Drugs in Pregnancy and Lactation: Tenth Edition



PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Low Risk



The human pregnancy experience with trastuzumab is limited to six cases, three of which involved 1st trimester exposure. No congenital malformations were noted in the infants and all were developing normally. However, fetal renal toxicity, as evidenced by oligohydramnios or anhydramnios, was observed in four cases. The toxicity might have been secondary to inhibition of epidermal growth factor receptor 2 (HER2) in the fetal kidneys but additional study is required. The toxicity appears to be reversible when trastuzumab is stopped. Although the action of this receptor in human fetal development requires study, HER2 protein expression is high in many embryonic tissues, such as cardiac and neural tissues, and blocking this expression may be harmful. Trastuzumab has a very long elimination half-life and could be present in the maternal system for ≤5 months after the last dose.


Trastuzumab, a recombinant DNA-derived humanized monoclonal antibody (an IgG1 kappa), selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor 2 (HER2) protein. It is indicated, either alone or in combination with paclitaxel, for the treatment of patients with metastatic breast cancer whose tumors overexpress the HER2 protein. Trastuzumab is administered as an IV infusion. The mean elimination half-life, after a 4 mg/kg loading dose followed by a weekly maintenance dose of 2 mg/kg, was 5.8 days (range 1–32 days) (1).

No evidence of impaired fertility or fetal harm were observed in female cynomolgus monkeys administered doses up to 25 times the weekly human dose of 2 mg/kg. However, HER2 protein expression is high in many embryonic tissues, such as cardiac and neural tissues. Early death was observed in embryos of mutant mice that lacked this protein. Trastuzumab was not mutagenic in multiple assays or clastogenic in one test (1).

It is not known if trastuzumab crosses the human placenta. The antibody does cross the placentas of cynomolgus monkeys in both early (gestational days 20 and 50) and late (gestational days 120 and 150) pregnancy. The presence of trastuzumab in the serum of infant monkeys had no adverse effect on growth or development from birth to 3 months of age (1).

Six case reports have described the use of trastuzumab during pregnancy (27). A 28-year-old woman had undergone bilateral mastectomy for breast cancer, followed by chemotherapy with cyclophosphamide, doxorubicin and paclitaxel, and then radiation therapy (2). She then received trastuzumab 580 mg every 3 weeks. Pregnancy was diagnosed at 23 weeks’ gestation, 3 weeks after the last dose of trastuzumab. Anhydramnios was present with normal appearing fetal kidneys and an estimated fetal weight of 475 g. The anhydramnios slowly resolved and a normal 2950-g female infant was delivered vaginally at 37.5 weeks’ with Apgar scores of 8 and 9, at 1 and 5 minutes, respectively. The placenta pathology was unremarkable with normal fetal membranes. The infant had normal renal function at birth and no evidence of pulmonary hypoplasia. The 6-month-old child was doing well with growth at the 75th percentile (2).

In another 2005 case report, a 26-year-old woman with breast cancer was treated with trastuzumab, paclitaxel, fluorouracil, epirubicin, and cyclophosphamide, followed by a left mastectomy and radiation therapy (3). Fourteen months later, in the 27th week of pregnancy, multiple hepatic metastases were detected. She was treated with trastuzumab (4 mg/kg loading dose, then 2 mg/kg every week) and vinorelbine (25 mg/m2 weekly for 3 weeks followed by a week of rest) until 34 weeks’ gestation. Oligohydramnios was noted during therapy. Because of decreased fetal movement, labor was induced at 34 weeks’ gestation and a healthy 2.6-kg male infant was delivered vaginally with Apgar scores of 9, 9, and 10 at 1, 5, and 10 minutes, respectively. At 6 months of age, the infant was healthy and developing normally (3).

A 30-year-old woman with breast cancer was treated with epirubicin, cyclophosphamide, fluorouracil, a bilateral mastectomy, and radiation therapy (4). She was enrolled in a clinical trial and was randomized to receive trastuzumab 736 mg as a loading dose and then 523 mg every 3 weeks for the first year. Conception occurred 3 days after her second cycle. A third cycle was apparently given before she was withdrawn from the study. She delivered a normal female infant at term (no other details provided) (4).

A 38-year-old woman at 17 weeks’ in her second pregnancy had spinal-cord compression secondary to metastatic disease 7 years after undergoing treatment for breast cancer (5). Treatment had consisted of surgery, six cycles of fluorouracil, methotrexate, and cyclophosphamide, radiotherapy, and then 5 years of tamoxifen. She was given radiotherapy to the cervical vertebrae, with lead shielding of the uterus to protect the fetus. At about 26 weeks’ gestation, she received trastuzumab 8 mg/kg and paclitaxel 175 mg/m2. A second cycle of trastuzumab (6 mg/kg) and paclitaxel was given 3 weeks later. At 26–32 weeks’, fetal abdominal circumference stopped growing and amniotic fluid decreased to near anhydramnios. At the end of this period, the volume of both fetal kidneys was below the 5th percentile and the fetal bladder was barely visible. Corticosteroids were given for fetal lung maturity and a cesarean section delivered a growth-restricted 1.460-kg (10th percentile) male infant. Complications in the newborn included bacterial sepsis with hypotension, transient renal failure, and respiratory failure. The renal impairment resolved within 14 days. The infant was discharged home at 6 weeks weighing 2.335 kg and was developing normally at 12 weeks of age. Although the cause of the fetal renal impairment was not known with certainty, it was noted that epidermal growth factor receptors are expressed in the kidney during fetal development and blocking these receptors may have prevented normal kidney growth and development (5).

A 2007 case report described a woman treated during the first 24 weeks of pregnancy with trastuzumab (6). The patient had a history of breast cancer with multiple metastases that had been treated with surgery, paclitaxel, carboplatin, trastuzumab, and radiation. She had been on trastuzumab exclusively for a year when pregnancy was diagnosed at 5 weeks’ gestation. Trastuzumab was continued until 24 weeks’ at which time it was stopped because of reversible, asymptomatic maternal heart failure (low ejection fraction). At 37 weeks’, a healthy 2.6-kg female infant was delivered by cesarean section with Apgar scores of 9 and 10 at 1 and 5 minutes, respectively. At 2 months of age, the infant’s weight, height, and head circumference were 4.4 kg (25th percentile), 55 cm (25th percentile), and 40 cm (50th percentile), respectively. No abnormalities were found on physical and neurological examination and her development was within normal limits for age (6).

Another 2007 case report described a 28-year-old woman with a history of radical mastectomy, chemotherapy, and radiotherapy 1 year before pregnancy (7). Because of metastases, she was treated with docetaxel and trastuzumab at 23 and 26 weeks’ gestation, trastuzumab alone at 27 weeks’, and docetaxel alone at 30 weeks’. Trastuzumab was omitted at 30 weeks’ because an ultrasound revealed anhydramnios and fetal growth at the 5th percentile. The anhydramnios was thought to be due to trastuzumab. At 33 weeks’, oligohydramnios was noted. An elective cesarean section was conducted at 36 weeks’ to deliver a 2.23-kg male infant with Apgar scores of 7 and 9 at 1 and 5 minutes, respectively. No evidence of positional deformations or respiratory abnormalities from the prolonged low amniotic fluid was noted and the neonatal urine output was normal. The development of the infant also was normal (7).

Because of the unknown potential for embryo–fetal harm, two reviews recommended that the use of trastuzumab in pregnancy should be avoided or limited until adequate human pregnancy experience is available (8,9). However, as noted in one review, compared with standard chemotherapy, the use of trastuzumab could improve the pregnancy outcome for both the mother and her fetus (8).


No reports describing the use of trastuzumab during human lactation have been located.

Human immunoglobulin G also is excreted into breast milk (1,7). The effect of this exposure on a nursing infant is unknown. In adults, adverse effects include left ventricular dysfunction and congestive failure, anemia, leucopenia, diarrhea, and an increased incidence of infection. The manufacturer recommends that women should not breastfeed while receiving trastuzumab and for 6 months after the last dose (1).


1.Product information. Herceptin. Genentech, 2007.

2.Watson WJ. Herceptin (trastuzumab) therapy during pregnancy: association with reversible anhydramnios. Obstet Gynecol 2005;105:642–3.

3.Fanale MA, Uyei AR, Therialult RL, Adam K, Thompson RA. Treatment of metastatic breast cancer with trastuzumab and vinorelbine during pregnancy. Clin Breast Cancer 2005;6:354–6.

4.Waterston AM, Graham J. Effect of adjuvant trastuzumab on pregnancy. J Clin Oncol 2006;24:321–2.

5.Bader AA, Schiembach D, Tamussino KF, Pristauz G, Petru E. Anhydramnios associated with administration of trastuzumab and paclitaxel for metastatic breast cancer during pregnancy. Lancet Oncol 2007;8:79–81.

6.Shrim A, Garcia-Bournissen F, Maxwell C, Farine D, Koren G. Favorable pregnancy outcome following trastuzumab (Herceptin®) use during pregnancy—case report and updated literature review. Reprod Toxicol 2007;23:611–13.

7.Sekar R, Stone PR. Trastuzumab use for metastatic breast cancer in pregnancy. Obstet Gynecol 2007;110:507–10.

8.Leslie KK. Chemotherapy and pregnancy. Clin Obstet Gynecol 2002;45:153–64.

9.Kelly HL, Collichio FA, Dees EC. Concomitant pregnancy and breast cancer: options for systemic therapy. Breast Dis 2005–2006;23:95–101.