Effects of prenatal exposure to cancer treatment on neurocognitive development, a review

Accepted Manuscript Title: Effects of prenatal exposure to cancer treatment on neurocognitive development, a review Author: Doroth´ee C.-M. Vercruysse Sabine Deprez Stefan Sunaert Kristel Van Calsteren Frederic Amant PII: DOI: Reference:

S0161-813X(16)30022-5 http://dx.doi.org/doi:10.1016/j.neuro.2016.02.013 NEUTOX 1950

To appear in:

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Received date: Revised date: Accepted date:

22-7-2015 28-2-2016 28-2-2016

Please cite this article as: Vercruysse Doroth´ee C-M, Deprez Sabine, Sunaert Stefan, Van Calsteren Kristel, Amant Frederic.Effects of prenatal exposure to cancer treatment on neurocognitive development, a review.Neurotoxicology http://dx.doi.org/10.1016/j.neuro.2016.02.013 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Effects of prenatal exposure to cancer treatment on neurocognitive development, a review. Dorothée C.-M. Vercruyssea, Sabine Deprezb, Stefan Sunaertb, Kristel Van Calsterenc, Frederic Amantd

a

KU Leuven – University of Leuven, Department of Oncology; University Hospitals Leuven,

Department of Obstetrics and Gynecology, Gynecological Oncology, B-3000 Leuven, Belgium. Address: Herestraat 49, B-3000 Leuven, Belgium. E-mail: [email protected]. b

KU Leuven – University of Leuven, Department of Radiology; University Hospitals Leuven,

Department of Radiology, B-3000 Leuven, Belgium. Address: Herestraat 49, B-3000 Leuven, Belgium. E-mail: [email protected], [email protected]. c

KU Leuven – University of Leuven, Department of Obstetrics and Gynecology; University Hospitals

Leuven, Department of Obstetrics and Gynecology, B-3000 Leuven, Belgium. Address: Herestraat 49, B-3000 Leuven, Belgium. E-mail: [email protected]. d

KU Leuven – University of Leuven, Department of Oncology, B-3000 Leuven, Belgium; The

Netherlands Cancer Institute/Antoni van Leeuwenhoek, Amsterdam, The Netherlands. E-mail: [email protected]. Corresponding author: Frédéric Amant at Department of Oncology, KU Leuven, Belgium, and The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. Email: [email protected].

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Highlights “Effects of prenatal exposure to cancer treatment on neurocognitive development, a review” by Vercruysse et al.

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Cancer can be treated adequately during pregnancy Subtle changes in cognition are found after prenatal exposure to cancer treatment Direct and indirect pathways for brain damage could explain the cognitive changes Further large scale long-term follow up studies are necessary

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Abstract Due to the increasing incidence of cancer during pregnancy, the need to better understand long-term outcome after prenatal exposure to chemo- and/or radiotherapy has become more urgent. This manuscript focuses on the neurocognitive development after prenatal exposure to cancer treatment. We will review possible pathways for brain damage that could explain the subtle changes in neurocognition and behavior found after in utero exposure to cancer treatment. Contrary to radiation, which has a direct effect on the developing nervous system, chemotherapy has to pass the placental and blood brain barrier to reach the fetal brain. However, there are also indirect effects such as inflammation and oxidative stress. Furthermore, the indirect effects of the cancer itself and its treatment, e.g. poor maternal nutrition and high maternal stress, as well as prematurity, can be related to cognitive impairment. Although the available evidence suggests that cancer treatment can be administered during pregnancy without jeopardizing the fetal chances, larger numbers and longer follow up of these children are needed. Keywords: Chemotherapy; radiotherapy; cancer; pregnancy; neurocognitive development

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1. Introduction The incidence of cancer during pregnancy is increasing, most likely due to the fact that the age of pregnant women increases in combination with the increasing probability of cancer with age [1, 2]. Today, approximately 1 to 2 in 2000 pregnancies are complicated with cancer. Most frequently it concerns breast cancer, hematological malignancies, melanoma and cervical cancer [3], as is the case in non-pregnant women from the age range of 20-40 years old. Maternal treatment consists of chemotherapy, radiotherapy and/or surgery. The use of targeted therapy in the case of cancer in pregnancy is mostly contraindicated due to high fetal risks [4-6]. Non-obstetric surgery during pregnancy exposes the fetus to a potential risk of not only the anesthetics, but also of surgical complications such as hypotension, hypoxia and a decreased uteroplacental perfusion after prolonged supine positioning [7]. However, research has shown that most commonly used anesthetics are relatively safe to use [7]. Furthermore, a review of 12,452 women stated that there might be an increased of miscarriage when surgery was performed in the first trimester, but there was no evidence of an increased risk of maternal death, congenital malformation or long term neurodevelopmental issues [8, 9]. Overall, surgery can be safely performed during pregnancy, given adequate monitoring of the mother and the use of anesthetics that have been previously used and proven safe during pregnancy. The most commonly used chemotherapeutic agents are anthracyclines, cyclophosphamide and 5fluorouracil (5-FU) for breast and hematological cancers; taxanes for breast, cervical and ovarian cancers; vinca alkaloids for hematological malignancies; and platinum agents for cervical, breast and ovarian cancer [10]. All of these agents have their own specific working mechanism. Cyclophosphamides, 5-FU and platinum agents will interfere directly with the DNA and DNAreplication, whereas vinca alkaloids and taxanes will inhibit mitosis by disrupting microtubule function [11]. Drug toxicity is dose dependent. Important to note is that due to changes in physiology during pregnancy, the pharmacokinetics of drugs are affected. The most important changes are a decreased gastrointestinal motility, a significant increase in plasma volume and extracellular fluid, an 4

increased glomerular filtration and tubular function, up- or downregulation of hepatic enzymes, an increased fat mass and the amniotic fluid which increases the distribution volume. These changes interfere with drug absorption, distribution, metabolism and excretion. Van Hasselt et al. [12] have recently shown that this leads to a decreased plasma volume of certain chemotherapeutic drugs such as docetaxel and paclitaxel in pregnant women [13]. The use of radiotherapy during pregnancy is only indicated when it concerns tumors remote from the pelvis (breast cancer, brain tumors, lymphoma), especially during the first and second trimester of pregnancy when the uterine volume is smaller. It is important to carefully estimate the fetal dose from internal scatter and leakage radiation. A fetal exposure of maximum 100 mGy is considered to be acceptable with regard to fetal risk [14]. Of concern is the potential effect of cancer treatment on fetal development. Apart from the dose, the timing will determine the impact of prenatal chemo- and radiotherapy exposure. In the first two weeks after conception cells are omnipotent, thus administration of chemo-/radiotherapy in this stage will result in an all-or-nothing phenomenon depending on the amount of disrupted cells. From week 2 until 8 organogenesis takes place. Drug administration or radiation exposure in this organ development phase will result in malformations of mainly the heart, neural tube, limbs, palate and ears [9, 15]. However, organogenesis of the central nervous system (CNS) continues until well into the postnatal development. Therefore, even if the administration of anti-cancer drugs or radiation exposure occurs after 14 weeks of gestation, which is well after the end of the general organogenesis, the development of the brain can be influenced [16]. 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 memory (temporal area), attention and executive functions (frontal area). With advanced neuroimaging techniques, structural and functional changes in the brain have been reported in these patients after cytotoxic treatment [17-21]. This raises the assumption that, if chemotherapeutic drugs and/or radiation reaches the fetus, similar effects could arise in the child. 5

In this paper we will review the current knowledge about the neurocognitive outcome after prenatal exposure to chemo- and radiotherapy and possible confounding factors.

2. Radiotherapy 2.1 Neurotoxic effect of radiotherapy Although it is poorly documented, there is a general concern about the safety of radiotherapy during pregnancy. The International Commission on Radiological Protection reviewed the risks of medical irradiation of pregnant women [22, 23]. However, the results referred to are mostly derived from animal studies and human data from pregnancies during nuclear disasters and exposure to diagnostic X-rays [23, 24]. Based on these results the time- and dose-dependent deterministic risks are lethality, malformations, mental retardation and cancer induction. The damage due to radiation can be caused directly to the DNA or cell components that are important in the signal transduction pathways involved in damage repair, or, as is mostly the case, indirectly through the formation of reactive oxygen species (ROS) [25]. A significant increase in ROS will cause DNA damage, which in its turn can lead to a number of cellular responses, including cell cycle arrest (reduced level of neurogenesis), senescence, p53-mediated apoptosis and even tumor growth [26-28]. Animal studies have shown various structural brain effects after prenatal exposure to ionizing radiation. A high fetal dose (1-2 Gy) in the late organogenesis period leads to a decreased brain weight and size [27-32]. Another often recurring effect is a decreased migratory activity of neural cells [25, 33, 34]. Even a low dose of ionizing radiation (0.15 Gy) can interfere with the neuronal migration, as stated by Fushiki et al. [34]. After in vitro and in vivo research, threshold doses for the fetus were determined. According to Stovall et al. [35], a fetal dose of >100 mGy induces a significant risk of damage, for 50-100 mGy the risk is uncertain and when the dose is below 50 mGy the risk is small. However, one must bear in mind that the risks associated with certain doses are dependent of treatment timing [9, 14]. As 6

mentioned above, the CNS is most sensitive to radiation in weeks 8-25 after conception, which is confirmed by the findings of Otake et al. [36] in a study with survivors of the atomic bombings in Japan. During this period, exposure to a fetal dose of 100 mGy can result in a significant decrease in IQ (21 points per 1 Gy), as has been seen in 10-11y old children who had been in utero during the nuclear explosions. A similar but smaller shift in IQ is detectable after exposure in weeks 16-25 [14, 37, 38]. These findings are confirmed by Mettler et al. [39]. Apart from the deterministic effects, there are stochastic effects, for which there is no threshold dose. Exposure to prenatal irradiation with a fetal dose of 10 mGy increases the relative risk of childhood cancer and leukemia by 40%. However, since the spontaneous incidence of childhood cancer and leukemia is low (2-3/1000), the absolute risk is still only 3 to 4 in 1000 exposed children [14]. Nonetheless, these risks do not imply that radiotherapy must be completely avoided during pregnancy. If the radiation field is sufficiently far from the fetus, and with proper lead shielding to minimize radiation leakage and collimator scatter, radiation can be applied to pregnant women [9, 40]. Internal scatter, which depends largely on the source of irradiation and the size and proximity to the fetus of the treatment fields, cannot be avoided [41]. To make sure not to exceed the accepted threshold dose of 100 mGy, the anticipated radiation dose to the fetus can be estimated using phantom models [42]. Note that cancers in the pelvis cannot be treated with radiotherapy due to severe or even lethal consequences for the fetus because of the close proximity [22].

2.2 Neurocognitive outcome after prenatal exposure to radiotherapy An overview of studies reporting on the outcome of fetuses exposed to radiation is given by Nulman et al. [7], Kal and Struikmans [14] and Luis et al. [43]. Unfortunately, the information about long-term follow up is limited, since most papers report only on case reports and small case series. Luis et al. [43] performed the largest study, including the long-term follow up of 9 patients, and an extensive literature review of 100 additional patients. Of the 109 cases, 13 had adverse outcomes, including 7

one in utero death, one elective termination, two spontaneous abortions and five perinatal deaths. Neurocognitive impairment was reported in only two cases. In none of the cases a dose of >100 mGy was reported [35]. However, since data on most cases is incomplete, further follow up research is necessary.

3. Chemotherapy 3.1 Neurotoxic effect of maternal chemotherapy 3.1.1. Barriers Before the maternal chemotherapeutic drug can reach the fetal brain and cause local damage, two barriers need to passed: the placenta and the fetal blood-brain barrier, as is shown in Fig.1. 3.1.1.1 Placental barrier The placenta plays a key role in the defense mechanism of the fetus against exposure to chemotherapeutic drugs. Although it forms the connection between the drug containing blood flow of the mother and the blood flow of the fetus, it will also act as a barrier to protect the fetus from xenobiotics in the maternal blood [10]. The main transfer mechanism is passive diffusion, i.e., the permeation of a molecule following its concentration gradient [44]. It does not require energy. The rate of passive diffusion is determined by the physicochemical properties of the drug, such as lipid solubility, polarity and molecular weight [45]. Small (<500-600 Da), un-ionized, lipid-soluble drugs will easily pass through [46, 47]. Since the placenta has the characteristics of a lipid bilayer membrane, only the non-protein bound fraction of a drug is free to cross the placental barrier by passive diffusion [44]. Note that when the lipid-solubility is too high, the drugs will accumulate in the placental cells instead of passing through and the placenta will act as a temporary storage. Afterwards the particles may be released in either of both compartments [48].

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Another, energy-requiring, transfer mechanism is active transport by protein pumps. These drug efflux transporters can work against a concentration gradient, but can become saturated. They are adenosine triphosphate (ATP)-binding cassette proteins such as P-glycoprotein, multidrug-resistant associated proteins, and breast cancer-resistant protein, and may play an important role in the protection of the fetus from chemotherapeutics [44]. Published transplacental transfer studies using in vitro placental perfusion models of term human placentas, which examined the transfer of epirubicin and doxorubicin respectively [49, 50], observed a limited transfer (3-4%) to the fetal compartment. Van Calsteren et al. examined transfer rates of various chemotherapeutic drugs in both mouse and baboon models [51-53]. The mouse model revealed a remarkably lower transplacental transfer rate for P-glycoprotein substrates such as anthracyclines (i.e. 5%), compared to cytarabine and carboplatinum (i.e. 56-117%) [52]. Prenatal exposure to vinblastine and doxorubicin caused subtle changes in behavior and brain morphology in the mice [53]. However, one must bear in mind that rodents differ substantially from humans concerning their metabolism and placentation. Therefore, further research was done using a baboon model, considering the close phylogenetic relationship between humans and nonhuman primates [51]. These studies showed a high transfer rate for carboplatinum (57%), but a limited transfer for anthracyclines, taxanes and vinblastine (range 2-18%). Important to note is that fetal baboon protein plasma levels increase near term (similar to human pregnancies). Hence it is possible that in an earlier stage of the pregnancy a higher proportion of the fetal drug concentration is free and thus toxic [51]. Furthermore, one should bear in mind that certain drugs, such as antiepileptic drugs [54], can influence the placental transport mechanisms, which could lead to increased fetal doses.

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Fig.1: Illustrative figure of the possible pathways of neurotoxic effect of maternal chemotherapy on the fetus

3.1.1.2 Fetal blood-brain barrier The adult blood-brain barrier consists of the capillary endothelial cells of the brain, linked by tight junctions. Since the brain endothelial cells contain no fenestrations and exhibit low pinocytosis 10

activity, a rigid wall is formed. Furthermore, the presence of efflux transporters such as Pglycoprotein increases the protection against invasion of cytotoxic drugs [55]. Therefore, drugs will need to fulfill certain requirements in order to be able to penetrate the blood-brain barrier. Only sufficiently small (<400-500 Da) and lipophilic drugs that can pass due to passive diffusion and drugs that can (ab)use inward transport systems while unrecognizable by the efflux transporters, will be able to enter the brain in substantial amounts [56]. Often it is suggested that the brain barriers are immature and leaky during fetal development. This stems from the experimental observation of high protein concentrations in fetal cerebrospinal fluid (CSF) and decreases in apparent permeability of passive markers during the development of the fetus [57]. This is, however, due to changes in transcellular transfer and volume of distribution rather than changes in paracellular permeability of the blood-CSF barrier, as stated by Johansson et al. [57]. Also multiple other studies suggest that the fetal brain is well protected. Both Saunders et al. and Virginto et al. have stated that the morphological features of the blood-brain barrier, namely the tight junctions, low rates of transcytosis and the efflux transporters (e.g., P-glycoprotein) are present early in embryological development [58, 59]. Moreover, pericytes inhibit the expression of molecules that increase vascular permeability and CNS immune cell infiltration [60]. Furthermore, strap junctions at the inner and outer neuroependymal surface provide additional morphological protection [58]. Although there is preclinical data on actual transfer of dasatinib in rats [61] that suggests a higher blood-brain transfer of drugs in the fetus compared to adults, the functionality of the fetal blood-brain barrier is confirmed by the baboon study of Van Calsteren et al. [51]. While looking

for

the

transplacental

transfer

of

anthracyclines,

vinblastine,

and

4-hydroxy-

cyclophosphamide, they found no detectable levels of doxorubicin or epirubicin in the fetal baboon CSF or brain, despite of the elevated fetal plasma levels for these chemotherapeutic drugs.

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3.1.2 Possible mechanisms of neurotoxicity However, despite these barriers that aim to protect the fetus from the cytotoxic maternal treatment, a certain fraction of the maternal drug concentration is transferred to the fetus where it can cause harm, as illustrated in Fig.1. First of all, the metabolism of a fetus is immature. As in adults, the fetal drug metabolism functions in two ways: on one hand it acts as a protective mechanism against chemical aggression by transforming active molecules into inactive products, on the other hand it can act as a toxifying system due to the transformation of banal compounds into reactive metabolites [62]. In some cases also the placental enzymes can activate xenobiotic compounds making them toxic to the fetus [44]. For example cytochrome P450 enzymes are involved in the bioactivation of many compounds that lead to adverse effects in the fetus [63]. Little is known about the fetal biotransformation of different cytotoxic agents, making it hard to predict the effect of the respective drugs on the fetus. The basic structures of the liver are developed by the end of the first trimester [64]. However, the drug-metabolizing enzymes which are present in the adult liver, are depressed in the fetus. This prevents the conversion of the drugs into water-soluble metabolites that are unable to cross the placental barrier to get handled by the maternal system, which would increase the fetal exposition time [65]. Furthermore, the maturation of renal function is a dynamic process, which starts during fetal organogenesis and continues until early childhood [66]. It is known that the glomerular filtration rate (GFR) increases substantially in the last trimester and the first months postpartum [67-69]. Note that the fetal urine, as a part of the amniotic fluid, is swallowed by the fetus, leading to a potential reabsorption of drugs previously cleared by the renal system and excreted in the urine [70]. Taking all this into account, the fetal pharmacokinetics and toxicity of drugs penetrating the placenta are very hard to predict.

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Neurobiological processes causing cognitive impairment after administration of chemotherapy are discussed in literature, albeit mostly in animal studies. First, since chemotherapeutic drugs are aimed at the inhibition of cell division, they are likely to interfere with the process of neurogenesis as well, if they are able to pass the blood-brain barrier [55]. Fetal life is characterized by a very high degree of cell divisions and cell growth and therefore fetal organs are highly vulnerable for cytotoxic drugs. Several animal studies have shown decreased neurogenesis and/or hippocampal cell proliferation after administration of, among others, 5-FU [71, 72], cisplatin [73] and cyclophosphamide [74]. Second, Han et al. have shown neurotoxicity of 5-FU for non-dividing oligodendrocytes, which can lead to decreased myelination later in life [71]. Third, the disturbance of DNA by cytostatic agents might alter mitochondrial DNA, leading to ROS formation and oxidative stress. This effect is shown for multiple agents in animal studies, e.g., cyclophosphamide [75] and doxorubicin [76-78]. Furthermore, chemotherapeutic drugs can indirectly affect cognition by acting on the immune system. Although certain cytotoxic agents such as taxanes cannot easily pass the blood-brain barrier, they cause the peripheral release of pro-inflammatory cytokines, which can enter the brain. These cytokines like tumor necrosis factor-alpha (TNF-α) and interleukins are released as a result of tissue injury caused by not only the administered cytostatic agents, but also the tumor growth itself. In the CNS, these cytokines can activate microglia [79] which could lead to neuroinflammation and associated cognitive impairment [80]. One could even develop a cycle of increasing DNA damage and cytokine activity, even more instigated by oxidative stress due to chronic inflammation [81]. In addition, the anti-angiogenic effect of cytostatic agents such as methotrexate can reduce the density of blood vessels in the hippocampal area [82], resulting in a reduction of energy supply and proliferative signals. This may be another possible cause of the decreased hippocampal cell proliferation seen in several studies [71-73].

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3.2 Neurocognitive outcome after prenatal exposure to chemotherapy The short-term outcome of children after exposure to chemotherapy in the second or third trimester seems comforting since no more incidences of congenital malformations are found compared to the normal population [83, 84]. As for long-term neuropsychological outcome, most important studies available so far are descriptive and give no comparison between study and control groups. A summary of these studies, focusing on the cognitive outcome, is given in Table 1. In 2001 a study was published evaluating the risk of children whose mother received chemotherapy for hematological malignancies during the second and third trimester [85]. A long-term follow up of 84 children with a median age of 18.7 years old (range: 6-29 years) showed an overall normal outcome. Although very little information was provided concerning the methodology, the neurological and psychological examinations showed no abnormalities. From school results was concluded that there were no learning disorders among the children. A few years later, Hahn et al. reported on the follow up of 40 children, age ranging from 2 to 157 months, in utero exposed to chemotherapy for maternal breast cancer [86]. More specifically, their mothers were treated with fluorouracil-adriamycin-cyclophosphamide (FAC) during the second and third trimester. A survey of the parents and guardians of the children was conducted to obtain information on health status, development and school performance. One of the children was diagnosed with Down syndrome, all others were reported to have normal development compared to siblings/other children. Of the school-aged children (n=18) only two required special attention in school, of which one was the child with Down syndrome. The overall results on health and cognitive outcome were reassuring. A third study reported on the long-term outcome of 70 children (median age 22.3 months, range 16.8 months – 17.6 years), in utero exposed to chemotherapy for various maternal cancers [87]. General health and development, and cardiologic, cognitive, behavioral and neurological development were assessed using standardized, age-appropriate tests. The test-battery for the

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cognitive assessment focused on intelligence, verbal and non-verbal memory, attention, working memory and executive functions. The results were compared with normative data for the specific age groups. Neonatal neurological outcome was normal in 91% of the children. Except for both members of a twin pregnancy who had a significant neurodevelopmental delay, all children appeared to have normal development. Although the overall IQ was within the normal range, 39% of the children showed a disharmonic intelligence profile, i.e., a discrepancy between verbal and performance IQ, in contrast to 15% in a general population. In addition, behavioral assessment using the standardized Child Behavior Check List (CBCL) showed that, despite normal average scores, 29% of children had high scores specifically for internalizing, externalizing and total problems, as opposed to 15% in the general population. However, these distinctive results were mostly found in children born preterm. Nevertheless, these are preliminary indications that antenatal exposure to cancer treatment may cause subtle changes in neurocognition and/or behavior that either appear or persist on the long term. In 2014 Murthy et al. [88] reported an update on their study of outcomes of children prenatally exposed to chemotherapy for treatment of breast cancer. 81 pregnant patients were treated with FAC in the second and third trimester. Of these participants, 50 filled in a health questionnaire on the postneonatal outcomes of their exposed child (median age 7 years, range <1 to 21 years). Six of them (12%) indicated that their child had developmental milestone delays, of which three were childhood language delays. However, no significant cognitive abnormalities were reported. The study executed by Cardonick et al. [89] compared the results of 35 children prenatal exposed to chemotherapy to 22 non-exposed children. They did not find a significant difference in cognition, school performance or behavior between the two groups. However, their sample size was small and the groups were very heterogeneous with ages ranging from 18 months to 10 years old. Recently Amant et al. [90] reported on an international multicenter case-control study comparing 129 children whose mothers received a diagnosis of cancer during pregnancy (median age 22 months, range 12-42 months) with matched children of women without a cancer diagnosis. Of these 15

129 children, 96 were exposed to chemotherapy in the second or third trimester, 11 to radiotherapy, 13 to surgery alone, 2 to other drug treatments and 14 to no treatment. All children underwent a neurological examination and the Bayley Scales of Infant Development test to assess the neurocognitive development. Overall the results were reassuring. At this age, no significant difference in cognitive outcome could be found between children exposed to chemotherapy and controls. However, a correlation could be found between the gestational age at birth and cognitive outcome. In conclusion it can be stated that thus far no major consequences on neurocognitive development after prenatal exposure to chemotherapy are found, however, more thorough long-term follow up is necessary. Moreover, as can be seen in the last column of Table 1, there are still some methodological issues that need to be addressed. Although the last studies already took an important step forward by including control groups, they should focus on single cancer types and treatment plans to be able to draw firm conclusions. Also covariates such as prenatal stress or maternal nutrition should not be neglected. A further discussion of methodological issues concerning these types of studies can be found below under Recommendations for future research.

4. Indirect effects of cancer (treatment) When studying long-term neurocognitive outcome, it is important to note that this is a multifactorial process (socio-economic class, education, family composition (divorce, possible death of the mother),…). And more specifically for pregnant women with cancer, there are apart from the direct effects of cytotoxic exposures also indirect effects of cancer and its treatment on the fetal neurological development, such as maternal stress, nutrition and prematurity.

4.1 Maternal stress Children exposed to high maternal stress in utero are known to have increased risk of delayed fetal maturation, impaired cognitive development, impulsivity, inattention and emotional problems [9116

94]. Furthermore, Mennes et al. observed an association between the level of prenatal maternal anxiety and the brain activity during an endogenous cognitive task [95], and significantly lower scores on tasks which required integration and control of different task parameters. Working memory, response inhibition, and visual orienting of attention on the other hand were not impaired [96]. The Generation R study by Henrichs et al. [97] found maternal prenatal family stress to be related to children’s low word comprehension and poorer nonverbal cognitive development at the age of 18 months. A study of Loomans et al. [98] reported on the association between antenatal maternal anxiety and the behavioral development in 5-year olds based on questionnaires filled out by the mother and school teachers. They found a correlation with overall problem behavior, attention problems, emotional symptoms, peer relationship problems, conduct problems and less prosocial behavior. The effect was more pronounced in boys than in girls. The main factor of impact of maternal stress on fetal development has been described to be the maternal stress hormones, and primarily glucocorticoids [99-101]. A first of two possible pathways is impaired uterine blood flow due to maternal stress [102], causing a lack of oxygen which results in a direct stress for the fetus [103]. The second pathway hypothesized is the direct crossing of the placenta of the maternal stress hormones, especially glucocorticoids. Some studies suggest that this effect is enhanced due to the downregulation of the placental barrier enzyme 11β-hydroxy steroid dehydrogenase type II caused by the maternal stress [104, 105]. Both mechanisms lead to an increase in fetal cortisol levels which in turn may cause a disturbance of the hypothalamic-pituitaryadrenal (HPA) axis regulation [100, 101, 103, 106]. This HPA axis is a critical system in preserving physical health, mobilizing energy stores, promoting vigilance, and inhibiting inflammatory responses under stress and threat conditions [100, 107]. The dysregulation of this axis could contribute to cognitive, behavioral and emotional problems of children [108]. Corticotrophin releasing hormone (CRH) is, although to a lesser extent than cortisol, correlated in the maternal and fetal compartments of the placenta [109]. Elevated concentrations of pCRH can affect the developing brain both directly and indirectly. By upregulation of the expression of CRH receptors throughout the brain, certain 17

regions such as the hippocampus, amygdala and prefrontal cortex can be directly affected [110]. The indirect effect is due to the stimulation of the fetal cortisol production, which has been shown to increase limbic neuronal excitation followed by seizures in rats [93, 110, 111]. Moreover, studies have shown that CRH has neurotoxic effects on hippocampal neurons [93, 112, 113], an effect that seems to be even more pronounced in the immature hippocampus [112, 114]. Imaging studies confirm that antenatal anxiety can cause changes in brain microstructure. The review by Charil et al. [105] gives an overview of the existing animal studies by focusing on certain brain regions that have been shown to be affected by prenatal stress: hippocampus, amygdala, corpus callosum, anterior commissure, cerebral cortex, cerebellum and hypothalamus. Most often it results in reduced tissue volumes. Buss et al. [115] found high pregnancy anxiety at 19 weeks gestation to be associated with decreased grey matter (GM) density in children at the age of 6-9 years. Recently Sarkar et al. [116] reported the first prospective study of prenatal stress and WM microstructure in children. They found changes in regions which underlay child social behavior.

4.2 Maternal nutrition and vitamin intake Poor maternal nutrition and vitamin intake during pregnancy can have serious consequences for the fetal development [117]. It hampers placentation, resulting in changes in placental size, morphology and blood flow [118], and thereby reduces the nutrient supply to the fetus [119]. This in turn will disturb organogenesis, growth and fetal programming and has been associated with short- and longterm effects on development and morbidity [120]. The list of known nutrients with prenatal effects on child neurocognitive development is extensive: copper, protein, iodine, B vitamins, folate, … Multiple reviews are written on the subject, which give an extensive overview of these nutrients and their specific impact [119, 121, 122]. Also the timing of the malnutrition period plays a role. Deficits in maternal nutrient intake early in pregnancy will have a greater impact on cell proliferation, whereas deficits later on in pregnancy will affect cell differentiation, including synaptogenesis and dendritic arborization [122], thereby influencing white matter microstructure. As stated by O’Donnell 18

et al. [104], the maternal diet might also affect the placental barrier enzyme 11β-hydroxy steroid dehydrogenase Type II, which converts cortisol to the inactive cortisone [123]. This suggests that malnutrition and prenatal stress are two confounding factors that enhance each other.

4.3 Prematurity A third indirect factor that could influence the neurocognitive functions in these children is prematurity. In all cancer during pregnancy studies, a large amount of children were delivered preterm (<37 weeks of gestation), and prematurity has been shown to be related to cognitive impairment. Although most studies investigate the effect of very preterm delivery (<32 weeks of gestation or birth weight <1500g), Voigt et al. [124] studied the cognitive functioning of moderate and late preterm children (32-37 weeks of gestation) as well. They found that at the corrected age of 24 months even moderately to late preterm children perform lower on the Bayley developmental index compared to children born full term. Van Baar et al. [125] looked at the neurocognitive outcome at school age (8 years old). A comparison was made between a group of moderately preterm born children (32-36 weeks gestational age) and a group of full term born children. They concluded that the preterm group showed behavioral and attention problems and had lower IQ scores than the full term born children. This was confirmed by the findings of Amant et al. in their long-term follow up study of children in utero exposed to chemotherapy [87]. They observed that children who scored below normal ranges were mainly from the preterm group. Neurobiological models of early brain injury suggest that primary destructive processes (injury of neurons and glia caused by hypoxia due to immature lungs) followed by secondary maturational disturbances, form the base of the adverse outcome after preterm birth [126, 127]. Furthermore, preterm neonates are often physiologically instable and exposure to early adverse experiences could be an influencing factor on brain development [128]. The brain damage underlying these effects is also thoroughly studied using MR imaging techniques. However, most studies report on the neurodevelopment of children and young adults born very 19

preterm (<33 weeks of gestation) (Bäuml et al. [126], Nagy et al. [129, 130], Constable et al. [131], Lawrence et al. [132], Eikenes et al. [133], Duerden et al. [134], Kesler et al. [135, 136], Nosarti et al. [137-140], among others). To our knowledge, there is only one study that reports on alterations in resting state networks and structural connectivity in late preterm born children thus far. Degnan et al. [141] investigated the development of twin children (ages between 9 and 13 years, gestational age 34-36 weeks) in a developing region of Brazil. Although the late preterm children and term control children obtained similar scores on neuropsychological testing (however, no explicit results are given), prefrontal connectivity was altered in late prematurity. Alterations were found in both structural (probabilistic tractography) and functional connectivity (resting state fMRI).

5. Recommendations for future research Reviewing the available literature on the effects of prenatal exposure to cancer treatment on neurocognitive development shows that long-term follow up studies are still very scarce. The available neuropsychological data suggests relatively safe use of chemo- and radiotherapy during pregnancy when well-planned and controlled. There are, however, minor indications of cognitive impairment, which should be studied further. Especially since there are multiple direct and indirect pathways that can have an influence on the developing brain of the fetus during pregnancy in women treated for cancer. To determine whether a neural substrate exists for the cognitive impairment related to antenatal exposure to cancer treatment, a longitudinal study using advanced MR imaging techniques in combination with detailed neuropsychological assessment could be used. Due to the complexity and the many inherent confounding factors, some important considerations must be taken into account when setting up future studies. The preferred design is a prospective study, which starts with following the mother during pregnancy from the moment of cancer diagnosis and continues with long-term follow up of the child. This enables collecting detailed information on not only the maternal treatment, but also possible confounding factors such as poor nutrition and maternal stress. 20

To assess the prenatal stress to which a child is exposed, one could use a questionnaire, such as the State-Trait Anxiety Inventory (STAI) questionnaire [142], filled in by the mother at different time points during the pregnancy. Also biological parameters, such as the maternal salivary cortisol [143], measured on different time points along the pregnancy, can be used as a quantitative measure for stress. The inclusion of control groups is a key prerequisite to perform a reliable study. To enable the differentiation between the effects of treatment from the effects caused by the maternal disease itself, a first control group should consist of women who had cancer during pregnancy but no treatment and their offspring. Secondly, to account for possible effects of surgery during pregnancy, a control group of women with cancer who received no chemo- or radiotherapy but only underwent surgery, and their children should be followed. Note that there is the risk for confounding by indication, since patients who didn’t need treatment right away are inherently different from the study group and possible effects might therefore be partly due to the severity of the disease itself instead of the treatment. However, for ethical reasons, it is impossible to include the ‘perfect’ control group of people with the same indication who won’t receive treatment. Finally, a control group of children born after an uneventful pregnancy, matched for gender, age and gestational age (since prematurity is also associated with cognitive impairment) should be included. ‘Uneventful pregnancy’ meaning here that there were no gestational or maternal complications such as hypertension, preeclampsia, diabetes, substance abuse,… that could have an impact on the cognitive development of the child. For the same reason neonatal complications such as congenital malformation or infections and neurological diseases such as epilepsy should be taken into account as exclusion criteria. Ideally, also the social status (parents’ education,…) should be assessed by questionnaires and matched between study and control groups. Since all chemotherapeutic agents have different working mechanisms, as described above, which could be linked to different fetal risks, it is important to look at one cancer type and corresponding chemotherapy regimen at a time. 21

Because this is research concerning human health, it is especially important to also report on negative cases and drop outs. If health issues are the reason of dropping out, then this is a bias on the results and should be mentioned. In order to investigate the differential impact of chemotherapeutic agents, a very large sample is needed. However, till date the numbers of children antenatal exposed to chemotherapy remain very small, therefore multi center collaborations are necessary. Currently the International Network on Cancer, Infertility and Pregnancy (INCIP) [144] has a large scale multi center international follow up study ongoing that takes the above recommendations into account, which will hopefully lead to more insights in the future.

6. Conclusion In this paper we reviewed the literature on long-term neurocognitive outcome after prenatal exposure to cancer treatment. Although most follow up studies show reassuring results, there is evidence of subtle changes in neurocognition and behavior. A number of direct and indirect pathways for brain damage could explain the cognition and behavior differences found in some of the children in utero exposed to chemo- and/or radiotherapy. Radiation has a direct effect causing harm to the developing CNS. Therefore only tumors remote from the pelvis can be treated using radiotherapy and proper lead shielding should be used. Chemotherapy, on the other hand, has to pass some barriers before it can reach the fetus. It is shown that only a limited part of the maternal dose passes the placenta. To have a direct effect on the developing brain, such as inhibition of cell division, also the fetal blood-brain barrier needs to be passed. There are, however, also indirect effects of the cytotoxic treatment such as inflammation and oxidative stress. Furthermore, the metabolism of the fetus is immature, which is why the fetal pharmacokinetics and toxicity of drugs penetrating the placenta are very hard to predict. It is worth noting that also indirect effects of cancer and its treatment can cause harm to the fetus. Poor maternal nutrition and vitamin intake and high maternal stress are both factors that are proven 22

to have serious consequences on neurocognitive development of the fetus. Moreover, the rate of preterm births is higher in the cancer in pregnancy population, and prematurity has been shown to be related to cognitive impairment. Taking everything into account, patients diagnosed with cancer during pregnancy can be treated adequately in pregnancy [145-148]. With regard to the fetal outcome after prenatal treatment we can conclude that current data show a normal short-term outcome after chemotherapy in the second and third gestational trimester, or radiotherapy with a fetal exposure below 100 mGy. Yet, long-term outcome data are poor, and since it requires years of follow up also ongoing studies will need more time before firm conclusions can be drawn with regard to behavior, neurocognitive development, late cardiotoxicity, fertility and carcinogenesis.

Acknowledgements We thank Alexander Vercruysse for the illustration.

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Tables Table 1. Long-term follow up studies reporting on the neurocognitive development after in utero exposure to chemotherapy.

Aviles et al., 2001

Sample / Malignancy N=84 / Hematological malignancies

Timing exposure (trimester) 1st / 2nd / 3rd

1st / 2nd / 3rd

Duration follow up (range) 6-29 years

2-157 months

Measures

Methodological issues

Neurological, psychological, educational outcome and health

Main results (cognitive outcome) No congenital, psychological or neurological abnormalities. Normal educational and learning performances.

General health and development (parent survey)

One child Down’s syndrome, one child with ADD. All others had normal development.

(+) Focus on one cancer type and one treatment plan (-) Large differences in timing of exposure, no control groups included, no covariates taken into account, neural development only based on parent survey

Overall neurocognitive results within normal ranges, except for a twin with severe cognitive delay. Correlation between prematurity and lower cognitive developmental outcome. Six reported developmental milestone delays, but no significant cognitive abnormalities

(+) Extensive developmental follow up, covariates such as gestational age taken into account (-) No control groups included, diverse types of cancers and diverse treatment plans, large age differences at follow up

(+) Extensive developmental follow up, control group cancer without treatment, covariates taken into account (-) Small sample size, inclusion of diverse cancer types and different chemotherapy regimens, large age differences at follow up, no matched healthy controls (+) Matched control groups included, extensive developmental follow up, covariates taken into account

Hahn et al., 2006

N=40 / Breast cancer

Amant et al., 2012

N=70 / Diverse

2nd / 3rd

16.8-211 months

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

Murthy et al., 2014

N=50 / Breast cancer

2nd / 3rd

<1-21 years

Health questionnaire (parent survey)

Cardonick et al., 2014

N=35 (+22 cancer no chemo) / Diverse

2nd / 3rd

18-124.8 months

Behavior by parent report, tests for mental development, intelligence

No significant difference between study and control group

Amant et al., 2015

N=129* (+129 general population) /

2nd / 3rd

12-42 months

Health questionnaire, neurological examination and Bayley

No significant difference between chemotherapy exposed children and controls.

(+) Focus on one cancer type and chemotherapy regimen (-) Large differences in timing of exposure, no control groups included, no covariates taken into account, very little information on methodology used to determine cognitive outcome

(+) Focus on one cancer type and treatment plan (-) No control groups included, no covariates taken into account, only parent survey for cognitive outcome analysis

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Diverse

Scales of Infant Development test

Correlation between gestational age and cognition.

(-) Diverse cancer types and treatment plans

*Including 96 exposed to chemotherapy, 11 to radiotherapy, 13 to surgery alone, 2 to other drug treatments and 14 to no treatment. N = sample size, ADD = attention deficit disorder

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