Cancer diagnosed during pregnancy is uncommon, complicating between 0.02% and 0.1% of all pregnancies. Nonetheless, due to increasing age of childbearing, the incidence of cancer during pregnancy is likely to increase due to higher incidence of several age-dependent malignancies. The most common malignancies include breast cancer, cervical cancer, malignant melanoma and lymphoma. One of the key challenges in the management of cancer in pregnancy is treating the women with standard chemotherapy regimen, without compromising the safety of the developing foetus. Exposure of chemotherapy in the first trimester is associated with an increased risk of major birth defects, whereas use in the second and third trimesters is associated with intrauterine growth restriction, low birthweight and stillbirth. In this article, we review available data regarding the use of chemotherapeutic agents in pregnancy, and we summarise the neonatal outcomes, including malformations, perinatal complications and long-term follow-up. In addition, the management plan during pregnancy is also discussed.
Highlights
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Pregnant women with cancer should be managed by a multidisciplinary team.
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Maternal benefits and foetal adverse effects should be considered before chemotherapy.
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Chemotherapy in trimester 1 is associated with congenital malformations.
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Chemotherapy in trimesters 2 and 3 is associated with lower birthweight.
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Delivery should be delayed for 2–3 weeks following administration of chemotherapy.
Introduction
Cancer diagnosed during pregnancy is uncommon, complicating between 0.02% and 0.1% of all pregnancies . Nonetheless, due to increasing age of childbearing, the incidence of cancer during pregnancy is likely to increase due to higher incidence of several age-dependent malignancies. The most common malignancies diagnosed in pregnancy include breast cancer, cervical cancer, malignant melanoma and lymphoma , accounting for about 70–80% of pregnancy-associated tumours . Other cancers that have been reported included mainly leukaemia, ovarian cancer and thyroid cancer.
Diagnosis of cancer during pregnancy poses a great challenge to the pregnant women, her family and the medical team. The benefits of cancer treatment for the women and the potential adverse effects to the developing foetus must be carefully considered before commencing treatment. Nonetheless, the health and interests of the women should usually prevail over that of her foetus. Some women may decline treatment even in life-threatening situations due to concern for adverse effects of the treatment on their foetus. Therefore, it is paramount that the women and her family be provided with adequate information, support and sufficient time to allow informed decision.
In order to minimise the risk of foetal exposure, comprehensive and updated information about pregnancy-related risks must be conveyed to women undergoing cancer treatment. As approximately 50% of pregnancies are unplanned, they would have been exposed to the teratogens by the time the pregnancy is confirmed . Therefore, women who are diagnosed with cancer during their reproductive years should be counselled about the use of effective contraception to avoid unplanned pregnancy. Moreover, health-care providers including the woman’s family physicians, oncologists, haematologists, obstetricians and gynaecologists should actively initiate discussions regarding the women’s sexual activity and pregnancy intention, and to avoid any assumptions about the women’s pregnancy plans. For women who are contemplating pregnancy, detailed information should be given on potential teratogenic and reproductive risks associated with the use of antineoplastic drugs in pregnancy.
There are controversies concerning whether pregnancy alters the prognosis of cancer. Several studies have reported that pregnant women tend to have a worse outcome than non-pregnant women . Some have suggested that the changes in hormonal status during pregnancy may adversely affect outcome. However, according to the literature available, it appears that pregnancy does not have a significant adverse effect on maternal survival when compared with non-pregnant women . In this article, we review available data regarding the use of chemotherapeutic agents in pregnancy, and we summarise the neonatal outcomes, including malformations, perinatal complications and long-term developmental follow-up. In addition, the management plan during pregnancy is also discussed.
Teratology
Teratogenesis is defined as the process by which congenital malformations are produced in an embryo or a foetus. Generally, exposures that cause irreversible damage to the structure, function or normal development of an embryo or a foetus are teratogenic . Teratogens include environmental factors such as radiation, therapeutic drugs such as thalidomide, chemicals such as alcohol and certain viruses such as rubella . Teratogenic effects can be variable in range and severity, and they comprise death (miscarriage or stillbirth), malformations, impaired organ function and impaired fertility . In the general population, congenital abnormalities including defects in the structure or function of an organ occur in 1–3% . Among the major abnormalities, around 25% are due to genetic factors and 65% are due to unknown factors. Defects that are associated with drug treatment account for only 2–3% of the abnormalities .
The teratogenicity of a drug is influenced by many factors, such as the timing of exposure, the dose administered, the extent of placental transfer and the duration of exposure. In addition, genetic variability in drug metabolism of the mother and the foetus might explain the different susceptibility of people to the same drugs . In order for the teratogens to result in adverse foetal outcomes, there must be significant amounts reaching the foetus during the critical time period. The majority of drugs reach the foetus through the maternal bloodstream, and the transfer of drugs from the mother to the foetus is enhanced where there is high lipid solubility, loose binding to plasma protein and low molecular weight .
Teratology
Teratogenesis is defined as the process by which congenital malformations are produced in an embryo or a foetus. Generally, exposures that cause irreversible damage to the structure, function or normal development of an embryo or a foetus are teratogenic . Teratogens include environmental factors such as radiation, therapeutic drugs such as thalidomide, chemicals such as alcohol and certain viruses such as rubella . Teratogenic effects can be variable in range and severity, and they comprise death (miscarriage or stillbirth), malformations, impaired organ function and impaired fertility . In the general population, congenital abnormalities including defects in the structure or function of an organ occur in 1–3% . Among the major abnormalities, around 25% are due to genetic factors and 65% are due to unknown factors. Defects that are associated with drug treatment account for only 2–3% of the abnormalities .
The teratogenicity of a drug is influenced by many factors, such as the timing of exposure, the dose administered, the extent of placental transfer and the duration of exposure. In addition, genetic variability in drug metabolism of the mother and the foetus might explain the different susceptibility of people to the same drugs . In order for the teratogens to result in adverse foetal outcomes, there must be significant amounts reaching the foetus during the critical time period. The majority of drugs reach the foetus through the maternal bloodstream, and the transfer of drugs from the mother to the foetus is enhanced where there is high lipid solubility, loose binding to plasma protein and low molecular weight .
Critical periods in prenatal development
The gestational age when exposure occurs is important because the effect exerted by a teratogen is determined by the developmental stage.
The all-or-none period
The all-or-none period covers the time from conception until the formation of somite, on average 8–14 days from conception. Usually, exposure to teratogen during this period leads to either embryonic death or further normal development. Teratogenic insult during this phase may disrupt the processes of implantation, causing miscarriages. However, if implantation is successful despite teratogen exposure, the foetus will usually survive intact. This is because the undifferentiated embryo contains totipotent cells during this period, which can repair and recover damaged tissue. Typically, exposure during this period does not result in congenital defects unless the exposure continues after this phase .
Organogenesis
Organogenesis includes the embryonic period about 2–8 weeks post conception. It is the most sensitive period of drug exposure, particularly at 3–5 weeks post conception when gastrulation occurs. This is due to rapidly dividing and differentiating tissues, which are prone to irreversible damage . Moreover, each organ system has a period of greatest susceptibility, with the heart, neural tube and limbs affected earlier than the ear and palate. Subsequent to organogenesis, the eyes, genitals, central nervous system and haemopoietic system continue to be susceptible to teratogen exposure .
Foetal phase
The foetal phase occurs from the end of embryonic period until term. It involves the growth and functional maturation of formed organs and systems. Teratogen exposure during this later part of pregnancy increases the risks of perinatal complications such as intrauterine growth restriction (IUGR), low birthweight and functional defects of several organs .
In summary, the teratogenicity of a drug is a complex interplay, influenced by the timing, dosage, molecular properties of the drugs and by persistent exposure.
Chemotherapeutic agents
Although most chemotherapeutic agents are teratogenic in animals, information regarding its safety in human pregnancy is limited. The role of antineoplastic agents, which is often necessary for the optimal treatment of cancer, is to interrupt vital cell functions during different phases of the cell cycles ( Table 1 ). Therefore, they may induce significant risk to the developing embryo especially during the first trimester of pregnancy. Information on the pregnancy outcomes following cancer treatment is scarce because cancer in pregnancy is rare, and the majority of women with cancer will opt for pregnancy termination and decision to delay treatment until the end of critical foetal periods. To date, there are no prospective clinical trials investigating the short- and long-term effects of chemotherapy during pregnancy. The limited knowledge available on diagnostic, management and outcome issues is mostly reliant upon small retrospective studies and case reports. Furthermore, the potential teratogenic effects of an individual chemotherapy drug are difficult to assess because the treatment of cancer often involves multidrug regimens. Although there is an abundance of evidence from animal studies showing high rates of teratogenicity for most cytotoxic agents, it is impossible to correlate the data to human development.
| Class | Mode of action | Examples |
|---|---|---|
| Alkylating agents | Bind covalently to DNA via their alkyl group, causing DNA cross-links and strand breaks; work in all phases of cell cycle | Busulfan, Cyclophosphamide, Dacarbazine, Ifosfamide, Mechlorethamine, Procarbazine, Chlorambucil |
| Antimetabolites | Act as false substrate during DNA and RNA synthesis, resulting in formation of truncated cellular proteins; work in S phase of cell cycle when new DNA is synthesised for formation of new cells | 5-fluorouracil, 6-mercaptopurine, Cytarabine, Gemcitabine, Methotrexate |
| Antitumour antibiotics | Bind with DNA, prevent RNA synthesis, generate highly reactive free radicals that damage intercellular molecules and inhibit the enzyme topoisomerase, work in all phases of the cell cycle |
|
| Topoisomerase inhibitors | Interfere with the enzyme topoisomerase, which help separate the strands of DNA so they can be copied during S phase of cell cycle |
|
| Antimitotic agents | Stop mitosis in the M phase of cell cycle | |
| Plant alkaloids | Prevent formation of microtubules, which form the cytoskeletal framework of a cell that allows intracellular transport of cellular components | Vinblastine, Vincristine |
| Taxanes | Inhibit disassembly of microtubules, which form the cytoskeletal framework of a cell that allows intracellular transport of cellular components | Paclitaxel, Docetaxel |
| Platinum compounds | Bind to DNA, causing DNA cross-links and eventually cell apoptosis | Cisplatin, Carboplatin, Oxaliplatin |
One of the key challenges in the management of cancer in pregnancy is treating the women with a standard chemotherapy regimen, without compromising the safety of the developing foetus. To date, none of the current chemotherapy regimens has been shown to be safe for use in pregnancy. Studies of women receiving chemotherapy during pregnancy are presented in Table 2 . The administration of chemotherapy cannot always be delayed until the end of pregnancy due to a potential impact on maternal survival. The majority of chemotherapy drugs cross the placenta and reach the foetus due to their relatively small molecular weight . In addition, when treating pregnant women with antineoplastic drugs, it is important to consider the normal physiological changes in pregnancy, such as increased plasma volume, enhanced renal clearance, faster hepatic metabolism, decreased albumin concentration and the third space formed by the amniotic fluid . These changes may result in lower or higher concentration of active drugs compared with non-pregnant women of the same weight, leading to under- or overtreatment of pregnant women with cancer. A study that compared the toxicity of cisplatin between pregnant women undergoing chemotherapy and non-pregnant women demonstrated higher concentration of cisplatin in pregnant women, although all were asymptomatic . To date, no pharmacokinetic studies have been performed to examine the effectiveness of treatment regimens in pregnancy, and whether pregnant women should receive different doses of chemotherapy. Nonetheless, chemotherapy should generally be dosed according to the actual body weight of the pregnant women and adjustments made for weight changes during treatment.
| Antineoplastic agents | Study description | Pregnancy outcome | Reference |
|---|---|---|---|
| Alkylating agents | |||
| Busulphan | 15 women with different malignancies (8 in T1) | 1 pyloric stenosis (T2 exposure) 1 unilateral renal agenesis (T2 exposure) | |
| Cyclophosphamide | 11 women with haematological malignancies treated with cyclophosphamide containing regimens in T1 | No congenital malformations | |
| 5 case reports with exposure to various regimens in T1 | Several congenital malformations including absent toes/thumbs, single coronary artery, imperforate anus, umbilical hernia, cleft palate, multiple eye abnormalities, oesophageal atresia. 1 set of twins: male twin born with congenital anomalies (oesophageal atresia, right arm deformity, abnormal inferior vena cava), later developed thyroid cancer at age 11 years and neuroblastoma at age 14 years; female twin normal | ||
| 61 women with different malignancies treated in T2/T3 | 1 hip subluxation (also received doxorubicin) 1 rectal atresia (also received epirubicin and 5-FU) | ||
| 110 women with different malignancies exposed to multidrug regimens, including cyclophosphamide in T2/T3 | 1 intrauterine death (normal autopsy) 1 neonatal death (due to autoimmune disorder) 1 IgA deficiency 1 pyloric stenosis 1 holoprosencephaly 7 (6%) IUGR | ||
| 81 women with breast cancer treated with 5-FU, doxorubicin and cyclophosphamide in T2/T3 | 1 Down syndrome 1 talipes 1 congenital bilateral ureteral reflux | ||
| 28 women with breast cancer treated with different cyclophosphamide containing regimens in T2/T3 | No congenital malformations | ||
| Dacarbazine | 19 women with lymphoma treated with ABVD regimens in T2/T3 | 1 plagiocephaly 1 fourth and fifth finger syndactyly | |
| 16 women with Hodgkin’s disease treated with ABVD or EBVD or MOPP/ABVD or MOPP/ABD regimens (in all three trimesters) | No congenital malformations | ||
| Ifosfamide | 2 women with Ewing sarcoma (given with doxorubicin in T2) | No congenital malformations | |
| Mechlorethamine, Procarbazine | 12 women with Hodgkin’s disease treated with MOPP or MOPP/ABVD or MOPP/ABD regimens (in all three trimesters) | No congenital malformations | |
| 1 woman treated with MOPP regimen in T1 | Hydrocephaly, died 4 h after birth | ||
| 1 woman treated with MOPP/ABV regimen in T2 | Bilateral partial second and third finger syndactyly | ||
| Antimetabolites | |||
| Capecitabine | 1 women with colorectal cancer treated in T1 | No congenital malformations | |
| Cytarabine (cytosine arabinoside) | 4 case reports of women with leukaemia treated with cytarabine containing regimens in T1 (all had limb malformations) | 1 case of limb malformations, bilateral microtia and atresia of external auditory canals 1 case of bilateral absent of medial two digits of feet and distal phalanges of both thumbs (also received thioguanine) 1 case of severe brachycephaly, hypoplasia of anterior cranial base and midface, bilateral four-finger hands and absent radii (also received daunorubicin, doxorubicin and thioguanine) 1 case of bilateral absent radii and fifth digits, and atrial septal defect (also received vincristine, doxorubicin and prednisone) | |
| 3 case reports of women with leukaemia treated in T2/T3 | 1 case of permanent mild dilated cardiomyopathy, short digits and limbs, macrognathia, membranous ventricular septal defect (also given idarubicin) 1 case of group C trisomy mosaicism 1 case of 46 chromosome karyotype with gaps and a ring chromosome | ||
| 22 women with haematological malignancies (in all three trimesters) | No congenital malformations | ||
| 91 women treated with regimens including cytarabine in all three trimesters | 6 (6%) intrauterine death 12 (13%) IUGR 2 neonatal death (secondary to sepsis and gastroenteritis) | ||
| 5-Fluorouracil | 107 women with different malignancies (5 in T1) | 1 inguinal hernia (T1 exposure) 1 syndactyly, cleft hands, absent distal finger phalanges, high-arched palate, microcephaly and flat nasal bridge (T1 exposure) 1 intrauterine death 1 neonatal death (normal autopsy; T3 exposure) 3 (19%) IUGR (also given cyclophosphamide and methotrexate) | |
| 57 women with breast cancer treated with combination of 5-FU, doxorubicin and cyclophosphamide (in T2/T3) | 1 Down syndrome 1 talipes 1 congenital bilateral ureteral reflux | ||
| 22 women with breast or colorectal cancers (in T2/T3) | Bilateral partial second and third finger syndactyly | ||
| 12 women with breast cancer (given with cyclophosphamide, methotrexate) in T2/T3 | No congenital malformations | ||
| Gemcitabine | 1 woman with pancreatic cancer (T2/T3) | No congenital malformations | |
| 2 women with non-small-cell lung cancer (1 treated in T1) | No congenital malformation | ||
| 6-Mercaptopurine | 50 women treated with 6-mercaptopurine containing regimens in all three trimesters (29 treated in T1) | No congenital malformations 1 intrauterine death (also given daunorubicin) 2 neonatal death 4 IUGR | |
| Methotrexate | 20 women treated in T1 | 7 malformations similar to aminopterine syndrome (cranial dysostosis with delayed ossification, hypertelorism, wide nasal bridge, micrognathia and ear anomalies) 1 skeletal abnormalities with ambiguous genitalia 3 spontaneous miscarriages | |
| 12 women with breast cancer (given with cyclophosphamide, 5-FU) in T2/T3 | No congenital malformations | ||
| 10 women with leukaemia (in all three trimesters) | No congenital malformations | ||
| Anti-tumour antibiotics | |||
| Bleomycin | 45 women with lymphoma treated with regimens including bleomycin (in all three trimesters) | No congenital malformations | |
| 20 women with lymphoma treated with ABVD regimens (in T2/T3) | 1 plagiocephaly 1 fourth and fifth finger syndactyly | ||
| 4 women with ovarian cancer (given with etoposide, cisplatin) | 1 genetic hearing loss (both parents were genetic carriers) | ||
| Daunorubicin | 46 women with different malignancies (in all three trimesters) | 1 congenital adherence of iris to cornea (also given cytarabine and thioguanine in T3) 4 (9%) intrauterine death (1 complicated by severe preeclampsia, 1 complicated by severe maternal anaemia) 5 (11%) IUGR | |
| 25 women with different malignancies (in T2/T3) | 1 bilateral partial second and third finger syndactyly 1 rectal atresia | ||
| Doxorubicin | 127 women (98 with breast cancer, 29 with lymphoma) treated with various regimens containing doxorubicin in T2/T3 | 1 intrauterine death (normal autopsy) 1 neonatal death (due to autoimmune disorder) 1 IgA deficiency 1 pyloric stenosis 1 holoprosencephaly 1 plagiocephaly 1 fourth and fifth finger syndactyly | |
| 81 women with breast cancer treated with 5-FU, doxorubicin and cyclophosphamide | 1 Down syndrome 1 talipes 1 congenital bilateral ureteral reflux | ||
| 70 women with haematological malignancies | No clinical, laboratory or cytogenetic abnormalities Normal growth and development (neurological and psychological) No clinical or echocardiogram evidence of late cardiac toxicity | ||
| 36 women with different malignancies treated with doxorubicin containing regimens | 1 hip subluxation (also given cyclophosphamide) 1 doubled cartilage rings in both ears | ||
| 11 women with breast cancer (given with cyclophosphamide in T2/T3) | No congenital malformations | ||
| Epirubicin | 49 women with different malignancies | 2 intrauterine death 1 neonatal death (normal autopsy; also given cyclophosphamide and 5-FU in T3) | |
| 5 women with breast cancer (given with cyclophosphamide in T2/T3) | No congenital malformations | ||
| Idarubicin | 1 woman with acute myeloid leukaemia treated in T1 | No congenital malformations (given with all-trans-retinoic acid) | |
| 9 women with different malignancies treated with idarubicin containing regimen in T2/T3 | 1 transient dilated cardiomyopathy 2 permanent mild dilated cardiomyopathy, 1 of which had congenital malformations including short digits and limbs, macrognathia, membranous ventricular septal defect. 1 intrauterine death (also given cytarabine) 2 IUGR | ||
| Topoisomerase inhibitors | |||
| Etoposide | 6 women with different malignancies (in T2/T3) | 1 genetic hearing loss (both parents were genetic carriers) | |
| Mitoxantrone | 3 women with acute leukaemia (given with cytarabine in T2/T3) | No congenital malformations | |
| Antimitotic agents | |||
| Docetaxel | 19 women with breast cancer (2 in T1) | 1 pyloric stenosis (also given doxorubicin, cyclophosphamide and paclitaxel) 2 cerebral ventriculomegaly (diagnosed before administration of chemotherapy) | |
| Paclitaxel | 25 women with breast cancer | 1 pyloric stenosis (also given doxorubicin, cyclophosphamide and docetaxel) | |
| 4 women with ovarian cancer | No congenital malformations | ||
| Vinblastine | 15 women with Hodgkin’s disease (in all three trimesters) | No congenital malformations | |
| 21 women with lymphoma treated with vinblastine containing regimen in T2/T3 | 1 plagiocephaly 1 fourth and fifth finger syndactyly | ||
| Vincristine | 45 women with different malignancies treated with vincristine containing regimen (in all three trimesters) | 1 male twin with multiple congenital anomalies (T1 exposure) 1 case of 46 chromosome karyotype with gaps and a ring chromosome 1 atrial septal defect, absent radii and fifth digits (T1 exposure) 1 atrial septal defect, death day 2 1 hydrocephalus, died 4 h after birth (T1 exposure) 1 intrauterine death 2 spontaneous miscarriage | |
| 39 women with haematological malignancies treated with vincristine containing regimen | No congenital malformations | ||
| 13 women with different malignancies treated with vincristine containing regimen in T2/T3 | 1 intrauterine death (autopsy normal) | ||
| Platinum compounds | |||
| Cisplatin | 7 women with different malignancies treated with various regimens in T2/T3 | 1 genetic hearing loss (both parents were genetic carriers) | |
| 4 women with cervical cancer (in T2) | No congenital malformations | ||
| 3 women with ovarian cancer treated in T2/T3 | 1 cerebral ventriculomegaly and cerebral atrophy (given with bleomycin, etoposide) | ||
| 1 woman with small cell lung carcinoma (given with etoposide in T2/T3) | No congenital malformations | ||
| Carboplatin | 4 women with ovarian cancer treated in T2/T3 | No congenital malformations | |
| 1 woman with CNS malignancy treated in T2/T3 | Spontaneous miscarriage, foetus with gastroschisis | ||
| Molecularly targeted agents | |||
| Imatinib | 180 women with chronic myeloid leukaemia (outcome data were available for 125 women, all congenital malformations were associated with T1 exposure) | 3 similar complex malformations with a combination of omphalocoele, severe renal and skeletal abnormalities 1 complex abnormalities, including communicating hydrocephalus, cerebellar hypoplasia, and cardiac defects 1 craniosynostosis 1 meningocoele (stillbirth) 1 cleft palate, polydactyly 1 pyloric stenosis 2 hypospadias | |
| Rituximab | 231 women with lymphoma or autoimmune diseases (outcome data were available for 153 women, most were confounded by concomitant use of potentially teratogenic medications) | 1 cardiac malformations 1 talipes 1 neonatal death (unknown cause) 33 (21%) first trimester miscarriages | |
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