinoin) | Carboxylic acid form of vitamin A [47] | Placental transfer documented [47] | Fetal development [47] | Spontaneous abortion [47] | Abnormal cardiac function [47] | Case reports [47] |
| Interferon-a | cytokine | Insignificant placental transfer [47] | Organogenesis [47,52] | 2% major malformations (combination therapy with imatinib) [47] | No data | Case reports [47] |
| Dasatanib | Second-generation TKIs | Placental transfer [47] | Organogenesis [47] | No congenital malformation (three cases) [47] Hydrops fetalis (one case) |
No data | Three cases [47] |
| Nilotinib | Second-generation TKIs | No data | Organogenesis [47] | One case, no congenital malformation [47] | No data | One case [47] |
| Vemurafenib | BRAF-inhibitor | Placental transfer documented [47] | Cardio-faciocutaneous development [47] | No data [47] | No major malformations (one case) [47] | |
| PARP inhibitors (Niraparib, Rucaparib, Olaparib) | Poly adenosine diphosphate [ADP]-ribose polymerase (PARP) inhibitor | No data [53] | No data [53] | No data [53] | No data [53] | No data [53] |
| Anti-PD-1/PD-L1 | Immune checkpoint inhibitors | No data [54] | Maintaining normal fetal tolerance [55] | One case report without spontaneous abortion [56] | No data [54] | One case report [56] |
IgG = immune globulin G; FDA = federal drug administration; HER2 = human epidermal growth factor receptor 2; T-DM1 = transtuzumab emtansine; mAB = mouse antibody; VEGF = vascular endothelial growth factor TKIs = tyrosine kinases inhibitors; bcr-abl = fusion between the Abelson tyrosine kinase gene and the break point cluster gene, EGFR = epidermal growth factor receptor; ATRA = alltrans retinoic acid; BRAF = gene encoding the protein B-Raf; PARP = Poly adenosine diphosphate [ADP]-ribose polymerase; PD-1 = programmed death protein 1; PD-L1 = programmed death-ligand 1 protein.2.5.