Cancer during pregnancy: long-term follow-up of neuropsychological and behavioral development of children after antenatal exposure to chemo- and/or radiotherapy

Today, cancer during pregnancy has become increasingly prevalent, largely because of the recent trend to postpone childbearing until a more mature age. The current prevalence in Europe is 1 in 1000 pregnancies, with breast cancer and hematological cancers accounting for more than half. When cancer is diagnosed in an expecting mother, the decision whether or not to start treatment strikes a delicate balance between the well-being of the mother and that of the fetus. The primordial concern is the possible exposure of the fetus to imaging, surgery, chemotherapy, radiotherapy and the associated stress, with potential ensuing toxic effects. In the past, the lack of evidence on fetal outcome after prenatal exposure to cancer treatment withheld physicians from initiating cancer treatment during pregnancy. This commonly led to a delay in the treatment of the mother, termination of pregnancy or premature induction of delivery. Moreover, a cancer diagnosis during pregnancy may be considered as an emotional challenge for the expecting parents. To date, there is a lack of knowledge about the concerns and distress these women and their partners experience, how they deal with these concerns and who is at risk for high levels of distress.

Therefore, this PhD project focused on two lines of research. In the first line of research, we investigated the effects of prenatal exposure to maternal cancer and its treatment on the cognitive development in infancy and early toddlerhood (1.5-3 years), and on the cognitive development and behavior in early childhood (6 years) and in middle childhood (9 years). The results were compared to those of a control group of children born after an uncomplicated pregnancy who were one-to-one matched to the study group for country, test age, gestational age at birth, and in the 6 years and 9 years cohort also for gender and language of the tests.

In infancy and early toddlerhood (1.5-3 years), 129 children born from pregnancies complicated by maternal cancer were included, together with 129 controls. The children were examined by means of the Bayley Scales of Infant (and Toddler) Development – second or third edition. The cognitive outcome on the Bayley test was not significantly different between the study and control group. Subgroup analyses according to treatment type (no treatment, surgery alone, chemotherapy, radiotherapy) or to the type of chemotherapy (anthracyclines, taxanes, platin-based treatment) also did not reveal significant differences compared to the control group, although caution is needed as some subgroups were very small.

In early childhood (6 years), we included 132 children born to mothers diagnosed with cancer during pregnancy and 132 controls. The children were subjected to a comprehensive neuropsychological test battery, including intelligence, attention and memory tests, and a parent-report behavior questionnaire. No significant between-group differences were found in Performance IQ, Processing Speed, alertness, selective attention, divided attention, response inhibition, verbal and visuospatial memory span, verbal working memory, short- and long-term memory for visuospatial information and faces, and internalizing and externalizing behavior problems. However, children from the study group scored significantly lower on Full Scale IQ (5 IQ points difference) and Verbal IQ (8 IQ points difference) than their matched controls, although the values were within the normal range. Significant between-group differences in Full Scale IQ and Verbal IQ were also found in the subgroup of 97 chemotherapy-exposed children and their matched controls.

In middle childhood (9 years), we included 43 children prenatally exposed to maternal cancer and its treatment, together with 43 controls in an interim analysis of the data. Cognitive development was examined using an intelligence test and several attention and memory tests. Additionally, the parents filled out a questionnaire on behavior problems. The groups did not significantly differ on any of the tests measuring Full Scale IQ, Verbal IQ and Performance IQ, Processing Speed, alertness, sustained attention, selective attention, divided attention, attentional control, response inhibition, verbal and visuospatial memory span, verbal working memory, verbal proactive and retroactive interference, verbal and visuospatial short- and long-term memory, and short- and long-term memory for faces. The number of parent-reported internalizing and externalizing behavior problems was not significantly different between children from the study and control group. No subgroup analyses according to treatment type or type of chemotherapy were performed, due to the small overall sample size.

In conclusion, it has become clear that for specific cancers and under well-defined circumstances, cancer treatment during pregnancy is possible. In our three cohort studies, the cognitive development of children aged 1.5 to 3 years, 6 years and 9 years can be in general considered as normal for their gestational age. However, Full Scale and Verbal IQ were significantly lower in the study versus control group at the age of 6 years, although the values were within the normal range and these differences were not found in our interim analysis of 9-year-old children. Further research in larger samples and at older ages is needed to evaluate the evolution of these findings and to explore whether a differential impact of different types of maternal cancer treatment exist on the longitudinal development of specific cognitive functions.

In the second line of research, we investigated the impact of the diagnosis and treatment of cancer during pregnancy on the psychological distress and use of cognitive coping strategies in pregnant women and their partners. In our study, 61 patients and their partners retrospectively (70.5%, after delivery) or prospectively (29.5%, during pregnancy) filled out the validated Cognitive Emotion Regulation Questionnaire (CERQ) and the newly constructed Cancer and Pregnancy Questionnaire. We found that pregnant women diagnosed with cancer and their partners experience similar levels of concerns and distress with regard to the child’s health, the disease and treatment, and the pregnancy and delivery. We identified three subtypes of patients and partners in their use of cognitive coping strategies to deal with their cancer diagnosis and treatment: 48.3% of women and partners preferably used positive coping strategies (acceptance, putting into perspective, positive refocusing, positive reappraisal), 32.8% mainly used internalizing coping strategies (rumination, catastrophizing, refocus on planning, blaming self and others, a lack of acceptance and of positive refocusing) and 18.9% mainly blamed themselves and others for what happened. Patients and partners who mainly used internalizing coping strategies experienced the highest levels of concerns and distress and may benefit from additional psychosocial support. However, women and partners who mainly searched for someone to blame reported the lowest levels of concerns and distress. Possibly, denial and avoidance of emotions may be underlying mechanisms in this group of participants, and as a consequence they may have reported lower levels of concerns and distress. Moreover, it is likely that other ways of emotion regulation, such as physiological (e.g., rapid pulse, rate of breathing, muscle tension), social (e.g., expression of feelings, distraction), behavioral (e.g., withdrawing, crying, angriness, information seeking) and other conscious and unconscious cognitive processes (e.g., selective attention, projection) are intertwined with the cognitive emotion regulation processes investigated in this study. Future research may focus on the validation of the newly constructed Cancer and Pregnancy Questionnaire in a prospective sample in order to implement it as a tool for distress screening and psychosocial care in pregnant women diagnosed with cancer and their relatives.