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Cancer in Pregnancy: Neurodevelopment of Children Exposed in Utero to Treatment for Maternal Malignancy
Chemotherapeutic agents and/or radiation are known teratogens. Although the available reports on children's neurodevelopment following in utero exposure to treatment for maternal malignancy are encouraging, mental health effects, which act as strong predictors of a childís quality of life, merit close attention, as do the cognitive and behavioural effects. Future research endeavors should elucidate the behavioural teratologic issues which should be an integral component of fetal safety determinations.
Cancer is the second most common cause of death among women during the reproductive years, complicating approximately 1/1000 pregnancies 1-4. When cancer occurs in pregnancy, there is frequently a conflict between optimal maternal therapy and fetal well-being. In general, malignant conditions during pregnancy are probably not associated with poor fetal and perinatal outcomes when compared to non-pregnant women. However, there is sparse data on children's higher order brain functioning following in utero exposure to maternal cancer and its associated treatment.
The literature has mainly focused on the structural observations made very close to the time of delivery and suggests that exposure to antineoplastic medications after the first trimester does not pose an increased teratogenic risk. However, since brain development occurs throughout gestation, exposure in later pregnancy may result in neurodevelopmental consequences.
From the mental health perspective, addressing children's safety following maternal malignancy is essential and a systematic search of the literature is summarized in this report.
The undesirable effects due to maternal cancer in pregnancy on the developing fetus and cognitive development in childhood remains largely unknown. Cancer patients have an increased tendency to undergo febrile illnesses due to infections and/or as a result of the tumor itself. The relationship between hyperthermia, fetal brain development, and the incidence of child cognitive and functional impairment in humans has not been addressed. Human studies do support the hypothesis that maternal fever in early pregnancy may be associated with neural tube defects and microphthalmia 5 - 12 . Children's long-term cognitive outcome could also be affected by maternal malnutrition, which may be linked to malignancy 13 - 16 . Human data obtained during historical periods of starvation (i.e., during World War II) have shown little or no adverse child effects 17. Some studies have suggested that severe ketoacidosis, due to dehydration or severe weight loss, may pose an additional risk to the developing fetus 18-19 . Conversely, analysis of military screening examinations of all Dutch males at age 19 failed to discover any difference in IQ score between boys whose mothers starved during pregnancy and the general male population.20
In order to evaluate and treat malignancies diagnosed in pregnancy, surgical interventions may be required 21-22. Approximately 0.5% to 2% of pregnant women in North America undergo surgery for reasons unrelated to their pregnancy 7, 8, and approximately 7000 to 30,000 of these women are in their first trimester of pregnancy 25, which is a very critical time for the development of the central nervous system (CNS) 26. Furthermore, this is the time period when the woman is often unaware that she is pregnant. Surgery during pregnancy may also be associated with hypotension, hypoxia, coagulation and metabolic disturbances 27, and decreased utero-placental perfusion secondary to prolonged maintenance in the supine position28 . In a review of the possible adverse effects of general and/or local anesthestics and occupational exposure to anesthetic agents, a major teratogenic risk in humans was not observed 29. However, Kallen and Mazze, in a case control study, 30 assessed the pregnancy outcome of 2,252 infants born to women who had first trimester surgery. Six neonates (expected number = 2.5) had neural tube defects (NTDs). Five of these six mothers underwent operations during the fourth and fifth weeks of gestation, the time window for the development of the neural tube. Sylvester 25 found a strong association between anesthesia exposure, hydrocephalus, and eye defects (OR = 1.7, 95%, CI = 0.8 - 3.3). However, we could not find any study that addressed the effects of these procedures on later childhood neurodevelopment.
Cancer treatment protocols require the use of chemotherapy and/or radiation as well as immuno-suppressive agents. Numerous studies have concluded that chemotherapy, administered to women before conception or after the first trimester, results in normal births in the majority of cases. 31 - 39 These conclusions may not apply to the CNS which develops throughout gestation and even after birth. Some chemicals, such as xenobiotics, alcohol and heavy metals are known to adversely affect CNS development in the second and third trimester 40 - 41. Research specifically addressing the long-term developmental outcome is sparse and mainly consists of small series and case reports42 - 47. Table 1 presents the results of 126 children in whom neurodevelopment and school performance, following in utero exposure to chemotherapy, was addressed. In 80 children, 5 with occupational exposure, formal cognitive tests were performed and compared with a control group 38-41. Of the remaining 46 children, results relied only on maternal and school reports 48 - 51.
These studies are very important as they are the only existing source of information about neurodevelopmental outcome associated with in utero exposure to chemotherapeutic agents. The general impression, based on these reports, suggests that chemotherapy does not have a major impact on later neurodevelopment. However, the majority of these reports utilized a retrospective design, inappropriate control groups and a cross sectional rather than longitudinal approach. Most authors did not conduct formal motor, cognitive or behavioural tests, thereby decreasing the probability of detecting more subtle neurodevelopmental abnormalities. Thus, these studies may not have the power to detect small but clinically significant effects.
Table 1-In Utero Exposure to Chemotherapeutic Agents
|Indication/ Authors||Time of Exposure in Pregnancy/ N||Age Assessed||Medications||Tests||Results|
|Different forms of malignancies/ Blatt et al. 1980||Pre-conceptionally or 1st trimester/ N=4||1 mth to 12 years||Combination chemotherapy||Denver Developmental Screening Test/ School reports||Normal development and school performance|
|Hodgkin's disease/ Baisogolov & Shishkin, 1985||N=19||1 to 14 years||Combination chemotherapy||Parent and school reports||Normal development|
|Hodgkin's disease/ Balcewicz-Sablinska, et al. 1990||1st trimester/ N=3||Up to age 6||MOPP||No formal testing||Normal development|
|Hodgkin's disease/ Aviles, et al. 1991||1st and 2nd trimesters/ N=15||3 to 17 years||MOPP, ABVD||Wechsler and Bender-Gestalt cognitive tests/ School reports||Not different from controls|
|Non-Hodgkin's lymphoma/ Aviles, et al. 1990||1st trimester, 2nd and/or 3rd trimester and throughout pregnancy/ N=15||3 to 11 years||Combination chemotherapy||No formal testing||Normal development|
|Haematological malignancies/ Aviles, et al. 1991||1st , 2nd and 3rd trimester/ N=43||3 to 19 years||Combination chemotherapy||Wechsler and Bender-Gestalt cognitive tests/ School reports||Not different from controls|
|Acute leukemia/ Aviles, et al. 1988||1st trimester or sometime during pregnancy/ N=17||4 to 22 years||Combination chemotherapy||Wechsler and Bender-Gestalt cognitive tests/ School reports||Not different from controls|
|Rheumatic disease/ Kozlowsky, et al. 1990||1st trimester/ N=5||3.7 to 16.7 years||Low-dose methotrexate||Parent reports||Normal development|
|Occupational exposure/ Medkova, 1990||Preconceptionally and/or during pregnancy/ N=60||85.3% asssessed at school age||Low dose cytostatics||No formal testing||Normal development|
N = number of children in study
Glucocorticoids are part of the treatment protocol for malignancies, in patients following organ transplantation, and for fetal lung maturation when preterm delivery is suspected. Although there have been several studies on the neurodevelopmental effects of glucocorticoids when administered late in pregnancy 70-74 , there are few well designed studies on the effects when taken early in pregnancy or throughout gestation 75-77.
Table 2 presents the results of 540 children, exposed in utero to glucocorticoids, in whom neurodevelopment and school performance was addressed 70-77. Formal cognitive tests were performed in 490 children and were compared with a control group 70-74, 77. The data on the remaining 50 children was collected from maternal and/or school reports only 75, 76. The pregnancy and long-term outcome of 514 children exposed during late pregnancy is presented 70-76. The NIH Consensus Conference 74 data was based on the analysis of all available reports pertaining to corticosteroid exposure in pregnancy and indicated that there was not an increased risk for long-term neurodevelopmental impairments. McArthur et al. 71, 72 studied a cohort of 139 children at age 4 and age 6. Their results suggested that there were no significant differences in the cognitive or psychosocial development between the betamethasone exposed group and control group.
Trautman et al 77 assessed the pregnancy outcome of 26 children exposed to dexamethasone in early pregnancy and found that those children who were exposed displayed more internalizing and higher avoidance behavior and were more shy and emotional and less sociable than unexposed children. The children from the study group were not found to be different from the control group on cognitive performance.
The available results regarding the use of glucocorticoids in late pregnancy are reassuring. However, the findings from the Trautman et al 77 report should be confirmed by future prospective, controlled, cohort studies.
Table 2 - Children Exposed In Utero To Glucocorticoids
|Indication/ Author||Time of Exposure in Pregnancy/ N||Age Assessed||Substance||Tests||Results|
|Lung maturation ** in Hungarian/ Veszelovszky et al. 1981||3rd trimester/ N=125||12 - 36 months||Dexamethasone||Neurological and psychological||Not different from controls|
|Fetal lung maturation/ MacArthur et al. 1981 and 1982||3rd trimester/ N=139||Age 4 and 6||Betamethasone||Stanford-Binet Intelligence Scale,Frostig Visual Percetption Test, Vineland Social Maturity Scale, Illinois Test of Psycholinguistic Abilities, Peabody Vocabulary Test, Raven's Matrices, Bender-Gestalt Test||Not different from controls|
|Fetal lung maturation/ Collaborative Group on Antenatal Steroid Therapy||3rd trimester/ N=200||36 months||Dexamethasone||Bayley Scales, McCarthy Scales||Not different from controls|
|Fetal lung maturation/ NIH Consensus Conference, 1995||3rd trimester||up to age 12||Corticosteroids||No increased risk of long-term neurodevelopmental impairement|
|Maternal SLE/ Tincani et al. 1992||Throughout pregnancy/ N=21||1 - 85 months||Fluocortolone + aspirin and azathioprine (if needed)||No formal tests||No long-term consequences|
|Maternal heart transplants/ Wagoner et al. 1994||During pregnancy/ N=29||3 months to 6.5 years||Corticosteroids + other immuno-suppresives||No formal tests||All children reported to be in good health|
|Fetal congenital adrenal hyperplasia/ Trautman et al. 1995||Pilot study. Started from week 1 to 21 weeks of gestation/ N=26||6 months to 5.5 years||Dexamethasone
(2 - 29 weeks duration)
|Denver Developmental Questionnaire, Minnesota Child Development Inventory, Child Behaviour Checklist, Temperament Questionnaire, EAS Temperament Survey||More shy, emotional, less sociable, and a trend for greater avoidance than control group. No differences in cognitive abilities.|
N = number of children in study.
Pituitary adenomas are not uncommon forms of tumors in women of child bearing age. Bromocriptine is an alkaloid that functions as a dopamine receptor agonist which suppresses prolactine production and is the treatment of choice for pituitary tumors during pregnancy.
Pregnancy outcome and children's well being at long-term follow-up (up to age 9) of hundreds of children exposed in utero to bromocriptine were reported to be normal 78-81. However, no formal cognitive and behavioural tests were performed.
Although bromocriptine was not found to be associated with an increased risk for neurodevelopmental disorders in children exposed in utero, more well designed studies including formal cognitive and behavioral testing should be performed in order to detect more subtle effects of this medication.
Radiation is commonly used for diagnostic and therapeutic purposes in various malignancies. Based on live birth rate statistics in the United States, approximately 33,000 women each year are exposed to diagnostic abdominal radiation in early pregnancy 52. The developing embryo and fetus are extremely sensitive to ionizing radiation 53 and the human brain seems to be the most sensitive organ. However, the effects of exposure are dose - and time - dependent.
Significant variability in radiation effects on the developing brain, such as cell death, disoriented migration, impaired differentiation, disturbed myelin formation, and affected connectibility have been reported in animal studies. 54 Even in the absence of structural defects, cognitive or behavioural problems may present later in development.
Ionizing radiation is a known CNS teratogen and is recognized as a cause of mental retardation and has been suggested to be a more serious complication and risk than cancer itself. 55 However, there is a paucity of research on the long-term neurodevelopmental and behavioural development of children exposed to radiation in utero.
The dose-response effects from animal behavioural studies suggest that although behavioural changes in animals are observed after 1 Gy of radiation, damage to the brain was recorded after as low a dose as 0.2 Gy. However, the generalizability/applicability of animal studies to humans is questionable and uncertain. Brent 56 stated that radiation dose as low as 50 rad (0.5 Gy) in humans, may be harmful to the fetus, especially to the CNS.
The experiences at Hiroshima and Nagasaki are the most important sources of information on long - term effects of radiation on the human embryo and fetus. Analysis of the data of survivors in Japan using refined estimates of the absorbed dose in fetal tissues demonstrated that the highest risk of brain damage occurred between 8-15 weeks' of gestational age. 57 - 60, 62 - 63. Prior to the 8th week of gestation and after the twenty-fifth week, radiation exposure was not associated with an increased risk of mental retardation. The apparent absence of an effect prior to the eighth week suggests that neuronal cell migration during weeks 8-15 post conception may be the crucial component of cerebral damage caused by radiation. 61 Smith discussed two studies that demonstrated a downward shift in the Gaussian distribution of IQ with an estimated probability coefficient indicating a loss of 30 IQ points per 1 Gy fetal dose at 8 - 15 weeks after conception62. A similar, but smaller shift toward lower intelligence was detectable following exposure between 16 and 25 weeks of gestation, but not at other periods of pregnancy.
Otake et al. 63 evaluated the risk of ionizing radiation on the developing human brain and suggested a threshold in the low-dose region to be 0.05 Gy for 8-15 weeks of exposure and 0.25 Gy for 16-25 weeks of exposure.
Granroth64 reported an association between diagnostic x - ray examinations and the occurrence of CNS defects. He observed a significant increase in anencephaly, hydrocephaly, and microcephaly when compared with matched controls. Several studies did not find severe mental retardation in a total of 19 children exposed to 0.015 and 0.1 Gy and in 1455 children exposed to low doses of radiation 65 - 66. However, formal behavioural and cognitive tests were not performed. These results should be considered with caution because of methodological limitations of the study design. Fetal exposure to less than 0.05 Gy does not appear to increase the teratogenic risk68.
In summary, according to Wilson's criteria, ionizing radiation is a teratogen69. Being neurotropic, radiation is capable of producing cognitive and behavioral teratogenic effects, which are demonstrable at doses below those causing visible structural malformations70.
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