Tineke Vandenbroucke1, Magali Verheecke1, Dorothée Vercruysse1 and Frédéric Amant2, 3
(1)
Department of Obstetrics and Gynecology, Gynecological Oncology, KU Leuven - University of Leuven, Department of Oncology, University Hospitals Leuven, Leuven, Belgium
(2)
Department of Obstetrics and Gynecology, KU Leuven - University of Leuven, Department of Oncology, University Hospitals Leuven, Leuven, Belgium
(3)
Antoni van Leeuwenhoek - Netherlands Cancer Institute, Amsterdam, The Netherlands
Frédéric Amant
Email: frederic.amant@uzleuven.be
Keywords
ChemotherapyPregnancyCancerNeurocognitive developmentCardiac function
Introduction
Many physicians remain reluctant to use drugs during pregnancy. It is very challenging to demonstrate the safety of drugs during pregnancy, because it can take many years to prove an association between the drug and potential adverse effects for the child that may arise on the short or long term. The absence of an association is even more difficult to prove, because it requires a long-term study in a large group of patients. Cancer during pregnancy is a rare but increasing phenomenon due to delay of childbearing age, with an estimated incidence of 1 out of 1000–2000 pregnancies. Definitive evidence on the safety of cytotoxic treatment during pregnancy will require long-term follow-up with a thorough assessment of the children.
When a pregnant woman has been diagnosed with cancer and treatment is indicated, two lives need to be considered. Although the maternal benefit may outweigh the potential fetal risks in this life-threatening situation, the primordial concerns on the potential teratogenic risks for the fetus caused by chemotherapeutic agents remain. Chemotherapy is cytotoxic and interferes with cell growth. The consequences for the fetus may depend on the timing of exposure during pregnancy and the chemotherapeutic agents, the number of cycles and the dose. When cell damage occurs during the third or fourth week of gestation at the moment that conception and cell division take place, this will result in an all-or-nothing phenomenon: either a miscarriage or a normal developing embryo. During week 5 until 10 of pregnancy, when cell growth takes place and organs are formed, damage will result in structural anomalies. Therefore, chemotherapy administration during the first trimester of pregnancy is contraindicated. Vital organs including the heart and the central nervous system deserve our special attention. The heart is formed between the fourth and the tenth week of gestation, while the central nervous system starts to develop in the fifth week of pregnancy and its development continues throughout pregnancy and even after birth. The third trimester of pregnancy is characterized by fetal growth. Therefore, even when chemotherapy is administered during the second or third trimester of pregnancy, the potential impact on fetal development needs to be well considered.
In the following paragraphs, we review current knowledge on fetal, neonatal, and long-term outcome of children prenatally exposed to chemotherapy.
Intrauterine Growth Restriction and Postnatal Growth
Several studies have investigated the effect of in utero exposure to chemotherapy on fetal growth and weight. While some studies found normal birth weight and height according to gestational age [1–3], others reported an increased incidence of intrauterine growth restriction (IUGR). IUGR is generally defined as a birth weight below the 10th percentile of gender- and age-matched controls. In the study of Amant et al., 21 % of the children prenatally exposed to chemotherapy (N = 70) were born with IUGR [4]. Cardonick and Iacobucci found incidences of IUGR ranging from 7 to 17 %, depending on cancer disease and treatment [5]. IUGR places an infant at significant risk of perinatal morbidity and mortality and may have fetal, maternal, or placental causes. Several factors may be related to this increased risk. Placental causes, resulting in a mismatch between nutritional or respiratory demands and supply, and maternal factors including medical conditions with impact on the uteroplacental blood flow are the most frequent and present factors in pregnancies complicated by cancer and/or cancer treatment.
Although lower birth weights may be present in chemotherapy-exposed children, this growth restriction is in most cases caught up in the first months of childhood. Amant et al. found normal values for weight, height, and head circumference in 70 chemotherapy-exposed children aged 16.8 months to 17.6 years [4].
Neonatal Outcome (Table 9.1)
Table 9.1
Neonatal outcome of children in utero exposed to chemotherapy
|
First author |
Sample |
Malignancy |
Main results |
|
Van Calsteren [7] |
N = 185 (cancer in pregnancy) of which N = 62 (exposed to chemotherapy) |
Diverse |
Mean gestational age (GA) (N = 185), 36.3 weeks ± 2.9 weeks Prematurity in 54.2 % (of N = 185) of cases with an increase of 12.9 % (of N = 62) for children prenatally exposed to chemotherapy 24.2 % (of N = 62) were born small for GA 51.2 % (of N = 185) were admitted to a neonatal intensive care unit, mainly because of prematurity 2.9 % major and 4.6 % minor congenital malformations were reported, comparable to the general population |
|
Abdel-Hady [2] |
Study: N = 61 Controls: N = 60 matched for GA |
Diverse |
Incidence of neonatal survival, preterm birth, and small for gestational age was not significantly different between study and control group. No congenital malformations were reported |
|
Avilés [6] |
N = 54 |
Hematological malignancies |
No congenital malformations after first trimester chemotherapy exposure |
|
Murthy [8] |
N = 81 |
Breast cancer |
35.6 % of the children were born preterm after prenatal exposure to fluorouracil, Adriamycin, and cyclophosphamide |
|
Cardonick [9] |
Study: N = 35 exposed to chemotherapy Controls: N = 22 nonexposed |
Diverse |
51.4 % of the children prenatally exposed to chemotherapy were born preterm, compared to 38.1 % of the control children. The difference was not statistically significant |
N sample size, GA gestational age, Med median, IUGR intrauterine growth restriction
Congenital Malformations
In the first trimester of pregnancy, chemotherapy induces an elevated risk of congenital malformations, ranging from 7.5 to 25 %, compared to 4.1 % in general population. On the contrary, Aviles et al. reported on the outcome of 54 children born after chemotherapy exposure during the first trimester of pregnancy. Clinical examination at birth revealed no congenital malformations [6]. Although they concluded that chemotherapy may also be given during the first trimester, no reasons for this low risk of chemotherapy exposure during the most vulnerable period of life were specified. However, information that allows to estimate the teratogenic risks is lacking, for instance, the developmental stage at exposure, the dose, the duration, and the frequency of drug administration. As described in our introduction, the outcome may depend on the timing of exposure during the first trimester. The use of chemotherapy during the first trimester remains potentially dangerous, and therefore caution remains primordial. Chemotherapy given beyond the first trimester has been considered safe, with no increased risk of congenital malformations as reported in different retrospective studies (3 % major malformations, 7.5 % minor) [7].
Preterm Labor and Premature Birth
An increased incidence of preterm labor and prematurity was reported. Van Calsteren et al. observed an incidence of preterm labor of 12.9 %, compared to 4 % in the general population. This was mainly due to induction of labor and elective cesarean section to start (part of) treatment after delivery (76.7 %). The incidence of preterm premature rupture of the membranes (PPROM) was not increased (4.8 % compared to 3 %) [7]. In the study of Amant et al., 67.1 % of 70 children prenatally exposed to chemotherapy was born preterm, compared to a normal ratio of 4 % [4]. Murthy et al. and Cardonick et al. also found an increased preterm birth rate of 35.6 % in 81 children prenatally exposed to fluorouracil, Adriamycin, and cyclophosphamide (FAC) for breast cancer and in 51.4 % of 35 children prenatally exposed to chemotherapy, respectively [8, 9]. Till today no clear pathophysiologic pathway of cancer disease and treatment leading to preterm labor is known. Because chemotherapeutic agents may cause an increase of preterm contractions, a dedicated follow-up is indicated.
Hematologic Toxicity
A common side effect of chemotherapeutic agents is myelosuppression. When given during pregnancy, suppressed hematopoiesis may not only occur in the mother, but also in the unborn fetus. Hoopmann et al. described a case of maternal acute myelocytic leukemia (AML) for which she received one cycle of induction chemotherapy with cytarabine, thioguanine, and daunorubicin at 20w6d GA. At 25w4d GA, the fetal anemia was diagnosed and an intrauterine transfusion was performed [10]. Cardonick et al. discussed the use of chemotherapy during pregnancy and described the use of cytarabine and thioguanine in literature, with an increased risk of fetal malformations, fetal cytopenia, intrauterine death, neonatal infections, and mortality [5]. Therefore, these agents should be avoided during pregnancy. Other agents (e.g., anthracyclines, alkylating agents, taxanes, platinum-based agents, etc.) are nowadays more investigated and administered for cancer in young (pregnant) women and can be considered safe when given in the second and third trimester of pregnancy.
When delivery takes place in the first 2 weeks after chemotherapy administration, neonatal hematopoiesis may be suppressed [5, 7]. A 3-week interval between administration of chemotherapy and delivery is recommended to avoid a delivery at the nadir, which is related to increased maternal and fetal hemorrhage and infections. As the hepatic and renal clearance in the newborn are still immature, especially in preterm newborns, the 3-week interval allows the fetus to clear the drugs via the placenta [5].
General Health (Table 9.2)
Table 9.2
General health, neurocognitive development, and behavior problems of children in utero exposed to chemotherapy
|
First author |
Sample |
Malignancy |
Duration of follow-up |
Measures |
Main results |
|
Avilés [1] |
N = 84 N = 12 second-generation children |
Hematological malignancies |
Med = 18.7 years (range, 6–29) |
General health and neurological, psychological, and educational outcome |
No congenital, psychological, or neurological abnormalities Normal weight and height at birth Educational and learning performance were normal No observations of secondary malignancies during follow-up period |
|
Hahn [11] |
N = 40 |
Breast cancer |
Range 2–157 months |
Parent or guardian report on general health and development |
No registration of stillbirths, miscarriages, or perinatal deaths after exposure in second or third trimester Congenital anomalies were reported in two children: club foot and congenital bilateral ureteral reflux. All children had normal development, except for one child with Down syndrome Special educational needs for one child with attention deficit disorder and for the child with Down syndrome |
|
Amant [4] |
N = 70 |
Diverse |
Med = 22.3 months (range, 16.8–211) |
Mental development, intelligence, attention, and memory assessment. Behavior and general health questionnaires |
Median gestational age (GA), 35.7 weeks (range, 28.3–41.0) Normal incidence of central nervous system, heart, and hearing problems. General health and growth curves were normal Overall neurocognitive results were within normal ranges. However, a severe cognitive delay was observed in a twin A positive correlation was found between gestational age and cognitive outcome |
|
Murthy [8] |
N = 50 |
Breast cancer |
Med = 7 years (range, 1–21) |
Parent or guardian report on general health |
All children were in good health An increased incidence of allergy and/or eczema was reported (36 %) |
|
Cardonick [9] |
Study: N = 35 exposed to chemotherapy Controls: N = 22 nonexposed |
Diverse |
M = 4.5 years |
Cognitive, school performance, and behavioral assessment |
No significant differences were found for cognitive outcome, school performance, and behavioral problems between the chemotherapy-exposed and the unexposed group Older children had higher rates of internalizing problems than younger children. Behavior problems could not be predicted by maternal survival, mother’s health status at time of evaluation, or child sex For the exposed group, prematurity was associated with lower cognitive outcome |
N sample size, GA gestational age, M mean, Med median
Poorer health outcomes have been described in premature born children, with a gradient effect correlated to a decreasing gestational age. Not only the general health status (chronic medical, neurological, or mental health conditions) but also the parental reception of ill health is higher in very preterm children (born < 32 weeks GA). Considering children exposed to chemotherapy in utero, questions arise on the general health status and the risks of a diminished general health. Hahn et al. and Murthy et al. reported on the results of a parent or guardian survey of 40 and 50 children in utero exposed to chemotherapy, respectively [8, 11]. All parents and guardians indicated that their child was in good health. In the study of Murthy et al., allergies and/or eczema were more commonly found in the study group (36 %) than in the general population (11–25 %) [8]. Amant et al. investigated general health in 70 children prenatally exposed to chemotherapy by a pediatric examination and a general health questionnaire. The incidence and type of medical problems were comparable to the general population [4]. Considering these results, prematurity seems to induce more general health problems than the use of chemotherapy during pregnancy.
Neurocognitive Development and School Performance (Table 9.2)
Studies in adult cancer patients who have received chemotherapy have described an array of potentially long-lasting disturbances in cognitive functions such as attention, concentration, memory, language, reaction time, information processing, judgment, and planning, referred to as the “chemo brain.” Similarly, survivors of childhood acute lymphoblastic leukemia have been reported to exhibit variations in cognitive functions such as information processing speed, verbal, performance and total intelligence, attention, and verbal and visual memory. Imaging studies, such as a recent MRI study on a series of breast cancer survivors, have revealed an association between changes in cognitive functioning and changes in cerebral white matter integrity, indicating an anatomical substrate for chemotherapy-induced cognitive dysfunction [12, 13]. The pathophysiological basis for the relationship between chemotherapy and changes in brain functions, however, is largely unknown. Chemotherapy-induced excess of cytokines in the brain is thought to play a role; excess of TNF-α has been postulated to lead to oxidative stress and mitochondrial dysfunction, leading to impaired working memory.
As the development of the central nervous system continues throughout pregnancy and even after birth, there is a possible impact of prenatal exposure to chemotherapy on neurocognitive functioning that has to be investigated. Aviles and Neri reported on the normal neurological and psychological examinations of 84 children aged 6–29 years born to mothers treated with chemotherapy during pregnancy for hematological malignancies [1]. According to school informants, learning and academic performances were normal. Hahn et al. reported on the data of 40 children, aged between 2 months and 13 years, exposed to fluorouracil-Adriamycin-cyclophosphamide (FAC) chemotherapy for maternal breast cancer [11]. Except for one child with Down syndrome and one child with attention deficit disorder, all children were thought to develop normally, according to a parent or guardian survey. In 2012, Amant et al. published the first prospective multicenter evaluation of children with antenatal exposure to cancer treatment [4]. Seventy children aged 1.5–18 years (median 22 months) were tested at predefined time intervals using standardized age-appropriate assessment. Mental development, intelligence, attention, and memory results were compared to the norms of the respective tests and were considered normal. However, both children of a twin pregnancy were found to have a severe cognitive delay. Moreover, an increased incidence of disharmonic intelligence profiles was noticed (39 % compared to 15 % in general population). Results on the mental development and intelligence tests were found to be lower in preterm-born children and to be positively correlated to the gestational age at birth. Recently, Cardonick et al. compared 35 chemotherapy-exposed children to a control group of 22 nonexposed children born to mothers with cancer during pregnancy [9]. Assessment of mental development, intelligence, and school performance was executed at a mean age of 4.5 years for the study group and 4.9 years for the control group (range 18 months to 10.4 years for the whole group of 57 children). One child in the chemotherapy-exposed group and two children in the nonexposed group had cognitive results below the normal range. There was no statistical significant difference in the number of abnormal results on cognitive development between the two groups. No differences in school performance were found between the study and control group. On the tests of academic achievement, 75 % of the chemotherapy-exposed group and 67 % of the nonexposed group had normal results for mathematics, while 75 % of the study group and 83 % of the control group scored in the normal range for reading abilities.
Behavior Problems (Table 9.2)
Amant et al. reported on the results of 21 children aged 5.0–15.9 years prenatally exposed to chemotherapy, assessed with the Child Behavior Checklist (CBCL), a questionnaire to be filled in by the parents measuring behavior problems [4]. An increased score for internalizing, externalizing, or total problem behaviors (z > 1) was found in 29 % of cases. Cardonick et al. found no differences in internalizing, externalizing, or total problem behaviors on the CBCL between a group of 35 chemotherapy-exposed children and a group of 22 nonexposed children from mothers with cancer during pregnancy [9]. Behavior problems could not be predicted by maternal survival, mother’s health status at time of evaluation, child sex, or child age at evaluation. Scores in the clinical range were found for 23 % of the study group and 18 % of the control group. Although the scores between the two groups were not significantly different, it is not clear whether these scores are elevated compared to the general population and, if so, are related to prenatal or postnatal stress due to maternal cancer disease and treatment. Increased maternal stress hormone levels may cross the placenta and thereby increase fetal stress hormone levels, causing hypothalamic-pituitary-adrenal axis regulation and thereby increasing the incidence of behavior problems later in life.
Alterations in Brain Morphology and Functioning
The (minor) differences in neurocognitive functioning described above are preliminary indications that antenatal exposure to cancer treatment may cause subtle frontal lobe dysfunctions, responsible for attention and behavior that either appear or persist on the long term. This raises the hypothesis that there could be structural or functional differences in the brain such as microstructural differences in the white matter or differences in brain connectivity between different regions. A neural substrate for cognitive impairment after prenatal exposure to chemotherapy is so far not available.
However, recent studies in adults and children with cancer have shown that chemotherapeutic drugs can have an impact on cognitive functioning and brain regions responsible for attention, memory, and executive functions. Advanced neuroimaging techniques have detected structural and functional changes in the brain after cytotoxic treatment. Schuitema et al. studied the long-term effects of chemotherapy 25 years after treatment for pediatric lymphoid malignancies [14]. Compared to controls, they found a decreased fractional anisotropy (FA), a measure reflecting the degree of organization of the white matter (WM), which correlated with the observed neuropsychological dysfunction. Deprez et al. studied the WM integrity before and after treatment of women with breast cancer [13]. They found a decreased FA in frontal, parietal, and occipital regions. Moreover, a correlation could be found between the mean regional FA changes and the performance changes in attention and verbal memory. Supposed some chemotherapeutic agents pass the placenta (in part) and reach the fetus, this raises the assumption that similar effects could arise in the child.
Furthermore, there is a possible influence of the indirect effects of maternal cancer on the fetal neural development. As mentioned above, (late) preterm delivery is common in cancer in pregnancy cases, and prematurity has been shown to be related to cognitive impairment. The brain damage underlying these effects is thoroughly studied using magnetic resonance imaging. Although most studies report on the effects of very preterm birth (<33 weeks of gestation), Degnan et al. found that prefrontal connectivity in late preterm-born children (gestational age of 34–36 weeks) is altered [15].
In addition, children in utero exposed to high maternal anxiety are known to have increased risk of impaired cognitive development, mainly due to the impact of maternal stress hormones. It has been confirmed in imaging studies that antenatal stress can cause changes in brain microstructure. Buss et al. found an association between high pregnancy anxiety at 19 weeks gestation and decreased gray matter (GM) density in school-aged children [16]. Also changes in WM microstructure, more specific in the limbic prefrontal region which underlies child social behavior, have been related to prenatal stress [17].
Cardiac Functions (Table 9.3)
Table 9.3
Cardiac functioning of children in utero exposed to chemotherapy
|
First author |
Sample |
Malignancy |
Duration of follow-up |
Measures |
Main results |
|
Avilés [20] |
N = 81 |
Diverse |
M = 17.1 years (range, 9.3–29.5) |
Echocardiogram |
Normal echocardiogram and fractional shortenings |
|
Gziri [22] |
Study: N = 10 fetuses Controls: N = 10 fetuses matched for gender and age |
Diverse |
Biometry, amniotic fluid index, fetal two-dimensional echocardiography |
Normal fetal Doppler flow parameters but mild changes in the myocardial performance index and in the tricuspid inflow pattern were found |
|
|
Amant [4] |
N = 70 |
Diverse |
Med = 22.3 months (range, 16.8–211) |
Electro- and echocardiography |
Lower but clinically normal values were reported for ejection fraction, fractional shortening (FS), and interventricular septum thickness |
N sample size, M mean, Med median, IUGR intrauterine growth restriction, FS fractional shortening, TDI tissue Doppler imaging, LV left ventricle
Anthracyclines are commonly used in combination with other agents in the treatment of breast and hematological cancers. The relationship with acute and chronic cardiotoxicity in children and adults has been repeatedly demonstrated [18]. However, several factors influence the risk of cardiotoxicity: the cumulative dose (>250 mg/m2), gender, age, association with radiotherapy, stem cell transplantation, or a combination with other cardiotoxic chemotherapeutic agents (Herceptin, cyclophosphamide, amsacrine). Children as well as adults may develop cardiac toxicities; however, this seems to appear after longer time intervals and to have a different pattern of development. Despite low transplacental passage of anthracyclines, adverse cardiac fetal outcomes have been described. Cardiomyopathy has been reported after idarubicin exposure, a highly liposoluble anthracycline derivate [19]. Aviles et al. were the first to report on cardiac outcome after prenatal exposure to anthracyclines in 81 children aged 9.3–29.5 years [20]. Echocardiogram and fractional shortenings were normal for all children. Besides these limited data and different monitoring strategies, suggestions have been presented how to monitor cardiotoxicity in children and perform research on preventive measures [21]. A first pilot study to evaluate maternal and fetal cardiac functions by two-dimensional (2D) echocardiography, reporting on ten pregnant women and their fetuses compared to controls, showed no significant effect of maternal anthracycline exposure on both maternal and fetal cardiac functions during the acute phase [22]. Amant et al. reported on the results of a European multicenter long-term prospective follow-up of cardiovascular outcome of 65 children prenatally exposed to chemotherapy [4]. Global heart function was compared to controls and appeared to be normal. However, small differences in the ejection fraction (EF), fractional shortening (FS), and some of the diastolic parameters (isovolumic relaxation time (IVRT), mitral A-duration) were noticed. A long-term follow-up is necessary, given these small differences as well as the knowledge that anthracycline cardiotoxicity may only become apparent after many years. The assessment of global strain analysis and tissue Doppler imaging as early parameters of cardiotoxicity may also improve our knowledge on anthracycline-induced cardiac dysfunctions that may arise on the long term.
Hearing Loss
Ototoxicity, especially hearing loss, has been reported in children and adults with cancer treated with platinum-based antineoplastics (e.g., cisplatin, carboplatin). This ototoxicity is dose dependent and irreversible. Amant et al. reported on auditory functioning of 21 children with a median age of 6.5 years (range 5.0–17.4) [4]. Eighteen of these children had a normal hearing function, of which three were prenatally exposed to cisplatin. One child in utero exposed to cisplatin was diagnosed with hearing loss in the high regions. However, a perforated eardrum was observed on a computed tomography scan, possibly a consequence of middle ear infections, which may be a confounding factor. A twin in utero exposed to idarubicin and arabinoside cytosine was found to have minor hearing loss at the right side in the low regions. In these cases, neurodevelopmental problems may confound the results. Geijteman et al. also reported a single case of prenatal cisplatin exposure (5 cycles of 70mg/m2) with severe bilateral perceptive hearing loss [23]. Given the observation that platin derivatives cross the placenta in a substantial percentage and given the anecdotal hearing loss, cisplatin should only be administered after careful consideration.
Secondary Malignancies
Second malignant neoplasms have been associated with certain types of chemotherapeutic agents administered to adults and children with cancer. Mostly these malignancies are myeloid neoplasms. Leukemia has been reported to occur after the administration of platin-based chemotherapeutic agents, topoisomerase II inhibitors, and antimetabolites. The risk to develop secondary solid tumors is more limited, but has been reported. Side-specific risks have been reported for sarcoma and cancer of the lung, stomach, intestines, bladder, and thyroid after the administration of alkylating agents. Sasshi et al. reported on the occurrence of secondary malignancies after treatment for indolent Hodgkin lymphoma in a 16-year follow-up study. Thirty-nine of 563 patients developed a secondary malignancy, concluding on a cumulative incidence of cancer at 12 years of 10.5 % [24]. The risk of developing secondary malignancies in children prenatally exposed to chemotherapy still needs further investigation at long-term follow-up. One case has been reported by Reynoso et al. of a twin pregnancy exposed to cyclophosphamide in utero. The boy, also born with anomalies, developed thyroid cancer and a neuroblastoma at, respectively, 11 and 14 years of age. His twin sister had no abnormalities and did not develop any tumors [25]. Two long-term follow-up studies published up till now have reported on 70 and 84 children with a maximum follow-up duration of 18 and 29 years of age, respectively. In these cases, no secondary malignancies were found [1, 4].
Fertility
Chemotherapy induces infertility in young women with cancer. The type and dose of chemotherapy and the age of the patient are the most important prognostic factors. However, little is known about the impact of prenatal exposure to chemotherapy on fertility. Aviles and Neri reported on 12 second-generation children of 84 adults prenatally exposed to chemotherapy for hematological malignancies [1]. Although this may be an indication of normal fertility for these few patients, nothing is known about the nature of conception (spontaneous conception or assisted reproduction).
Conclusion
Chemotherapy is more commonly used during pregnancy for maternal cancer treatment. The available evidence is still based on small numbers and a short follow-up period. However, in general, results on neonatal outcome, postnatal growth, general health, neurocognitive development, and cardiac functions are comparable to the general population. Intrauterine growth may be affected and needs close monitoring. Term delivery is important in order to avoid long-term consequences. Insufficient data are available to draw conclusions for each type of chemotherapy. In particular, cisplatin in high dosage should be avoided given the concerns on ototoxicity. More children and a longer follow-up are necessary in order to have more solid data. In particular, more children are needed to investigate outcomes for each cytotoxic drug or combination of drugs. Such a studies are currently ongoing in the framework of the International Network on Cancer, Infertility and Pregnancy (INCIP) (www.cancerinpregnancy.org), the Pregnant with Cancer Network (United States, www.pregnantwithcancer.org), and the Motherisk Program (Canada, www.motherisk.org) that aim for a thorough follow-up of these children.
Acknowledgement
Frédéric Amant is senior clinical researcher for the Research Foundation-Flanders (F.W.O.). Tineke Vandenbroucke and Magali Verheecke are research fellows at the Research Foundation-Flanders.
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