Long‐term outcomes of children after prenatal exposure to maternal cancer and its treatment

Abstract

The incidence of antenatal cancer is increasing, prompting a medical‐ethical evaluation. The International Network on Cancer, Infertility, and Pregnancy (INCIP) was established to study cancer treatment safety during pregnancy and its impact on maternal and child health. Pivotal research has led to a paradigm shift in clinical management, demonstrating the feasibility and safety of most antenatal oncological treatments. Short‐term outcomes reveal normal growth and cardiac function in the exposed offspring, but caution is advised against first‐trimester chemotherapy. Psychological impact studies highlight the elevated levels of distress in pregnant cancer patients, underscoring the need for personalized information and ongoing psychological support. Long‐term follow‐up studies address gaps in postnatal impacts, while research into specific chemotherapeutic agents continues. Despite generally reassuring outcomes, continued monitoring is crucial, especially in families, such as those where the child was born premature after cancer (treatment) during pregnancy or where mothers are frequently absent due to continued illness or have died from. The ongoing INCIP child follow‐up initiative aims to further elucidate knowledge gaps, emphasizing the importance of large‐scale studies and personalized patient care.

We describe the short and long‐term child outcomes after prenatal exposure to maternal cancer(treatment) and the gaps of knowledge wich need to be elucidated in future research.

Abbreviation

INCIP

International Network on Cancer, Infertility and Pregnancy

Key message.

Despite reassuring insights in the long‐term outcomes of children prenatally exposed to cancer treatment so far, long‐term surveillance is crucial because of the tremendous (psychosocial) impact of cancer and its treatment during pregnancy on both the family and the offspring.

Antenatal cancer is a rare occurrence, affecting 1:10 000 pregnant women. ¹ , ² Nevertheless, the rate of pregnancies complicated by a maternal cancer diagnosis is rising in countries where women tend to delay childbearing. Additionally, early detection is increasing, due to improved prenatal testing (eg through the wide availability of noninvasive prenatal testing), which can incidentally identify maternal malignancies. ³ The medical‐ethical dilemma that cancer during pregnancy imposes, warrants a careful evaluation of clinical practice. To facilitate large‐scale registration and studies on the safety of cancer treatment during pregnancy and its impact on maternal prognosis and child health, we established the International Network on Cancer, Infertility and Pregnancy (INCIP), which will have been active for 20 years in 2025. Pivotal research has led to an important paradigm shift in the clinical management of these patients, with findings indicating that antenatal oncological treatment is mostly feasible during pregnancy and safe for fetal development. ⁴ Additionally, previous studies from the INCIP and the German Adjuvant Breast Cancer Group have shown that the prognosis for pregnant cancer patients (with cervical, breast and hematological cancers) is similar to that of nonpregnant patients. ⁵ , ⁶ , ⁷ An important part of the INCIP research portfolio is the follow‐up of the children focusing on the long‐term impact of prenatal exposure to cancer therapy on the development of children and adolescents.

Aligning with previous reports, short‐term outcomes indicate that children exposed to maternal cancer and its treatment in utero exhibit a normal growth development and no higher prevalence of medical problems. ⁶ Studies on the cardiac health of children prenatally exposed to chemotherapeutic agents, in particular anthracyclines, showed no abnormalities in cardiac function at the age of 36 months. ⁸ Analysis at a median age of 6 years, showed a higher diastolic blood pressure in anthracycline‐exposed children vs control children, though the clinical relevance may be limited. ⁹ However, caution is advised against administering chemotherapy during the first trimester due to the associated risk of congenital malformations, as evidenced by an association found between chemotherapy before 12 weeks of gestation and an increased risk of congenital malformations. ¹⁰

Regarding neurocognitive development, previous cohort studies on children prenatally exposed to chemotherapy, showed an overall reassuring development until the age of 6 years. ⁸ , ⁹ Furthermore, a report on the 9‐year‐old cohort, described a normal cognitive and behavioral development in late childhood when complex and executive functions are developing. ¹¹ Also, a Danish nation‐wide cohort study examined the general mortality, somatic diagnoses, and psychiatric diagnoses observed in offspring exposed to maternal cancer during pregnancy. The authors did not find any evidence of an elevated risk of mortality or severe morbidity among children exposed to cancer in utero. ¹²

Nevertheless, studies from the child follow‐up identified new questions regarding the development of children born after cancer during pregnancy, for which long‐term follow‐up is still ongoing. For example, the psychosocial impact of a cancer diagnosis during pregnancy on child development may need further research. A study relying on self‐reports from 74 pregnant women diagnosed with cancer revealed that almost 21%–51.5% reported clinically significant levels of distress, ¹³ as opposed to 2.3%–33.3% in healthy pregnant women ¹⁴ and 20%–40% in nonpregnant breast cancer patients. ¹⁵ Despite variations in distress measurement methods, these findings suggest that a cancer diagnosis poses an additional emotional challenge for pregnant women. A retrospective study, addressing the particular concerns and coping strategies of 61 pregnant women diagnosed with cancer and their partners, confirmed that parents experience high levels of distress concerning the diagnosis. ¹⁶ In this study, a correlation was identified between the utilization of cognitive coping strategies and the degree of distress experienced. Individuals, particularly mothers and partners, employing predominantly internalizing coping strategies exhibited the highest levels of distress in contrast to those utilizing positive or blaming coping mechanisms. Moreover, both mothers and their partners reported similar levels of distress regarding the child's health, the cancer disease and its treatment, and the pregnancy and delivery. Furthermore, a higher stage of disease at diagnosis correlated with more concerns about the disease and its treatment in mothers with breast cancer, but not for their partners. Drawing from earlier research that delineates the link between heightened maternal psychosocial stress during pregnancy and adverse neurobehavioral outcomes in offspring during early childhood, ¹⁷ these findings underscore the imperative for further studies to enhance our comprehension of the influence of parental stress during pregnancy on the well‐being of the offspring.

Additionally, these findings underscore the critical need for clear information about the disease, treatment, and prognosis of the mother, as well as evidence regarding the outcomes of children exposed to prenatal cancer treatment. Families should be advised with personalized information in an understandable format, to facilitate shared decision‐making about cancer treatment and pregnancy continuation. Moreover, in order to recognize the potential uncertainty, numerous questions, and diverse emotions faced by mothers and their partners, it is advisable to assess their levels of distress, concerns, and coping strategies. An ongoing INCIP study on parental psychological health will prospectively address levels of distress in parents at the moment of diagnosis and in the first year after birth to shed light on the psychosocial needs of families confronted with cancer during pregnancy and to further personalize the medical advice and decision‐making.

Another important gap of knowledge is the impact of the postnatal period. The interplay of maternal factors during pregnancy and the postpartum period, coupled with the physical and psychological burdens of cancer and its treatment during both pregnancy and the postpartum period, may contribute to adverse health consequences for offspring. A review on the indirect factors that may exert long‐term impact on child neurocognition describes the possible impact of maternal separation on the quantity and quality of parent–child interactions. ¹⁸ In the first sensitive period after birth, children are often separated from their mothers due to continuation of maternal treatment or maternal death as result of the cancer. Unfortunately, a considerable part of the mothers in the INCIP cohort still die from cancer shortly after birth. Therefore, it is important to obtain more insight in the outcomes of children who lost their mother in early childhood. Previous studies have identified maternal mortality as a significant contributor to adverse neurocognitive and behavioral outcomes, ¹⁹ , ²⁰ , ²¹ which is supported by previous findings from the INCIP cohort, showing subtle differences in both child language development and the child's need of supportive care after maternal death. ⁹ , ²¹ A subanalysis on chemotherapy‐exposed children with a median age of 9 years (n = 151) also showed a trend of a need for supportive care after maternal bereavement, although this trend was not statistically significant and may be confounded by the high incidence of prematurity in this cohort. ¹¹ Further research, especially in the long‐term, is thus required to elucidate the psychosocial and neurocognitive impact of maternal separation and maternal death on the child.

Despite the generally reassuring outcomes on general health, a comprehensive understanding of the long‐term effects of specific chemotherapeutic agents, such as cisplatin and carboplatin, is limited by small sample sizes. A larger cohort‐study on ototoxicity in children prenatally exposed to platinum derivatives, is ongoing. This will be the first study using reliable international standardized audiological classification systems to assess age‐appropriate auditory functioning and aims to provide a more nuanced understanding. Concurrently, pioneering cohort analyses into the specific impact of treatment types, including platinum compounds and radiotherapy, on child development are ongoing.

Considering the critical period within the first 1000 days after conception (until 2 years after birth), there is a likelihood that children exposed to maternal conditions related to cancer and its treatment may face detrimental health effects in their later years. Specifically, antenatal exposure to chemotherapy has been associated with lower verbal IQ, weaker emotional regulatory skills, higher blood pressure, and increased incidence of ototoxicity in children compared to controls. ⁵ , ⁸ , ⁹ , ²² Moreover, maternal stress, anemia, malnutrition, and a lack of parental attachment during pregnancy and the postpartum period pose potential risks. ¹³ Emotional challenges faced by pregnant cancer patients, leading to maternal depressive symptoms, can also negatively impact prenatal attachment and the mother–child relationship. ²³ The ongoing child follow‐up studies, similar to that for childhood and young adult cancer survivors, aim to elucidate concerns regarding the fetal risk of antenatal exposure to cancer and its treatment, drawing on insights from previous findings in pediatric oncology.

In conclusion, insights into the safety of prenatal exposure to maternal cancer (treatment) have improved significantly in the past decade. So far, evidence shows that children prenatally exposed to maternal cancer (treatment) in general show normal cognitive and behavioral development up to the age of 9 years.

These findings provide a comforting update on the neurocognitive development during late childhood, a crucial period marked by the maturation of complex functions. Despite this positive outlook, it is essential to maintain vigilant monitoring of the children, given the association of maternal cancer during pregnancy with preterm delivery and maternal mortality, both of which pose potential risk factors for developmental issues. Furthermore, future large‐scale studies by means of the ongoing INCIP child follow‐up initiative are warranted to further elucidate the gaps of knowledge on cancer during pregnancy. Finally, we encourage physicians to ask the Advisory Board on Cancer, Infertility and Pregnancy (www.ab‐cip.org) for advice on treating their specific patients in sometimes complex situations.

AUTHOR CONTRIBUTIONS

Evangeline A. Huis in 't Veld: Responsible for the main text. Indra A. Van Assche: Revising the text. Frederic Amant: Editing and supervising.

CONFLICT OF INTEREST STATEMENT

The authors confirm that there are no conflicts of interest.

Huis in ’t Veld EA, Van Assche IA, Amant F. Long‐term outcomes of children after prenatal exposure to maternal cancer and its treatment. Acta Obstet Gynecol Scand. 2024;103:757‐760. doi: 10.1111/aogs.14811