Fetal outcome after prenatal exposure to chemotherapy and mechanisms of teratogenicity compared to alcohol and smoking.

Review

1.

Introduction

2.

Chemotherapy in pregnancy

3.

Other well-known fetotoxic

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exposures 4.

Discussion

5.

Expert opinion

Fetal outcome after prenatal exposure to chemotherapy and mechanisms of teratogenicity compared to alcohol and smoking Tineke Vandenbroucke, Magali Verheecke, Kristel Van Calsteren, Sileny Han, Laurence Claes & Frederic Amant† †

KU Leuven -- University of Leuven, Department of Oncology, Leuven, Belgium

Introduction: The treatment of cancer during pregnancy is challenging because of the involvement of two individuals and the necessity of a multidisciplinary approach. An important concern is the potential impact of chemotherapy on the developing fetus. Areas covered: The authors review the available literature on neonatal and long-term outcome of children prenatally exposed to chemotherapy. Chemotherapy administered during first trimester of pregnancy results in increased congenital malformations (7.5 -- 17% compared to 4.1 -- 6.9% background risk), whereas normal rates are found during second or third trimester. Intrauterine growth restriction is seen in 7 -- 21% (compared to 10%), but children develop normal weight and height on the long term. Children are born preterm in 67.1%, compared to 4% in general population. Normal intelligence, attention, memory and behavior are reported, although intelligence tends to decrease with prematurity. Global heart function remains normal, although small differences are seen in ejection fraction, fractional shortening and some diastolic parameters. No secondary cancers or fertility problems are encountered, but follow up periods are limited. Expert opinion: Most evidence is based on retrospective studies with small samples and limited follow up periods, methodology and lack of control groups. A large prospective case--control study with long-term follow up is needed in which confounding factors are well considered. Keywords: cardiac functioning, chemotherapy, fetal outcome, neuropsychological development, pregnancy Expert Opin. Drug Saf. (2014) 13(12):1653-1665

1.

Introduction

The prescription of medication to pregnant women requires a thorough balancing of maternal benefits of the treatment versus the potential risks for the fetus. History showed that it is very challenging to say that a certain drug is safe to use during pregnancy. It can take years to prove an association with congenital anomalies, as was the case for thalidomide [1]. On the other hand, the (absence of an) association with functional disorders, such as neurocognitive impairments and behavioral or cardiac disorders, is even more difficult to examine since it requires years of study in a large group of patients with many confounding factors (environmental factors, education, socioeconomic status, maternal illness/death, etc.). One of the situations in which the maternal benefit of treatment can outweigh the potential fetal risks is when a life-threatening disease (e.g., cancer) is diagnosed during pregnancy. Cancer is diagnosed in approximately 1 out of 1000 to 2000 pregnancies. The incidence of cancer during pregnancy has increased in the past 10.1517/14740338.2014.965677 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted

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T. Vandenbroucke et al.

Article highlights. .

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Chemotherapy during the first (but not second or third) trimester of pregnancy results in an increase in congenital malformations. Prematurity has an important impact on neuropsychological outcome and should be avoided if possible. First results on global intelligence, attention, memory and heart function after prenatal exposure to chemotherapy are within normal ranges. A case--control study with large sample size and longer follow up period is needed to strengthen these findings. A multidisciplinary approach is required.

This box summarizes key points contained in the article.

decades, due to delay of childbearing until later age. Malignancies most frequently encountered during pregnancy are breast cancer, cervical cancer and hematological malignancies, tumor types for which chemotherapy is one of the key stones in treatment. Until recently, physicians often opted to terminate pregnancy or to delay maternal treatment till postpartum, due to the lack of studies on fetal outcome after chemotherapy exposure. Chemotherapy is by definition cytotoxic and so interferes with cell growth. If it passes the placenta in relevant concentrations, fetal cell growth is inhibited. The nature of the consequences for the fetus will depend on the timing of exposure in pregnancy, the type of chemotherapy administered and the dose. During the third and fourth week of gestation, when conception and cell division take place, cell damage will result in an all-or-nothing phenomenon: a miscarriage or a normal developing fetus. Interference with cell growth during organogenesis (week 5 till 10 of gestation) results in structural anomalies. Each organ has its own critical period [2]. The heart is the first organ to develop in the fourth week of gestation. First, the heart tube is formed from the mesoderm and starts to beat automatically around five completed weeks of gestation. Afterward, the form of the heart starts to take shape, which is called the heart looping stage. Finally, the heart starts to develop into four different chambers, which are completed around the 10th week of gestation. Next to the development of the heart, the CNS starts to develop in the fifth week of pregnancy. The CNS has its origin in the neural plate by thickening of the ectoderm [3]. Thereafter, when the neural groove is formed and closed, it becomes the neural tube. One can consider that the administration of chemotherapy during this critical period may cause serious damage for the fetus. During the fetal period of development (week 11 till delivery), which is characterized by organ growth and maturation, cell death will mainly result in functional damage, but for some organs the risk of structural anomalies remains. For instance, the development of the CNS proceeds throughout pregnancy and continues even after birth [3], which places the fetus 1654

exposed to teratogens during the second or third trimester at risk of neuropsychological impairments. There are a lot of different chemotherapeutic agents, all with their own potential impact on fetal development based on their working mechanism and adverse effects reported in adults and children diagnosed with cancer. Methotrexate has been associated with severe malformations, and therefore cannot be administered during pregnancy [4]. Four groups can be distinguished that are most frequently administered in pregnant cancer patients. First, anthracyclines (e.g., daunorubicin, doxorubicin, epirubicin, idarubicin) interfere with DNA replication by inhibiting topoisomerases, which are enzymes that regulate the overwinding or underwinding of the DNA so it can be copied. The main side effect of anthracyclines is cardiotoxicity [5,6]. Second, platinum-based antineoplastics (e.g., cisplatin, carboplatin) bind to and cause crosslinking of DNA, which leads to apoptosis. They may cause neurotoxicity when administered in high doses, resulting in peripheral neuropathies such as polyneuropathy [7,8]. Also, ototoxicity, especially hearing loss, has been described [8,9]. Third, cyclophosphamide is an alkylating agent commonly used in breast and hematological malignancies. It directly damages the DNA to prevent reproduction of cancer cells. Adverse effects, especially when administered in high doses, may include permanent infertility [10]. Finally, taxanes (e.g., paclitaxel, docetaxel) inhibit mitosis by disrupting the microtubule function, which is essential to cell division. Dose-limiting toxicity of taxanes is predominantly sensory or sensorimotor axonal polyneuropathy [7]. In this paper, we review current knowledge on fetal outcome after prenatal exposure to chemotherapy. Till date, there are no studies comparing the differential impact of different types of chemotherapeutic agents on fetal outcome, because the number of children antenatally exposed to chemotherapy is small and different types of chemotherapy are usually combined. To situate the risks of chemotherapy exposure during fetal development and the underlying mechanisms of structural and functional damage, we will compare available data on chemotherapy with other well-known fetotoxic agents like alcohol and tobacco and highlight the impact of maternal stress during pregnancy on fetal outcome. 2.

Chemotherapy in pregnancy

Prenatal and postnatal growth The effect of in utero exposure to chemotherapeutic agents on fetal growth has been investigated in several studies. Some studies found normal birth weight and height according to gestational age [11,12]. For instance, Loibl et al. [13] found 9% of 175 children prenatally exposed to chemotherapy to have a birth weight below the 10th percentile and this was not significantly different from those without prenatal exposure (4% of 139 children). However, birth weight was related to chemotherapy exposure but not to the number of chemotherapy cycles, when analyzed according to gestational age. Others 2.1

Expert Opin. Drug Saf. (2014) 13(12)


Fetal outcome after prenatal exposure to chemotherapy and mechanisms of teratogenicity

reported an increased number of children born small for gestational age. Amant et al. [14] found that 21% of 70 children were born with a birth weight below the 10th percentile of gender- and gestational age-matched controls. This frequency of so-called intrauterine growth restriction (IUGR) is considerably higher than seen in the general population (10%). Also, Cardonick and Iacobucci [15] reported presence of IUGR ranging from 7 to 17% in a lot of studies, depending on malignancies and chemotherapeutic agents. IUGR places an infant at a significant risk of perinatal morbidity and mortality and is known to have various potential causes [16]. Fetal causes are predominantly genetic factors, congenital anomalies and infections. Placental causes include various parenchymal and vascular lesions of structural, infectious or inflammatory nature, causing a mismatch between nutritional or respiratory demands and supply [17]. Maternal factors include systemic medical conditions with impact on the uteroplacental blood flow, and other factors such as low caloric intake, anemia, vitamin deficiency, substance use (alcohol, smoking) and exposure to toxic agents, all of which can directly affect the fetus (e.g., low intake, nausea/vomiting as side effects of treatment, multidrug therapy, high maternal stress, inflammatory reaction on the cytotoxic treatment) [16]. The influence of in utero exposure to chemotherapy on fetal growth has not yet been examined. One can envisage that several of the abovementioned factors are present in pregnancies complicated by cancer and/or cancer treatment. 2.2

Neonatal outcome Congenital malformations

2.2.1

When chemotherapy is administered during the first trimester of pregnancy, there is an increased risk of congenital malformations in the child, ranging from 7.5% [18], over 9.2% [19], to 17% [20] as compared to a normal ratio of 4.1% [21] to 6.9% [22] for major congenital malformations, due to the critical period of organogenesis (Table 1). After the first trimester, there is no increased incidence (3% major malformations, 7.5% minor) [23] or there are no specific types of congenital malformations [11,14]. Prematurity Amant et al. [14] described an increased incidence of prematurity (67.1%) in a case series as compared to an overall incidence of spontaneous preterm labor of 4% in the general population (Table 1) [24]. In the past, delivery was often induced to start cytotoxic treatment postpartum, resulting in higher incidence of prematurity. 2.2.2

Hematologic toxicity Neonatal hematopoietic suppression has been described when delivery occurred in the first 2 weeks after chemotherapy administration [15,23]. An interval of 3 weeks between the last cycle of chemotherapy and delivery should be taken into account to avoid a delivery at the nadir, with increased risk of maternal and fetal hemorrhage and infections. Moreover, 2.2.3

it enables fetal drug clearance via the placenta since, especially in preterm newborns, the hepatic and renal clearance is still immature [15].

Neuropsychological development As the CNS continues to develop after the first trimester, neurocognitive changes in the child may also show up when chemotherapy is administered in the second or third trimester of pregnancy. There is a lack of case--control studies dedicated to the neuropsychological outcome of children after antenatal exposure to chemotherapy. However, three important studies have been published on the long-term neuropsychological outcome, although they were descriptive and did not compare the results with a control group. The first study published by Aviles and Neri [11] reported on 84 children born from mothers treated with chemotherapy during pregnancy for hematological malignancies (Table 2). Median age of follow up of the children was 18.7 years (range: 6 -- 29 years). Although the methodology was suboptimally described, neurological and psychological examinations were normal. Intelligence was not tested. Learning and academic performances were also considered normal, according to information retrieved from schools. Hahn et al. [25] reported on 40 children (range: 2-157 months of age) in utero exposed to fluorouracil-adriamycincyclophosphamide chemotherapy for maternal breast cancer (Table 2). Data on follow up of the children were obtained by a parent or guardian survey. One child had Down’s syndrome, but all other children developed normal as compared to peers. Two children had special educational needs, of whom one was the child with Down’s syndrome and the other one was diagnosed with attention deficit disorder. A recent study reported on the long-term follow up of 70 children in utero exposed to chemotherapy for diverse maternal malignancies (Table 2) [14]. Children from Belgium, The Netherlands and Czech Republic were followed up at a median age of 22.3 months (range: 16.8 months -- 17.6 years). A standardized age-appropriate assessment was used to examine neurocognitive functioning, that is, intelligence, attention, memory and executive functions. Results were compared to normative data for the specific age-groups provided by the validated tests. Both children of a twin pregnancy revealed an important developmental impairment. However, all other children were thought to have normal development. In most children, scores on tests for cognitive development (as assessed by Bayley Scales of Infant Development, Wechsler intelligence test or Snijders-Oomen nonverbal intelligence test) were normal. Lower scores were usually found in children born preterm. The average intelligence quotient (IQ) was found to increase 11.6 points for each month increase in pregnancy duration. Memory and attention did not show abnormalities compared to norms. The average scores for internalizing and externalizing behavior and total problems were within normal ranges provided by the specific test. 2.3


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N = 10 (dose-dense chemotherapy) N = 99 (conventional chemotherapy)

Study: N = 61 Controls: N = 60 matched for GA N = 16

Cardonick

Abdel-Hady


2nd 3rd

2nd 3rd (taxane-based chemotherapy)

Breast or ovarian cancer

Not specified

1st 2nd 3rd

Trimester of chemotherapy exposure

Diverse

Diverse

Diverse

Malignancy

GA: Gestational age; IUGR: Intrauterine growth restriction; Med: Median; N: Sample size.

[93]

Cardonick

[12]

[92]

[23]

N = 185 (cancer in pregnancy) of which N = 62 (exposed to chemotherapy)

Sample

Van Calsteren

First author

Table 1. Neonatal outcome following prenatal exposure to chemotherapy.

Med = 46 months (interquartile range = 18.3 -- 96)

Duration of follow up

Med GA: 36.9 weeks. Three children were born small for GA (< 10%) Neonatal complications: apnea of prematurity, gastroesophageal reflux disease, neutropenia in one infant, hyperbilirubinemia and respiratory distress syndrome due to prematurity. Hypertrophic stenosis was diagnosed in one child. One child of a twin pregnancy had Asperger’s syndrome and speech delay, dyslexia and Tourette’s syndrome, whereas the other child developed normal. Incidence of IUGR was 18.75%, comparable to other chemotherapy regimens

Mean GA (n = 185): 36.3 weeks ± 2.9 weeks 54.2% (of n = 185) were born preterm with an increase of 12.9% (of n = 62) of children prenatally exposed to chemotherapy 24.2% (of n = 62) were born small for GA Admission to a neonatal intensive care unit in 51.2% (of n = 185) (mainly because of prematurity) Incidence of congenital malformations was not increased: 2.9% major and 4.6% minor congenital malformations Mean GA: 35.7 (dose-dense) and 36.6 weeks (conventional) Birth weight, GA at delivery, rate of growth restriction, congenital anomalies and incidence of maternal and neonatal neutropenia did not differ significantly No increased incidence of birth defects Dose-dense group: one transient neutropenia and born with congenital pyloric stenosis Conventional group: three congenital anomalies (holoprosencephaly, asymptomatic main pulmonary artery fistula and hemangioma of an eye) and one neonatal death, but resulting from a severe autoimmune disorder and thought to be unrelated to prenatal exposure to chemotherapy Delivery was planned at 34 -- 35 weeks No significant difference between study and control children in incidence of neonatal survival, preterm birth, small for GA and no congenital malformations were identified

Main results




Table 2. Long-term health and neuropsychological development following prenatal exposure to chemotherapy.


First author

Sample

Malignancy

Aviles [11]

N = 84 N = 12 Secondgeneration children

Hematological malignancies

Hahn [25]

N = 40

Amant [14]

N = 70



Measures

Main results

2nd 3rd

Med = 18.7 years (range: 6 -- 29)

Neurological, psychological, educational outcome and health

Breast cancer

1st 2nd 3rd

Range 2 -- 157 months

General health and development (by survey of the parents or guardians)

Diverse

2nd 3rd

Med = 22.3 months (range: 16.8 -- 211)

Behavior by parent report and tests for mental development, intelligence, attention and memory

No congenital, psychological or neurological abnormalities Normal biometry (weight, height) at birth Educational and learning performances were normal No cancer or acute leukemia was established during follow up After exposure in second or third trimester, no stillbirths, miscarriages or perinatal deaths were registered Two children had congenital anomalies (club foot, congenital bilateral ureteral reflux) and one child had Down’s syndrome. All others had normal development Special educational needs were required for one child with attention deficit disorder and for the child with Down’s syndrome Med GA: 35.7 weeks (range: 28.3 -- 41.0) No increased morbidity of CNS, heart or hearing function. Normal general health and growth Overall neurocognitive results were within normal ranges. However, two children of a twin showed a severe cognitive delay Prematurity was associated with lower cognitive developmental outcome

GA: Gestational age; Med: Median; N: Sample size.

2.4

Cardiac functioning

Anthracycline exposure, commonly used in combination with other agents for breast and hematological cancers, is known to be associated with acute and chronic cardiotoxicity in adults and children [5,6]. The risk of this cardiotoxicity is influenced by the cumulative dose (> 250 mg/m2), gender, age, association with radiotherapy, stem cell transplantation or other

cardiotoxic chemotherapeutic agents (herceptin, cyclophosphamide, amsacrine) [26,27]. Adverse cardiac fetal outcomes have been described after exposure to anthracyclines despite low transplacental passage. Idarubicin, a highly liposoluble anthracycline derivate may cause cardiomyopathy [28,29]. In 2006, Aviles et al. [30] reported on a normal cardiac outcome in 81 children who


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Table 3. Cardiac functioning following prenatal exposure to chemotherapy.


First author

Sample

Malignancy


Diverse

1st 2nd 3rd (anthracyclines) 2nd 3rd

Aviles [30]

N = 81

Gziri [33]

Study: Diverse N = 10 fetuses Controls: N = 10 fetuses matched for gender and age

Amant [14]

N = 70

Diverse

2nd 3rd

Gziri [34]

Study: N = 62 Controls: N = 62 matched for gender and age

Diverse

2nd 3rd


M = 17.1 years (range: 9.3 -- 29.5)

Measures

Echocardiogram

Main results

Echocardiogram showed normal values Normal FSs

Biometry, amniotic fluid index, fetal 2D echocardiography

Fetal Doppler flow parameters were normal but mild changes were found in the myocardial performance index and in the tricuspid inflow pattern No incidence of IUGR Med = 22.3 months Electro- and Ejection fraction, FS, and (range: 16.8 -- 211) echocardiography interventricular septum thickness showed lower but clinically normal values Med = 1.7 years TDI and 2D Significant differences (range: 1 -- 9.8) speckle tracking between study and echocardiography control groups were found in LV FS, LV ejection fraction, LV posterior wall thickness and interventricular septum thickness, although they were small Lower FS and mildly lower LV wall thickness were found in study children compared to controls TDI velocities and LV global strains did not differ significantly Normal TDI and strain measurements were observed Cardiac functional parameters and number of anthracycline cycles or cumulative dose were not associated

2D: Two-dimensional; FS: Fractional shortening; IUGR: Intrauterine growth restriction; LV: Left ventricle; M: Mean; Med: Median; N: Sample size; TDI: Tissue doppler imaging.

were prenatally exposed to anthracyclines during pregnancy (Table 3). Besides these limited data, and different monitoring strategies, suggestions have been presented as how to monitor cardiotoxicity in children and perform research on preventive measures [31]. In 2001, a case report was published by Meyer-Wittkopf et al. [32] in which they described a sequential assessment of the ventricular dimension and cardiac growth of fetuses in utero exposed to chemotherapeutic agents to increase a favorable neonatal outcome. A pilot study to evaluate maternal and fetal cardiac function by two-dimensional echocardiography showed no significant effect of maternal 1658

chemotherapy on both maternal and fetal cardiac function during the acute phase [33]. In 2012, the results of a European multicenter initiative collecting long-term prospective data on cardiovascular outcome of children exposed to chemotherapy in utero were published, concluding that global heart function remained normal compared to controls (Table 3) [14,34]. Only small differences in the ejection fraction (EF), fractional shortening (FS) and some of the diastolic parameters (isovolumic relaxation time, mitral A-duration) were seen. However these small differences as well as the knowledge that anthracycline cardiotoxicity may only become apparent after many




years, underscore the importance of a long-term follow up, as well as the assessment of global strain analysis and tissue Doppler imaging (TDI) as early parameters of cardiotoxicity. Recent investigations of global strain analysis and TDI show that these parameters may be more sensitive parameters with reasonable interobserver and intraobserver variability to detect the early signs of cardiac dysfunction induced by anthracyclines. Moon et al. [35] showed a decreased circumferential and longitudinal strain, respectively 8.5 and 7.4%, before and after anthracycline treatment in 55 pediatric cancer patients compared to controls, nevertheless maintaining a normal FS. Dietz et al. [36] also demonstrated that radial displacement was significantly depressed in 17 adult survivors of childhood cancer compared to controls and remained the most stable measurement over time, whereas the FS and EF are variable measurements and remained in the normal range. Implementation of these novel measurements may improve the detection of anthracycline-induced cardiotoxicity, however more large long-term studies are needed to address this further as its impact for clinical use. Auditory functioning Platinum-based antineoplastics (e.g., cisplatin, carboplatin) treatment in both child and adult cancer patients has been associated with ototoxicity, especially hearing loss [8,9]. Amant et al. [14] are the first to report on auditory functioning in a long-term follow up study of children prenatally exposed to chemotherapy (Table 2). Auditory functioning was assessed in 21 children (median age: 6.5 years, range: 5.0 -- 17.4) and no abnormalities were found in 18 children (86%; 4/21 mothers received cisplatin during pregnancy). Hearing loss was reported in three children, but middle ear infection in one child and neurodevelopmental problems in two children were confounding factors. 2.5

Secondary cancers Studies that reported on long-term follow up until 17 [14] and 29 years of age [11] in 70 and 84 children, respectively, found no secondary malignancies in children. However, longer follow up and larger sample sizes are needed to strengthen these findings. 2.6

Fertility There is a lack of evidence about the impact of chemotherapy exposure during pregnancy on fertility of the child, because most studies did not follow up until childbearing age. Only Aviles and Neri [11] included 12 second-generation children in their study, indicating normal fertility function for those patients. 2.7

3.

Other well-known fetotoxic exposures

To describe the potential underlying mechanisms of fetotoxicity, we will summarize the knowledge obtained from other well-known fetotoxic substances, such as tobacco and alcohol,

and review in short evidence on the impact of maternal stress during pregnancy on fetal development. Substance abuse Only very few human studies have been able to address the critical time periods of exposure to substance abuse, due to the fact that women either quit these habits during pregnancy or continue throughout pregnancy, which makes it hard to distinguish between time periods of abuse [37]. Moreover, mediating factors may be involved in the relationship between substance abuse and fetal outcome, specifically environmental factors (e.g., passive smoking, psychiatric disorders in the parents, nutrition, socioeconomic status, etc.) [38-40], genetic factors (e.g., similar personality traits in parents and children) [41] or the combined use of different substances. Therefore, the results of studies measuring outcome of children in utero exposed to substance abuse have to be interpreted with caution. 3.1

Smoking Maternal smoking during pregnancy has been associated with, among others, IUGR, changes in behavior and neurocognitive development in the child. The most important mechanism is the interference with normal placental function by reducing blood flow to the uterus leading to deprivation of nutrients and oxygen [37]. Moreover, nicotine, carbon monoxide and other ingredients in tobacco tar can directly affect the fetal brain and the developing CNS [37]. Prenatal exposure to nicotine may also result in hypoactive cholinergic neurotransmission, which may account for learning and memory deficits [37]. Finally, fetal exposure to nicotine may be responsible for dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which is linked to psychopathology [37]. In the neonate, hypertonicity, heightened excitability, tremors, startles and signs of stress and abstinence were reported [42,43], even after controlling for prematurity and other birth outcome-related factors [43]. In childhood and adolescence, attention deficit hyperactivity disorder (ADHD) [44-47] and externalizing (e.g., oppositional and aggressive) behavior [48-50] were found to be increased. Some studies suggest a dose--response relationship in which externalizing behavior, criminality and psychiatric inpatient treatment for substance abuse disorder were more frequent with higher levels of tobacco exposure during pregnancy [38,51]. However, Milberger et al. [52] found that ADHD families more commonly smoke than non-ADHD families, which might suggest a common genetic vulnerability for both ADHD and smoking. This can explain part of the variation in behavioral outcome of the child after in utero exposure to tobacco. Neurocognitive changes such as lower IQ scores in 6- to 17-year-olds [53], deficits in verbal learning memory, problem solving and eye-hand coordination in 10-year-olds [54], deficits in auditory processing and visual perceptual processing in 6- to 11-year-olds [55] and problems with sustained attention, response inhibition and memory in 6-year-olds [56,57] have also been reported. It 3.1.1


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is not clear whether these cognitive deficits can be explained by a syndrome like ADHD. Alcohol When alcohol is present in maternal blood, it easily crosses the placenta and the fetal blood--brain barrier [37]. Several mechanisms through which alcohol can affect the fetus have been described. First, the breakdown of ethanol by the liver results in acetaldehyde, a toxic chemical consisting of small molecules that can easily cross the placenta and accumulate in the fetal brain [58]. Second, ethanol itself can lead to an alteration of growth regulatory factors that inhibit or stimulate cell proliferation in the body [58]. Third, alcohol increases the generation of free oxygen radicals and reactive oxygen intermediates, which may lead to damage of proteins and lipids in the cells and consequently increased apoptosis [58]. Finally, high levels of ethanol were found to inhibit alcohol dehydrogenase-catalyzed retinol oxidation, which normally results in retinoic acid, a signaling mechanism for embryonic development [59]. Alcohol abuse during pregnancy can lead to fetal alcohol syndrome (FAS) in the child, a condition characterized by physical and mental retardation, craniofacial anomalies and minor joint abnormalities [58]. More specifically, FAS is associated with prenatal and postnatal growth restriction, neurodevelopmental abnormalities (e.g., developmental delay, mental retardation, learning difficulties with math and visual spatial materials, microcephaly), dysmorphic face characteristics (e.g., small eyes, epicanthic folds, long hypoplastic philtrum, thin upper lip, midfacial hypoplasia) and associated congenital anomalies (e.g., hemangiomas, cardiac defects, minor joint and limb abnormalities, genital abnormalities, single palmar creases, ptosis, strabismus) [60]. Moreover, cardiac malformations are common in children with FAS, specifically ventricular septal defects, pulmonary artery hypoplasia and interruption of aortic arch type A [58]. Heavy drinking, defined as 5 or 6 alcohol units per occasion and a minimum average intake of 1 -- 3 drinks a day, results in FAS rates between 2 and 4% [61]. Hence, only a minority of children of alcohol-abusing women exhibit FAS. There may be genetic factors that program vulnerability, as indicated by twin studies [62]. Maternal age is another contributing factor, because of increased tolerance to alcohol, deterioration of liver function due to many years of alcohol abuse and increase in body fat to water ratio with older age, leading to higher peaks of alcohol in maternal and fetal blood [61]. However, when symptoms are present in a lesser degree, the condition is described as fetal alcohol effects. Heavy drinking, but not mild or moderate exposure, is associated with a 5 -- 7 points decrease in IQ score [63], hyperactive behavior, attentional problems and abnormalities in executive functioning [64,65]. Attention deficit disorder, hyperkinetic behavior and autistic disorder have also been reported [58]. As is the case for smoking, it is not clear whether these cognitive


3.1.2

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deficits related to alcohol abuse can be accounted for by syndromes like ADHD or autism spectrum disorders. A topic of debate is the existence of a threshold above which alcohol may have detrimental effects in the fetus. Some researchers found alcohol effects in young children starting from 0.5 absolute alcohol ounces [66], whereas others did not find evidence for a threshold. Reviews on the effects of low and moderate prenatal alcohol exposure [67] and on fetal exposure to binge-drinking [68] did not find convincing evidence of alcohol-induced fetal effects nor did they conclude that it might be safe, due to weaknesses in methodology of reviewed studies. Maternal stress Pregnancy and suffering from cancer are challenging life events that may cause prenatal maternal stress. In healthy women, maternal stress and anxiety during pregnancy have been associated with adverse birth outcomes, developmental and cognitive impairments and psychopathology in the offspring. There is an increased risk of spontaneous abortion, preterm labor, malformations, growth restriction and low birth weight [69,70]. Huizink et al. [71] reported lower mental and motor developmental scores at 8 months after high levels of stress during pregnancy. Henrichs et al. [72] found prenatal stress to be related to low word comprehension and poorer nonverbal cognitive development at 18 months, as measured by parent report. Some studies also reported cognitive dysfunctions. Van den Bergh et al. [73] found increased impulsivity on a computerized attention task and lower scores on two intelligence subtasks measured in 14- and 15-year-olds, specifically Vocabulary and Block Design, which are highly correlated to Full Scale IQ. Mennes et al. [74] reported lower scores on tasks requiring integration and control of different task parameters in 17-year-olds, but no impairment in working memory, response inhibition or visual orienting of attention. Moreover, a link with psychopathology has been described. Loomans et al. [75] studied antenatal maternal state-anxiety in a large community-based cohort by parent and teacher report and noticed more overall problem behavior, emotional symptoms, peer relationship problems, conduct problems and less prosocial behavior. Stronger evidence for overall problem behavior was found in boys. Antenatal anxiety was also related to hyperactivity and inattention problems in boys, but not in girls. Van den Bergh et al. [76] found an association between antenatal exposure to maternal anxiety and high, flattened cortisol day-time profiles in 14- to 15-year-old offspring, which was related to depressive symptoms for female adolescents only. However, Huizink et al. [77] conclude in a review on fetal outcome after antenatal stress exposure that prenatal stress enhances susceptibility to psychopathology, rather than exerting a direct effect on specific disorders, based on the underlying mechanisms found in animal models. The role of maternal stress hormones during pregnancy has been described as the main mechanism explaining the impact 3.2




of maternal stress on fetal development. Gitau et al. [78,79] found a linear relationship between maternal and fetal cortisol levels in plasma. Two pathways are hypothesized [80]. First, increased maternal stress hormone levels, especially glucocorticoids, may cross the placenta and thereby increase fetal stress hormone levels. Second, maternal stress may result in impaired uterine artery blood flow and therefore cause oxygen restriction leading to direct stress for the fetus. Increased prenatal fetal cortisol levels may lead to disturbances in HPA axis regulation [76]. This may contribute to regulation problems at the cognitive, behavioral and emotional levels of children [80]. Moreover, the developmental processes that take place in different brain areas, such as the prefrontal cortex and the limbic system, may be altered by antenatal maternal stress hormone release [80]. Genetic susceptibility and other prenatal and postnatal environmental factors, such as smoking during pregnancy or postnatal stress, may also play a role in the outcome of the child [80]. More research is needed to determine the impact of maternal stress and anxiety due to cancer disease and treatment on fetal development. 4.

carboplatin in the fetal plasma. Till date, there are no studies on the differential impact of chemotherapeutic agents on fetal development. Based on the available research on cancer during pregnancy, we can provide the following guidelines for the treatment of patients with cancer during pregnancy. Administration of chemotherapy during the first trimester is contraindicated, due to the increased risk of congenital malformations in the child. Preterm delivery should be avoided, if possible, since prematurity has an important impact on cognitive development [83,84]. Delivery should be planned after a 3-week interval from the last cycle of chemotherapy to avoid a delivery at the nadir and to enable the fetus to eliminate the drugs via the placenta. Chemotherapy administration should be avoided after 35 weeks of gestation because of the increased risk of spontaneous delivery. Cancer during pregnancy is a complex problem, therefore requiring a multidisciplinary approach by gynecologists, oncologists, obstetricians, cardiologists, pharmacologists, neonatologists, pediatricians and psychologists. Theory- and evidence-based practice should be provided by centers specialized in dealing with this specific problem.

Discussion 5.

We have reviewed the available literature on the general health, neonatal outcome, long-term neuropsychological development and cardiac functioning after prenatal exposure to chemotherapy during the second and third trimester of pregnancy and concluded on reassuring results. This is counterintuitive, given the known toxicity of chemotherapeutic agents and the available evidence that alcohol and tobacco, which are still frequently (ab)used substances during pregnancy, may have detrimental effects on fetal development. The main explanation lies in the transplacental passage of these teratogens, causing a direct impact on the fetus correlated with the maternal intake/uptake. Nicotine, carbon monoxide and other ingredients in tobacco tar may cross the placenta and impact on fetal development, although the main mechanism of smoking-induced fetal effects lies in the reduced uterine blood flow and consequently deprived fetal nutrients and oxygen. While acetaldehyde, the breakdown product of ethanol, consists of small molecules that cross the placenta easily and accumulate in the fetal brain, most chemotherapeutic agents reach the fetus only in small concentrations. Van Calsteren et al. [81] studied the transplacental passage of fluorouracil-epirubicin-cyclophosphamide and doxorubicin-bleomycin-vinblastine-dacarbazine in a baboon model and found low fetal exposure to these agents in blood, tissue and plasma. Fetal exposure to doxorubicin and epirubicin was < 10% of maternal concentrations. In another study, Van Calsteren et al. [82] investigated the transplacental passage of paclitaxel, docetaxel, carboplatin and trastuzumab in a baboon model. Variations of fetal plasma concentrations between chemotherapeutic agents were found to range from hardly detectable fetal plasma concentrations of taxanes to 57% of maternal plasma concentrations of

Expert opinion

Most of the available studies on fetal outcome after antenatal exposure to chemotherapy are retrospective, based on small samples and have limited follow up periods. Methodology is often not well described, measurements of fetal development are mostly based on questionnaires or do not include validated tests, and all available studies lack a control group. Till date, numbers of children antenatally exposed to chemotherapy are too small to investigate the differential impact of chemotherapeutic agents on fetal outcome. A large prospective study is needed to further examine the fetal outcomes following in utero exposure to chemotherapy and to evaluate the impact of different chemotherapeutic agents. A case-control study with a control group matched for gestational age, gender and age would be of improvement to examine neuropsychological development, since prematurity has an important impact on cognitive development. As maternal diseases, certain drugs, infections, substance abuse and maternal stress during pregnancy can affect fetal development, one should also consider these confounding factors when examining the relationship between chemotherapy and fetal outcome. Such a study is currently ongoing [85] within the International Network for Cancer, Infertility and Pregnancy, endorsed by the European Society of Gynecological Oncology. Children in utero exposed to chemotherapy are in prespective follow up until 18 years at predefined ages and tested by a full neuropsychological assessment, including intelligence, attention and memory tests, a parent report questionnaire of behavior, electrocardiography and echocardiography (including TDI, strain and strain rate analysis), event-related potentials and a pediatric neurological examination to consider biopsychosocial health status and growth.


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Further, the transplacental passage of chemotherapeutic agents has been investigated in animal models [81,82], and ex-vivo placenta perfusion studies for a few chemotherapeutics have been performed [86,87]. The underlying mechanisms of transplacental transfer/barrier and the effect of multidrug treatment still have to be investigated. The influence of prenatal exposure to chemotherapy on fetal growth has not yet been examined. Although accumulating evidence indicates that treating cancer during pregnancy may become a standard of care, and the remaining normal values of weight, height and head circumference during long-term follow up of the children in utero exposed to chemotherapy compared to age- and gender-matched controls [11,14], this lack of knowledge on the underlying mechanisms in the IUGR cases remains an important concern of fetal safety. Current research is focusing on regulators for the placental angiogenesis (e.g., VEGF, placental growth factor, IGF) and the metabolic adaptations (e.g., leptin, cortisol) that may be disturbed, and/or increased inflammation, apoptosis and oxidative stress (e.g., interleukin, cortisol-releasing hormone) that may appear [88-91]. Bibliography

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F Amant is a senior clinical researcher for the Research Fund Flanders (FWO) and is supported by the Belgiam Ministry of Health (National Kankerplan).M Verheecke is a research fellow for the Research Fund Flanders (FWO). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Declaration of interest

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Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Affiliation Tineke Vandenbroucke1,2 MSc, Magali Verheecke1,2 MD, Kristel Van Calsteren3 MD PhD, Sileny Han1,2 MD, Laurence Claes4 PhD & Frederic Amant†1,2 MD PhD † Author for correspondence 1 KU Leuven -- University of Leuven, Department of Oncology, Herestraat 49, B-3000 Leuven, Belgium Tel: +32 16 34 42 52; Fax: +32 16 34 42 05; E-mail: [email protected] 2 University Hospitals Leuven, Department of Obstetrics and Gynecology, Gynecological Oncology, Herestraat 49, B-3000 Leuven, Belgium 3 KU Leuven -- University of Leuven, University Hospitals Leuven, Department of Obstetrics and Gynecology, B-3000 Leuven, Belgium 4 KU Leuven -- University of Leuven, Faculty of Psychology and Educational Sciences, B-3000 Leuven, Belgium

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