Physiologic adaptations during pregnancy
During pregnancy, the body undergoes major physiological changes because of hormonal changes and stimuli provided by the foetus. Pregnancy is considered to be a hyperdynamic, hypermetabolic, hypervolaemic and hypercoagulable state with low systemic vascular resistance, increased insulin resistance and compensated respiratory alkalosis.7 Physiological changes that may impact the pharmacokinetics of drugs during pregnancy are shown in Table 1.
Table 1. Potential impact of physiological changes during pregnancy on drug pharmacokinetics
|Increased plasma volume||Increased volume of distribution and decreased plasma concentration for water-soluble drugs|
|Decreased plasma albumin concentration||Increased volume of distribution for protein-bound drugs|
|Amniotic or allantoic fluids acting as a third space||Increased volume of distribution and decreased plasma concentration of water-soluble drugs; possible decreased rate of drug metabolism that may increase toxicity|
|Increased body fat||Increased volume of distribution and decreased plasma concentration of fat-soluble drugs; possible decreased rate of drug metabolism that may increase toxicity|
|Increase or decrease in liver enzyme activity||Increased or decreased rate of drug metabolism|
|Increased renal blood flow and glomerular filtration rate||Increased clearance of unbound water-soluble substances|
|Decreased gastrointestinal motility and increased gastric pH||Absorption of oral drugs may be altered|
|Increased peripheral circulation and oedema in extremities||Increased or decreased absorption of subcutaneously, intramuscularly and transdermally administered drugs|
Although physiological changes in pregnant animals are likely to resemble those in women, species differences have been documented.8 For instance, serum plasma volume has been reported to increase only 10–20% in sheep, goats and cows, but in people, guinea pigs and rats the increase is 30–50%.8 In women, plasma albumin concentration decreases during pregnancy, however, in mares plasma albumin levels did not change significantly when measured once monthly during pregnancy.9 One study compared gentamicin plasma concentrations in mares in late pregnancy.10 Despite the fact that gentamicin is a water-soluble antibiotic, and thus is likely to have increased volume distribution and clearance rate during pregnancy, no significant differences were noted when compared with previous studies in non-pregnant, non-lactating mares. However, in a different study, gentamicin concentrations were lower in pregnant ewes when compared with non-pregnant ewes.11 Ampicillin plasma concentrations have been reported to be lower in pregnant mares in contrast to non-pregnant mares.12 Ampicillin is eliminated unchanged by the kidneys and has an increased clearance rate in pregnant women.12 Pregnancy only had a minor effect on penicillin levels in both pregnant ewes and cows in another study, suggesting no revised dosage regimens are needed during pregnancy.13
As evidenced by the physiological changes that are known to occur in pregnant women as well as different changes documented between species, predicting the toxicity of chemotherapy drugs delivered during pregnancy is difficult and correct dosing is complicated.
Drug transfer through the placenta
To affect the foetus, chemotherapy agents must cross the placenta. Diffusion is the most common means of placental transfer. Most chemotherapy drugs are small, lipid soluble, unionized, unbound particles and are easily transferred to foetal circulation.14 The effect of drug properties on placental transfer and foetal drug exposure is shown in Table 2.
Table 2. Drug properties affecting placental transfer and foetal drug exposure
|Molecular weight||Small molecules (molecular weight <500 g/mol) readily pass the placenta. Large molecules (molecular weight >1000 g/mol) are unable to pass the placenta in significant concentrations.|
|Lipid solubility||Only lipid soluble substances are able to cross the placenta because of the hydrophobic inner layer of cell membranes.|
|Ionization||Ionization prevents diffusion through the placenta, and only non-ionized drugs are able to cross the placenta. Weak acids are non-ionized in maternal circulation, which enhances their transfer through the placenta. In a more acidic foetal circulation, they become ionized preventing transfer back to the maternal circulation, resulting in drug accumulation in the foetus.|
|Protein binding||Only unbound substances are able to cross the placenta. Decreased maternal albumin concentration increases the amount of free drug available for placental transfer, which may increase foetal exposure for highly protein-bound drugs.|
The placenta has protective mechanisms against transfer of toxic substances from the mother. Cell membranes of the normal placenta express P-glycoprotein (Pgp), a pump that actively transfers substances from the intracellular to the extracellular space protecting the foetus from toxic xenobiotics.15 In a recent study, Pgp was found to be important in preventing transfer of substances from the mother to the foetal circulation, but it did not impact the transfer of substances from the foetus to maternal circulation.16 Many of the commonly used chemotherapeutic drugs are recognized as a substrate by Pgp.17
The placenta also has transporters for specific physiological substances. If a drug mimics a normal physiological molecule, it may be recognized as a substrate and thus be transported to foetal circulation. This may occur in both directions; transporters may protect the foetus by eliminating substances from foetal circulation.18
Because of the increased metabolic demands of the foetus during the last trimester of pregnancy, placental blood flow increases and the placental interface becomes thinner as its surface increases. Therefore, this is likely to facilitate the transfer of drugs from the mother to the foetal circulation.19
Species differences in placental gross and microscopic anatomy are likely to influence the rate of drug transfer across the placenta. Based on the number of layers separating maternal and foetal circulation, placentas are classified into epitheliochorial, endotheliochorial and haemochorial.20 Epitheliochorial placentas have six tissue layers separating maternal and foetal circulation, and thus the epithelium of the endometrium is in apposition to the epithelium of the foetal membrane. This is the type of placentation observed in large animal domestic species including horses, cows, goats and pigs.20 In sheep, there is a slight variation in which the trophoblast (foetal) cells fuse with the epithelial cells of the endometrium thus forming a synthitium (designated as syndesmochorial).20
Endotheliochorial-type placentas lack the endometrial epithelium and underlying interstitium on the maternal side. Dogs and cats have this type of placenta in which the trophoblastic cells invade deeper into the endometrium thus surrounding endometrial capillaries.20 Finally in human beings and rodents, the maternal blood directly bathes the foetal trophoblast, and this intimate type of placentation is termed haemochorial.20
It would be expected that transfer of drugs from dam to foetus would be less marked in domestic animals, where more tissue layers separate maternal and foetal circulations. For instance, gentamicin administered to pregnant guinea pigs was detected in the circulation of foetal guinea pigs,21 but was undetectable in newborn foals.10 In contrast, trimethoprim was detected in foetal fluids and serum of three newborn foals after prepartum oral administration to the dam.22 Placentation type differences between guinea pigs and horses may at least partially explain these findings. Unfortunately, there is scant information about the impact of placentation type on foetal drug transfer from the dam.
Foetal development and potential teratogenesis with exposure to chemotherapy
Foetal development is divided into three different stages,20 albeit not well defined. The first stage, sometimes referred as early embryogenesis, begins at fertilization and lasts for approximately 2 weeks in most species. If the embryo is damaged during this phase, it may die or it may be able to repair the damage and continue to develop normally.14,19,25 The second stage is the period of organogenesis. Connective tissues, organs and body systems are formed during this period.20 Damage to the embryo during organogenesis induces either death of the embryo or a major malformation(s).14,19,25,26 Organs develop at different schedules during this time and thus their susceptibility to injury varies.14,25,26 The final stage of foetal development includes the period of foetal growth. During this stage, organs mature and grow; therefore, damage to the foetus during this phase results in functional rather than structural deficits. Growth and mental retardation and alterations in gestation length may be observed during this period.14,19,25,26 As the end of pregnancy nears, the foetus will react more like a newborn when exposed to various stimuli.25 The length of gestation and each developmental period for different species are shown in Table 3. Table 4 summarizes the teratogenic impact on each stage.
Table 3. Length of gestation and stages of embryonal/foetal development in domestic animals
Table 4. Potential outcomes of exposure to chemotherapy during gestation
|Early embryogenesis||Undifferentiated multicellular organism||Spontaneous embryonic loss or normal development|
|Organogenesis||Differentiation of major organs and organ systems||Spontaneous abortion or major congenital anomalies|
|Foetal stage||Intrauterine growth and maturation, continuing development of central nervous system, gonads, teeth, palate, eyes and ears||Stillbirth, premature birth, minor organ anomalies, functional defects, growth and physical retardation, myelosuppression|
Chemotherapy administered during pregnancy may result in teratogenecity (abnormal development of the foetus). Chemotherapy drugs have different mechanisms of action, but most induce cell death by damaging DNA or RNA, or by inhibiting certain enzymes or proteins important for cell metabolism. Chemotherapeutic agents primarily affect rapidly dividing cells of the body, including both normal cells and tumour cells. Because of their high mitotic rate, cells of the developing foetus are very sensitive to chemotherapy and thus exposure to chemotherapy drugs may result in foetal death, malformations, or mental/physical retardations. Most common adverse effects in children exposed to intrauterine chemotherapy include growth retardation as well as head and limb anomalies.27
Timing of exposure to a chemotherapeutic agent is the most important factor affecting the potential adverse effects on the foetus when using antitumoural drugs during pregnancy. Other factors including the type of chemotherapy drug, the dose and schedule of the drug given to the mother, pharmacokinetics of the drug, placental function, and maternal and foetal genetic and physiological status also play role in the occurrence of potential adverse effects.19
In human beings, chemotherapy given during the first trimester of pregnancy (including early embryogenesis and organogenesis), results in the greatest chance of foetal death or malformation.5,14,19,25,26 Cows have a pregnancy length comparable with that of human beings, but even in mares, where gestation is longer, the same kind of division with regards to foetal sensitivity can be used. In bitches and queens where the time required for foetal development is much shorter, the sensitive period for foetal death and malformations is almost half of the gestation time.
The Food and Drug Administration has categorized medications used during pregnancy into five different safety categories (Table 5).28 In veterinary medicine, Papich (1989) classified some commonly used drugs.29 Classification, mechanism of action and main treatment indications of commonly used chemotherapy drugs in veterinary medicine are given in Table 6.
Table 5. Pregnancy risk categories for medications (United States Food and Drug Administration, 1979)
|A||Controlled studies show no risk. Adequate, well-controlled studies in pregnant women have failed to show a risk to the foetus.|
|B||No evidence of risks in human beings. Either animal studies show risk, but human studies do not, or if no human studies have been performed, animal studies do not show risk.|
|C||Risk cannot be ruled out. Human studies are lacking, and animal studies are either positive for foetal risk or lacking. Potential benefits of drug administration may justify the potential risk.|
|D||Positive evidence of risk. Investigational or postmarketing data show risk to the foetus. Nevertheless, potential benefits may outweigh the potential risk.|
|X||Contraindicated in pregnancy. Studies or postmarketing reports in animals or pregnant women have shown risks, which clearly outweigh any possible benefit to drug administration.|
Table 6. Most commonly used chemotherapy agents in veterinary oncology
|Prednisone||C||C||Hormone||Inhibits DNA synthesis and induces apoptosis||Lymphoma, mast cell tumour, plasma cell tumour, brain tumours|
|Cyclophosphamide||D||C||Alkylating agent||Covalently binds to DNA and disturbs DNA and RNA synthesis||Lymphoma, lymphoid leukaemia, carcinomas, sarcomas|
|Mechlorethamine||D|| ||Alkylating agent||See cyclophosphamide||Lymphoma|
|Procarbazine||D|| ||Alkylating agent||See cyclophosphamide||Lymphoma|
|Dacarbazine||C|| ||Alkylating agent||See cyclophosphamide||Lymphoma, melanoma, sarcomas|
|Chlorambucil||D||C||Alkylating agent||See cyclophosphamide||Low grade lymphoma, chronic leukaemia|
|Melphalan||D|| ||Alkylating agent||See cyclophosphamide||Multiple myeloma|
|Lomustine||D|| ||Alkylating agent||See cyclophosphamide||Mast cell tumour, lymphoma, brain tumours, histiocytic sarcoma|
|Methotrexate||X|| ||Antimetabolite||Folic acid antagonist||Lymphoma|
|Cytarabine||D|| ||Antimetabolite||Pyrimidine antagonist||Leukaemia, lymphoma|
|5-Fluorouracil||D|| ||Antimetabolite||Pyrimidine antagonist||Carcinomas, sarcomas|
|Doxorubicin||D||C||Antracycline antibiotic||Inhibition of topoisomerase II, intercalates to DNA and inhibits its synthesis, oxidation because of free radicals||Lymphoma, leukaemia, haemangiosarcoma, other sarcomas and carcinomas|
|Vincristine||D||C||Plant alkaloid||Inhibits mitotic spindle formation||Lymphoma, lymphoid leukaemia, transmissible veneral tumour, sarcomas|
|Vinblastine||D||C||Plant alkaloid||See vincristine||Mast cell tumour|
|Cisplatin||D||C||Platinum drug||Binds within and between DNA strands inhibiting DNA replication||Osteosarcoma, other sarcomas, carcinomas, mesothelioma, melanoma|
|Carboplatin||D|| ||Platinum drug||See cisplatin||Osteosarcoma, other sarcomas|
|l-asparaginase||C|| ||Enzyme||Degrades asparagine||Lympoma, lymphoid leukaemia|
Adverse effects of chemotherapy drugs on the foetus
Only a few published reports documenting the use of chemotherapy during pregnancy exist in the veterinary literature. Laboratory animal studies cannot necessarily be extrapolated to clinical cases because drug doses and teratogenicity may differ among species.19
In human medicine, most of the available information about adverse effects of chemotherapy drugs on the foetus is derived from case reports or retrospective case series. In many studies, drugs are used in combination so it is difficult to evaluate the effects of individual chemotherapeutic agents. Serious adverse reactions include spontaneous abortion, intrauterine death, malformations, premature birth, low birth weight and retardations in growth and mental development; however, the use of chemotherapy in the second and third trimesters, after organogenesis is complete, is considered relatively safe.5,14,24–26 In one study, of 334 patients who received chemotherapy drugs during pregnancy, the risk for foetal malformations was reported to be 17% when treatment was administered during the first trimester versus 1.3% during the second and third trimesters.14 Chemotherapy is not recommended in women during the last 2–3 weeks of gestation to avoid myelosuppression in the newborn and to allow for placental excretion of the drug(s).19,24,26,30
Limited information is available on the long-term effects of intrauterine exposure to chemotherapy. Carcinogenesis, mutagenesis and infertility are potential complications following intrauterine exposure to chemotherapy. A study of 84 children whose mothers were treated with different combination chemotherapy protocols while pregnant documented that all the children developed normally, and none was known to develop cancer later in life.31 In this study, 38 of the children were exposed to chemotherapy during the first trimester. Furthermore, 12 grandchildren were included in the study and no abnormalities or malignancies were reported. In a case report of twins exposed to intrauterine cyclophosphamide and prednisone, thyroid carcinoma and neuroblastoma occurred in the male twin at the age of 11 and 14 years, respectively, but the female twin was unaffected.32
Corticosteroids are substrates of Pgp, and they are metabolized by the placenta.33 The chemical structure of individual corticosteroids affects their pharmacology and thus their ability to cross the placenta. For instance, dexamethasone readily crosses the placenta, but only about 10% of prednisolone reaches the foetal circulation.34
Surprisingly, there is little information available documenting the use of corticosteroids during pregnancy in veterinary medicine except to induce parturition at the end of gestation. In ruminants, foetal corticosteroids are responsible for initiation of parturition.20 Although in other species this pathway is less well understood, administration of corticosteroids during pregnancy may result in foetal death, abortion and/or initiation of labour.
Corticosteroids are known to have teratogenic effects in laboratory animals, including cleft palate and other congenital malformations.29 Foreleg deformities, phocomelia (short or absent long bones in limbs), anasarca (generalized oedema) and premature births have been reported in puppies after intrauterine exposure to corticosteroids.35 For instance, when dexamethasone (5 mg twice daily i.m.) was given to two pregnant Labrador bitches starting on day 30 of gestation for 10 days, it resulted in intrauterine death and resorption of all foetuses. When the same treatment protocol was started approximately on day 45 of gestation, abortion occurred 1 and 3 days after the last dose in two bitches, respectively.36
Corticosteroids are used for induction of parturition in cows after gestation day 275.20 Abortion can be induced with the combination of corticosteroids and prostaglandins from day 150.20 One study reported treatment of lymphoma in a 5-month pregnant cow with prednisolone (250 mg once daily i.m. for 4 days and in 7 days after that 500 mg once daily i.m. for 3 days) and l-asparaginase.37 The pregnancy was surgically terminated 20 days after the treatment was started, and no obvious abnormalities were noticed in the calf. In another case report, prednisone (0.22 mg/kg once daily i.m. for 2 days; then, 0.11 mg/kg once daily i.m. for 5 days) was used to treat thrombocytopenia in a 4-month pregnant cow.38 The cow recovered, and a healthy calf was delivered at term with no abnormalities reported up to 1 year of age. Isoflupredone acetate (30–40 mg once daily i.m. for 3 days) was used in the treatment of chronic respiratory infection or aseptic laminitis in 48 pregnant cows, and no abortions or congenital abnormalities were noted in the calves born to the treated cows.39
In horses, corticosteroids are not commonly used to induce parturition, and high doses administered for prolonged time periods are required. For example, when 100 mg of dexamethasone was given to 21 pregnant mares daily for 4 days from gestation day 321, healthy foals were born in 1 week.40 In two pregnant ponies, the same dosing regime resulted in stillbirths and retained foetal membranes,41 but in a further study of five ponies treated with the same protocol, all delivered healthy foals without complications.42
One report reviewed use of prednisolone and chemotherapy in two pregnant mares with cancer.43 The first mare had multiple myeloma and was 11 months pregnant at the time of diagnosis; she was treated with prednisolone (dose not published). The mare foaled normally and delivered a small, but otherwise healthy foal 2 weeks after starting prednisolone. The second mare was diagnosed with lymphoma when she was 6 months pregnant. She was treated with combination chemotherapy including vincristine, cyclophosphamide, cytarabine and oral prednisolone every other day (dose not published). A small but healthy foal was delivered 5 months after the diagnosis.
As reported for dogs, it has also been suggested that antenatal corticosteroid exposure may increase the risk of cleft lip and palate in humans.44,45 One retrospective study documented the results of corticosteroid administration in 20 pregnant women.34 Dosages and length of administration ranged from 5–40 mg and 1–40 weeks, respectively. Follow-up was only possible for 12 of the infants that were born. From this small study, it was concluded that infants exposed to prednisone were more likely to be born early and/or require caesarean section for delivery. Mothers reported that their infants were less difficult and more adaptable than a control group not exposed to corticosteroids. No difference in baseline or stress-induced cortisol levels were noticed at 2- and 4-month evaluations. A larger scale study would be required to definitely conclude that prednisolone administration is safe during pregnancy, as this report suggests.
Cyclophosphamide is one of the most commonly used antineoplastic agents in veterinary oncology. In laboratory animals, intrauterine exposure to cyclophosphamide induced facial abnormalities and central nervous system and skeletal deficits.50 A variety of anomalies have been reported in human beings after intrauterine exposure to cyclophosphamide, including facial, cardiac and distal limb malformations.24
As described above, a 6-month pregnant mare with lymphoma was treated with cyclophosphamide (once every 3 weeks) and vincristine (once weekly for 2 weeks when cyclophosphamide was not given) combined with oral prednisone (COP protocol).43 Cytarabine (twice weekly) was added to the protocol 1 month after starting the COP protocol because of lack of response. The clinical condition of the mare improved, and she foaled at term an otherwise normal foal, except small in size.
In four recent studies, 65 pregnant women with breast cancer were treated with cyclophosphamide-containing chemotherapy protocols.30,46–48 Only two patients were treated during the first trimester and both experienced spontaneous abortion.30,47 One intrauterine death was reported when treatment was started in the second trimester, and one newborn died on the eighth day of life without any evidence of anomalies.30 Otherwise, no serious adverse effects were reported in any of the remaining 61 neonates. In another review of 217 pregnant women treated with cytotoxic therapy, 92 of the patients received cyclophosphamide as a part of their treatment.25 Out of this group, five neonates exposed to chemotherapy in the first trimester had multiple anomalies. In addition, one spontaneous abortion was reported when chemotherapy was started in the first trimester, and one infant had chromosomal gaps and rings found on karyotyping when exposed to chemotherapy during the second trimester. In another clinical study, 32 pregnant women were treated with chemotherapy protocols where anthracyclines were combined with an alkylating agent.49 Two of the foetuses exposed to cyclophosphamide developed malformations.
Older alkylating agents include mechlorethamine and procarbazine. Foetal exposure to mechlorethamine and procarbazine has resulted in multiple malformations in several species.50 A mechlorethamine, vincristine, procarbazine and prednisone (MOPP) protocol was used in 10 pregnant women; some of them were in their first trimester of pregnancy, and no abnormalities were reported in any of the infants.31 However, procarbazine used in various multidrug chemotherapy protocols in four first trimester pregnancies resulted in spontaneous abortion (one case), malformations (two cases) and both spontaneous abortion and malformations (one case).25 Combination of procarbazine, vincristine and vinblastine in one woman during the second trimester of pregnancy resulted in an atrial septum defect, and the infant died 2 days after birth.24
Dacarbazine is a less commonly used alkylating agent in veterinary oncology. Craniofacial, skeletal and central nervous system malformations have been reported in laboratory animals after exposure of foetus to dacarbazine.50 Doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD protocol) used in 19 pregnant women in first, second and third trimester, resulted only in one minor malformation (syndactyly because of fusion of two digits) and intrauterine growth retardations.26
Chlorambucil, a slowly acting alkylating agent, has resulted in growth retardations, skeletal anomalies and renal hypoplasia in laboratory animals.50 One report of a combination of chlorambucil, actinomycin-D and methotrexate used in a pregnant woman resulted in the birth of normal twins.51
Other alkylating agents include melphalan and lomustine. A woman with breast cancer treated with melphalan during the first trimester of pregnancy experienced spontaneous abortion.5 No information is available of the potential adverse effects of lomustine used during pregnancy. However, lomustine is a small lipophilic agent and as such readily passes the blood–brain barrier and therefore is likely to easily cross the placenta.17 Another nitrosourea, carmustine, has been used for treatment of metastatic melanoma in combination chemotherapy protocol in one pregnant woman, and a healthy baby was born.52
A recent study reported the use of busulfan, an alkylating agent used in bone marrow transplantations and treatment of human chronic myeloid leukaemia, in pregnant sows to reduce the endogenous germ cell populations in male piglets and thus facilitate donor cell colonization in the testes after germ cell transplantation.53 Four sows were treated twice with busulfan (7.5 mg/kg in dimethyl sulfoxide s.c.) on days 98 and 108 after breeding. The litter size was normal but the piglets were smaller than controls and the testis weight of male pigs was reduced when compared with controls, with a concomitant decrease in spermatogenesis. By 32 weeks of age, spermatogenesis had recovered in 72% of tubule cross sections. When busulfan was given to the sow only once either on day 102 or 105 of gestation, no difference between piglets’ body and testis weight or germ cell population were noticed when compared with piglets from untreated sows. None of the piglets exposed to busulfan suffered from malformations, but some of the piglets had bilateral congenital cataracts presumable caused by exposure to vehicle dimethyl sulfoxide. The cataracts resolved by 5 months of age.
Antimetabolites are small, weak acids, and they are believed to be particularly teratogenic.24 In a review of 217 human pregnancies, 18 malformations were reported and of those 12 were exposed to antimetabolites.25
Methotrexate is a folic acid antagonist, and it is embryotoxic in cats and both embryotoxic and teratogenic in laboratory animals causing hydrocephalus, micropthalmia, cleft palate, dysplastic vertebrae and limb abnormalities.54 Methotrexate distributes into pleural fluid and ascites, so it would be expected to distribute to amniotic or allantoic fluid.14 The teratogenicity of folic acid antagonists was first described in human beings when aminopterin failed to induce abortion in the first trimester pregnancies, and newborns displayed an increased incidence of developmental anomalies, including neural tube, skull, limb and cardiac malformations.54 Consequently, this malformation pattern has been termed the aminopterin syndrome. In a review of 71 foetuses exposed to methotrexate in utero, 12 of 42 exposed during the first trimester developed congenital abnormalities involving the skull or the distal limbs.54 In another report, 8 of 15 spontaneous abortions resulted after administration of methotrexate to the mother.25 Methotrexate is used at low dosages for treatment of rheumatoid diseases. In a review of 23 foetuses exposed to low-dose methotrexate during the first trimester of pregnancy, four spontaneous abortions and one neonate with minor anomalies (metatarsus varus and eyelid angioma) were documented.55
Teratogenic effects of cytarabine, a pyrimidine antagonist, include cleft palate, limb, kidney and brain malformations in laboratory animals.50 A mare treated with COP chemotherapy combined with cytarabine (twice weekly i.m., dose not given), which begun when the mare was 7 months pregnant, delivered a healthy foal in 4 months as described.43 In a report of 84 pregnant women treated with cytarabine-containing chemotherapy, five infants developed congenital abnormalities; four of these had been exposed during the first trimester.25 In the same study, one chromosomal anomaly and five foetal deaths, one because of maternal death, were also documented.
Another reported highly teratogenic drug in animal studies is 5-fluorouracil. Commonly observed malformations include deficits of nervous system, palate and skeleton.50 Recently, 52 pregnant women with breast cancer were treated with 5-fluorouracil.30,46,47 Two spontaneous abortions were reported when treatment was given during the first trimester,30,47 but the remaining of the infants underwent normal development and had no major complications.
Hydroxyurea, an antimetabolite used to treat polycythemia vera, was used in pregnant healthy cats during days 10–22 of gestation.56 The doses of hydroxyurea were 5–10 times higher than the recommended dose. Teratogenic activity was low when hydroxyurea was given at 50 mg/kg daily, but when the dose was increased to 100 mg/kg daily, there was a high incidence of non-pregnancy, and fewer live foetuses were reported at necropsy, presumably because of foetotoxicity of hydroxyurea.
Anthracyclines are relatively hydrophilic molecules, and they have higher molecular weights than most other chemotherapeutic drugs, and they are substrates of Pgp.49 All these properties may limit their diffusion through the placenta. However, doxorubicin and daunorubicin have been detected in low concentrations in human placenta, amniotic fluid and foetal organs.49 Doxorubicin has produced malformations in chick embryos,57 and renal impairment, axial alteration and oesophageal anomalies have been reported in rat foetuses after administration to pregnant dams.50
A recent retrospective study reported foetal outcome when using anthracyclines during pregnancy in humans.49 Most patients received other chemotherapy agents as well. In this report, 20 of 160 foetuses were exposed to anthracyclines during the first trimester. Overall, malformations occurred in five (3%) cases, of which three administrations occurred during the first trimester. Foetal death (9%), foetal complications (8%), prematurity (6%) and spontaneous abortions (3%) were other ill effects. Of 15 foetal deaths, six were associated with maternal death. When the doxorubicin dose per cycle was > 70 mg/m2 the risk of foetal toxicity was significantly increased.
Anthracycline-based protocols have been used in the treatment of breast cancer in 59 pregnancies.30,46–48 Two of the treatments were started in the first trimester and both ended in spontaneous abortions.30 One stillbirth was reported when treatment was started during the second trimester.30 The rest of the pregnancies progressed with no significant complications.
Anthracyclines are known to be cardiotoxic. Toxicity is cumulative, and in veterinary medicine, a total dose greater than 180 mg/m2 is believed to increase the risk of cardiotoxicity.58 In human beings, cardiac toxicity was observed in three neonates born from 160 pregnancies in which the mother was treated with this drug; one of the infants died from myocardial distress.49 A long-term follow-up of 81 children exposed to antracyclines in utero did not show any evidence of cardiac disease.59
Plant alkaloids are believed to be less teratogenic than antimetabolites.14,24,26.24 Skeletal, eye and central nervous system deficits have been reported in foetuses of laboratory animals exposed to vincristine and vinblastine.50 Exposure of human foetus to vincristine and vinblastine have been associated with the development of atrial septum defect, bilateral radius and digit 5 absence, hydrocephalus, renal and cardiac abnormalities.25 As previously described, a 6-month pregnant mare received vincristine as a part of COP protocol for lymphoma and gave birth to a healthy, albeit small foal, 5 months after the treatment was started.43
A review of 113 pregnant women treated with vincristine documented three spontaneous abortions, one stillbirth, five malformations and a chromosomal abnormality in one infant. Four of the neonates with malformations were exposed to chemotherapy during the first trimester.25 Fourteen of 113 women, including women in their first trimester, were also exposed to vinblastine and all infants had normal development. One neonate with atrial septum defect was exposed to vincristine, vinblastine and procarbazine chemotherapy during the second trimester and died soon after birth as described above. The other infant was exposed to vinblastine and procarbazine and had multiple anomalies, as also described above. In addition, foetal exposure to vinblastine, cisplatin and bleomycin resulted in a spontaneous abortion when the treatment was administered just before pregnancy and a normal foetal development when administered during second trimester.
The most commonly used platinum drugs are cisplatin and carboplatin. Cisplatin is a highly protein-bound drug, and lower albumin concentrations during pregnancy may increase its toxicity to the foetus.60 Cisplatin and carboplatin are embryotoxic in laboratory animals, and growth retardation, digital and tail anomalies and brain necrosis have been reported.24,50,61
There are only a few reports describing the use of platinum drugs during human pregnancies. Fourteen case reports using cisplatin during pregnancy for the treatment of ovarian cancers documented no adverse effects on neonates.5,62–67 One neonate exposed to cisplatin combination therapy during the third trimester of pregnancy was diagnosed with bilateral sensorineural hearing loss at 1 year of age.68 Prematurity, exposure to cisplatin and/or postnatal treatment with gentamicin may all have contributed to the deficit. Another case report documented a significant ventriculomegaly with cerebral atrophy in an infant exposed to cisplatin, bleomycin and etoposide during the second trimester.69 Three pregnant women, one during the first trimester, were treated with carboplatin, and all of them were reported to deliver healthy neonates.65,70,71
Paclitaxel and docetaxel are antineoplastic drugs that bind to microtubules inhibiting cell division and disturbing cell function.17 They have been used in human beings in the treatment of carcinomas. Use of taxanes in veterinary medicine is limited.72–74 Craniofacial malformations, diaphragmatic hernia, renal, cardiovascular and tail deficits have been reported in rat pups exposed to taxanes in utero.75 Five pregnancies, one being a twin pregnancy, exposed to paclitaxel after the first trimester resulted in the birth of six healthy infants.71,76–78 One case report documents the birth of a normal infant after being exposed to docetaxel during the second and the third trimesters.79
l-asparaginase is an enzyme, which degrades asparagine, an amino acid needed for protein synthesis.17 Most normal cells are able to synthesize asparagine, but many malignancies of lymphoid origin lack this ability. l-asparaginase is teratogenic in rabbits, rats and mice, and malformations reported after intrauterine exposure to l-asparaginase include lung, kidney, skeletal and neural anomalies.80
One case report reviewed a treatment of a 5-month pregnant cow diagnosed with lymphoma with L-asparginase (60 000 IU i.v.) and prednisolone (250 mg daily i.m. for 4 days).37 The cow clinically improved after starting the treatment, but her symptoms worsened 11 days after she received l-asparaginase. She received prednisolone (500 mg daily i.m.) for 3 days without clinical improvement and was treated again with l-asparaginase 2 weeks after her first dose (day 14). The cow responded to treatment, but 6 days after the second dose of l-asparaginase, she became anorexic and had developed a left displaced abomasum. Left flank abomasopexy was performed, and the pregnancy was terminated through caesarean section (day 20). Eventually, complications of the disease lead to euthanasia 57 days after the treatment begun.
In a review of 96 patients with leukaemia treated with chemotherapy during pregnancy, 15 received l-asparaginase in the first, second or third trimester.25 One baby, who was exposed to multiple chemotherapy drugs in the second trimester, had a chromosomal anomaly as previously described. The rest of the infants had normal development.