Health Services and Outcomes
Long-Term Morbidity and Mortality in Children After In Utero Exposure to Maternal Cancer
2Danish Cancer Society Research Center, Copenhagen, Denmark
3Department of Pediatrics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
*L.M. and C.S.H. contributed equally to this work.
In utero exposure to maternal cancer and cancer treatment might influence the child's short- and long-term health and development. The objective of the study was to investigate short- and long-term somatic and psychiatric outcomes in children exposed to maternal cancer in utero.
This nationwide cohort study identified all liveborn children in Denmark between January 1978 and December 2018. Exposure was defined as maternal cancer diagnosis during pregnancy, and in a subgroup analysis, exposure to chemotherapy in utero. The main outcomes of interest were overall mortality, somatic diagnoses, and psychiatric diagnoses identified in the National Health Registers. Follow-up started at birth and ended at an event, death, emigration, or end of 2018. Hazard ratios of end points adjusted for potential confounders were estimated using Cox regression analysis.
Of 2,526,163 included liveborn children, 690 (0.03%) were exposed to maternal cancer in utero. Compared with unexposed fetuses, children exposed in utero had no higher overall mortality, adjusted hazard ratio 0.8 (95% CI, 0.4 to 1.5), nor increased risk of congenital malformations, overall somatic or psychiatric disease. During the period 2002-2018, of 378 (0.03%) children exposed to cancer in utero, 42 (12.5%) were exposed to chemotherapy. Among these 42 children, in utero exposure to chemotherapy was not associated with selected somatic diseases nor to congenital malformations when compared with in utero exposure to maternal cancer without chemotherapy.
Cancer in pregnancy (CIP) composes a clinical and ethical challenge, requiring optimal maternal oncologic management while ensuring fetal health and development. The incidence of cancer diagnosed during the pregnancy period is approximately two in 10,000 livebirths.1
Diagnosis of cancer in pregnancy is associated with concerns about the short- and long-term health consequences of the unborn child. This study aims to investigate whether fetal exposure to maternal cancer and chemotherapy is associated with excess child mortality and morbidity.
To our knowledge, this study is the first to use nationwide health registers in the follow-up of children born to mothers with cancer in pregnancy. In this nationwide cohort study including 2,526,163 Danish children, fetal exposure to maternal cancer was not associated with increased overall mortality, nor was it associated with somatic or psychiatric morbidity. No health consequences of chemotherapy exposure in utero were detected.
These findings suggest that fetal exposure to maternal cancer and treatment did not have implications for the long-term somatic and psychiatric health of the children, which is reassuring for the affected families and their health care providers.
Fetal development plays a pivotal role in the neonate's and child's general health and neurocognitive development. Many exposures such as teratogenic drugs, radiation, smoking, alcohol, placental hypoperfusion during surgery, maternal illness, and poor maternal nutritional state may influence fetal development.2,3 Furthermore, children exposed to cancer in utero are at increased risk of prematurity associated with neonatal morbidity and long-term health consequences.4-11
Pediatric outcomes in children exposed to maternal cancer in utero have been reported in case-based studies focusing on congenital malformations, neurocognitive and cardiac function assessed by clinical examinations, and parent-reported questionnaires. Although it would be intuitive to suspect it to be hazardous, exposing an unborn fetus to drugs targeting dividing cells evidence from case studies have been reassuring concerning general health and development in children exposed to maternal cancer in utero, even after exposure to chemotherapy.12-19 In Denmark, a shift in treatment strategy of CIP took place in the beginning of the millennium, when recommendations regarding use of chemotherapy during pregnancy were introduced.20
More evidence regarding the short- and long-term effects of fetal exposure to maternal cancer and chemotherapy is warranted. Using Danish nationwide health registers, we present a comprehensive follow-up study on children born to mothers with CIP investigating somatic and psychiatric outcomes for a period of up to 40 years. Furthermore, in utero exposure to chemotherapy was included in a subgroup analysis.
In this cohort study, we linked data from the Danish health registers using the unique personal identification number assigned to all residents at birth or immigration. The continuously updated Danish Civil Registration System provided data on death, immigration, and emigration.21,22 The Danish Medical Birth Register23 provided a link between mother and child and contained obstetrical information, whereas oncologic data were obtained from the Danish Cancer Register.24 All inpatient and outpatient health care contacts, including information on discharge diagnoses and treatment, were supplied from the National Patient Register.25 Diagnoses were coded using the International Classification of Diseases (ICD), eighth revision (ICD-8) before 1994, and 10th revision (ICD-10) after 1994. A list of registers and data used is provided in Appendix Table A1 (online only) in Appendix 1 (online only).
All children born alive in Denmark between January 1, 1978, and December 31, 2018, were identified in the Medical Birth Register.
Exclusion criteria were (1) maternal age at pregnancy onset younger than 15 years or older than 54 years, and (2) children with an outcome diagnosis before birth (likely because of administrative errors; Fig 1).
Children whose mothers were diagnosed with cancer (not including nonmelanoma skin cancer) during pregnancy were considered as being exposed to maternal cancer in utero. The pregnancy period was defined as the interval from the estimated pregnancy onset (day of birth subtracted by gestational age in days and adding 14 days [ovulatory time phase]) to the day of birth (see Appendix 1 for the management of missing gestational age). Children born to mothers not diagnosed with cancer during or before pregnancy were considered unexposed and were included in the reference group.
In sensitivity analyses for selected outcomes, we included children born to mothers with a cancer diagnosis before pregnancy onset as an additional reference group (termed prepregnancy cancer). This was done to investigate the impact of unmeasured confounding by genetic disposition to cancer and psychosocial impact of maternal cancer on psychiatric disease.
In a subgroup analysis including children born from 2002 to 2018, exposure to chemotherapy during pregnancy was defined as having a mother with CIP who had a treatment code for chemotherapy BWHA and a corresponding treatment date during pregnancy in the National Patient Register. We compared children exposed to cancer and chemotherapy in utero with two reference groups: (1) unexposed children and (2) children exposed to maternal cancer in utero but not to chemotherapy. If women received chemotherapy during pregnancy for other causes than cancer, their children were excluded from this subgroup analysis.
The main outcomes of interest were overall mortality as well as overall somatic and psychiatric disease burden. Disease burden was defined by at least one incident diagnosis in five main diagnostic groups of the ICD-8/10 system for endocrine, respiratory, cardiovascular, urinary tract, neurologic, and psychiatric disease. Diagnosis codes used are listed in Appendix Table A2 (online only) in Appendix 1.
Outcomes of particular interest included cancer, congenital malformations, and puberty disturbances/infertility. Preselected specific somatic diagnoses were chosen as outcomes if these could be expected to be influenced by in utero exposure to cancer or cancer treatment. Preselected endocrine disease included thyroid diseases and diabetes mellitus type 1; respiratory disease included chronic lung disease in the lower respiratory tract; cardiovascular disease included valvular disease, cardiomyopathies, pulmonary heart disease, hypertension, arrhythmias, and heart failure; urinary tract disease included glomerular dysfunction, tubulointerstitial disease, kidney failure, and urethral disease; and neurologic disease included epilepsy and cerebral palsy.
In the chemotherapy subgroup analysis, hearing loss was investigated as an additional outcome because of the known ototoxicity of platinum-based agents. Furthermore, anemia, leukocytopenia, and thrombocytopenia were added because of the known suppression of myelopoiesis in patients exposed to chemotherapy.
Preselected psychiatric outcomes included autism spectrum disorders and attention-deficit hyperactivity disorder (ADHD). In the analysis of autism spectrum disorders, we excluded individuals with a somatic diagnosis inherently linked to autism (congenital rubella syndrome, Down syndrome, fragile x-syndrome, Angelman syndrome, DiGeorge syndrome, Prader-Willi syndrome, tuberous sclerosis, and neurofibromatosis) in accordance with previous studies.26-28
Psychiatric hospital contacts were available in the Danish National Patient Register from 1995.
Follow-up commenced on the day of birth and ended at an outcome of interest (restricted to the specific outcome category analyzed), death, emigration, or end of follow-up (December 31, 2018), whichever came first. In accordance with the availability in the registers, analyses on psychiatric outcomes were performed with a delayed entry in 1995.
Selected baseline characteristics were identified and summarized. Exposure and reference groups were compared using Cox proportional hazards regression to estimate crude and adjusted hazard ratios (HRs) and 95% CIs for the outcomes. Time since birth was used as the underlying time scale in the analyses to assure comparison of children of the same age (Appendix Tables A3 and A4, online only). In the subgroup analysis on chemotherapy exposure, all preselected endocrine, respiratory, cardiovascular, and urinary tract diagnoses were combined in one category in the Cox proportional hazards regression analysis because of small numbers.
Covariates were chosen after assessing which factors could potentially confound the association between exposure and outcome, and therefore, covariates varied depending on the outcome examined, as seen in Figures 2 and 3 and Appendix Table A5 (online only) in Appendix 1. The following variables were entered as covariates: calendar period (10-year intervals), gestational age (2-week intervals), maternal age at birth (15-24, 25-29, 30-34, 35-39, and 40-54 years), birth weight (< 2,500, 2,500 to < 4,000, or ≥ 4,000 g), sex, maternal educational level according to the International Standard Classification of Education (ISCED29; low [ISCED 0-2], medium [ISCED 3-4], and high [ISCED 5-8]), maternal death (time-dependent), and maternal diagnosis of preselected endocrine disease (time-dependent). Missing data on the covariates were handled using complete case analysis. Table 1 shows the number of children with missing data for each variable.
The proportional hazards assumption was assessed using Schoenfeld residuals. We stratified the baseline hazard by covariates that did not satisfy the assumption. A two-sided 95% CI not overlapping 1.0 was considered statistically significant. SAS version 9.4 was used for data management (SAS Institute Inc, Cary, NC). Statistical analyses were conducted in R version 22.214.171.124 The study was reported using the Strengthening the Reporting of Observational Studies in Epidemiology checklist for cohort studies.31
Data were provided from the Danish Health Data Authority under license FSEID-00004424. No ethical approval is needed for registry-based research in Denmark. The study was performed in accordance with the Declaration of Helsinki. In Denmark, consent is not required for studies that are entirely register-based.
During the study period, 2,534,811 liveborn children were identified and 2,526,163 were included in the cohort. A total of 690 children were exposed to maternal cancer in utero (Fig 1). The median duration of follow-up was 14.4 years (interquartile range, 6.4-25.0 years) for children exposed to maternal cancer in utero and 19.7 years (interquartile range, 9.9-29.2 years) for unexposed children. As shown in Table 1, children exposed to maternal cancer in utero were more often born premature and had a lower birth weight compared with unexposed children. Their mothers were older, had a higher educational level, and were more likely to die before the child's 15-year birthday. The most common cancer types diagnosed during pregnancy among mothers were melanoma (38.1%), breast (17.5%), cervical (13.8%), and ovarian cancer (4.5%).
Children exposed to maternal cancer in utero did not demonstrate a higher overall mortality than the unexposed reference group; adjusted HR 0.8 (95% CI, 0.4 to 1.5; Fig 2). There was no excess of congenital malformations; adjusted HR 1.0 (95% CI, 0.8 to 1.2). The risk of cancer was elevated compared with the unexposed reference group; adjusted HR 2.2 (95% CI, 1.0 to 4.9), however, on the basis of six events in the exposed group. In a sensitivity analysis, the exposed children were compared with children of mothers with prepregnancy cancer, which attenuated the estimate; adjusted HR 1.2 (95% CI, 0.5 to 2.7).
The adjusted HR for all endocrine diseases was 1.2 (95% CI, 1.0 to 1.6) in children exposed to maternal cancer in utero versus no exposure, whereas the adjusted HR was 1.9 (95% CI, 1.1 to 3.3) for preselected autoimmune endocrine diagnoses (thyroid disease and type 1 diabetes) on the basis of 12 events in the exposed group. There were no excesses of puberty disturbances, respiratory, cardiovascular, urinary tract, or neurologic disease whether assessed in main diagnostic groups or as preselected diagnoses.
Children exposed to maternal cancer in utero did not have an increased risk of overall psychiatric disease in comparison with unexposed children; adjusted HR 1.0 (95% CI, 0.8 to 1.3; Fig 3). When the comparison group consisted of children whose mothers had cancer before the pregnancy, the adjusted HR was largely unchanged; 1.1 (95% CI, 0.9 to 1.4). For the specific diagnoses, ADHD, and autism spectrum disorders, there were no associations with CIP when using anyone of the two comparison groups as reference (Fig 3).
In the subgroup analysis, we included 1,053,109 children born after 2002. There were 378 (0.03%) children exposed to maternal cancer in utero, of whom 42 (12.5%) were exposed to chemotherapy. Chemotherapy was given during second trimester in 73.8% of the mothers and during third trimester in 26.2%. In utero chemotherapy exposure was not associated with preselected somatic diseases combined or congenital malformations compared with no in utero chemotherapy exposure (Fig 4). No deaths or events of cancer, autism spectrum disorder, ADHD, hearing loss, or suppressed myelopoiesis were identified during follow-up of the 42 children exposed to chemotherapy in utero (Appendix Table A4, online only).
In the current study, in utero exposure to maternal cancer was not associated with increased risk of death, congenital malformations, somatic disease including cancer, or psychiatric disease except for an increased risk for specific endocrine disorders. In utero exposure to chemotherapy was not associated with overall somatic disease or congenital malformations; however, the results are based on small numbers. Our findings contribute with novel knowledge to the scientific body of evidence concerning short- and long-term consequences for children born to mothers with CIP and are overall reassuring to families and health care professionals.
Few studies have published data on long-term effects after age 6 years of children born to mothers with CIP.13,15,19,32 Available research has focused on neurodevelopment and cardiac function because of the toxic effect of chemotherapeutics on the CNS and myocardium.14,17,33 Similar to these studies, this study did not find an increased risk of cardiovascular diseases in children exposed to maternal cancer in utero. In the subgroup analysis assessing the impact of in utero exposure to chemotherapy, no events of cardiovascular disease were found, but the number of exposed children was small.
The studies focusing on neurocognitive evaluation of children to mothers with CIP do not report a significant difference in comparison with control groups regarding intelligence, school attendance, short-term memory, attention, and memory span.12,13,16,17,19,34 Lower verbal intelligence at age 6 years has been observed in a study comparing 97 children exposed to chemotherapy in utero with 97 matched unexposed controls. A post hoc analysis evaluated the effect of maternal death and found a larger between-group difference in the children who had lost their mother compared with those with surviving mothers. The full-scale intelligence test was comparable for the exposed children and controls, and the authors questioned the clinical relevance of the difference in verbal intelligence since the values were within the normal range.12 None of the studies have investigated risk of psychiatric disease. The current study found that children exposed to maternal cancer in utero did not have higher risk of psychiatric diseases combined than children in the unexposed or the prepregnancy cancer reference group. Similarly, no association with ADHD or autism was found.
Previous studies have assessed cancer risk in offsprings of cancer survivors and found no significantly elevated risk of nonhereditary cancer types.35-38 To our knowledge, no prior study has specifically investigated cancer risk among children whose mothers had cancer during pregnancy. One study investigated children born to a parent diagnosed with cancer within 9 months before delivery, and did not find an increased risk of cancer among the children.36 However, this study did not stratify according to affected parent, and consequently, a direct comparison with the results of the current study is not possible. In the current study, only six events of cancer were seen among children exposed to maternal cancer in utero, and the adjusted HR was borderline significantly increased when compared with the unexposed reference group. We did not restrict this analysis to nonhereditary cancer types, but the comparison with children of mothers with prepregnancy cancer indicated that the excess risk of cancer seen in comparison with children in general is likely to be explained by familial predisposition among children of mothers with CIP. Furthermore, no cancer events were seen in the children exposed to chemotherapy in utero. The follow-up in the current study is short, especially in the chemotherapy exposed study group; thus, the results should be interpreted with caution.
Our results indicate a possible association between exposure to CIP and endocrine dysfunction (thyroid disease and diabetes mellitus type 1) that warrants further investigation. To our knowledge, this is a new finding not described in previous studies, and although the finding was statistically significant, it should be interpreted with caution because of few events, and risk of type I error because of multiple comparisons.
The current study is, to our knowledge, the most extensive epidemiologic study on this topic including a nationwide cohort of more than 2.5 million children with over 45 million years of follow-up. Using national registers permits studying a rare condition such as CIP and effects on various outcomes. By use of nationwide registers, we identified physician assigned diagnoses of somatic and psychiatric diseases, thus eliminating recall bias. The extensive Danish registers provide solid outcome data on all citizens, thus minimizing informative censoring and strengthening the analysis. Data on exposure and outcomes were collected prospectively and independently of the study hypothesis, reducing selection and information bias.
A possible limitation of the current study is exposure and outcome misclassification of diagnosis codes in the registers. Assuming nondifferential misclassification, this would bias the results toward the null. However, validation studies on outcomes have shown high positive predictive values of several of the exposure and outcomes in the current study; 99% for breast cancer diagnoses, 86.8% for ADHD, and 94% for childhood autism diagnoses in Danish registers.24,25,39-41 Subgroup analyses on chemotherapy were limited to the past 2 decades when treatments have been registered in the National Patient Register with valid information on the timing of the administration of chemotherapy. Several confounders were considered in the study; however, residual confounding could still persist. We had inadequate information to identify hereditary cancer syndromes in the cohort. Instead, we established a second comparison group of children whose mothers all had cancer before the pregnancy to account for heredity in the cancer analysis. Because CIP is rare, we had to combine several outcomes to enhance statistical power. This resulted in a loss of detail. Besides, the results from analyses with low numbers of events should be interpreted with caution.
In conclusion, this is the first nationwide study on long-term outcomes in children exposed to maternal cancer in utero. We found no increase in overall somatic or psychiatric disease burden, nor mortality in these children. Exposure to chemotherapy in utero among children born within the past 2 decades could not be linked with any adverse health consequences.
The funders had no role in the design of the study, in the collection, analysis, and interpretation of the data, in the writing of the report; or any decision related to the publication.
Supported by a grant from The Research Fund of Rigshospitalet, Copenhagen University Hospital Grant No. E-23669-01, The Novo Nordisk Foundation Grant No. NNF18OC0052571, Johannes Clemmesen Research Foundation, Helsefonden Grant No. 20B-0350, Holm Memorial Foundation, and the Danish Cancer Research Foundation.
Data were available from Statistics Denmark (https://www.dst.dk/en/Statistik) and Danish Health Data Authority (https://sundhedsdatastyrelsen.dk/en/forskerservice). R-code of analyses is available from the corresponding author upon request. The corresponding author had full access to the included data and is responsible for the submission for publication.
Conception and design: Iben K. Greiber, Jakob H. Viuff, Lone Storgaard, Mona A. Karlsen, Øjvind Lidegaard, Lene Mellemkjær, Cristel S. Hjortshøj
Collection and assembly of data: Iben K. Greiber, Jakob H. Viuff, Lone Storgaard, Mona A. Karlsen, Lene Mellemkjær, Cristel S. Hjortshøj
Data analysis and interpretation: Iben K. Greiber, Jakob H. Viuff, Lone Storgaard, Mona A. Karlsen, Øjvind Lidegaard, Anders P. Mikkelsen, Lene Mellemkjær, Cristel S. Hjortshøj
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
Research Funding: Exeltis (Inst)
Employment: Novo Nordisk (I)
Stock and Other Ownership Interests: Novo Nordisk (I)
No other potential conflicts of interest were reported.
The data in the Danish registers used in this study were linked using the unique personal identification number, assigned to all residents in Denmark. See Appendix Table A1 for information on all registers.
The Medical Birth Register provided information on all livebirths and has a high validity.3 It contains information on all births in Denmark and contains a link between the mother and the neonate, date of birth, gestational age, parity, gravidity, multiple birth, and obstetric information of delivery mode and birth weight. The gestational threshold for a stillbirth to be registered was 28 weeks before 2004 and 22 weeks thereafter. We applied restrictions to address invalid gestational ages. Those with an extreme gestational age were set to missing/invalid. If gestational age was missing or invalid, we used the mean gestational age.
The National Patient Register was used to identify information about somatic and psychiatric outcome diagnoses. All physician-assigned diagnoses from hospitalizations in somatic hospital departments and since 1995, from outpatient and emergency visits as well as from contacts to psychiatric departments in Denmark, are included in this register.2 Discharge diagnoses were coded using the International Classification of Diseases (ICD), eighth revision, before 1994 and ICD, 10th revision, from 1994. See Appendix Table A2 for specific diagnosis codes.
The Cancer Register provides information on all new cancer diagnoses, including date of diagnosis, cancer diagnosis (the ICD, seventh revision during 1943-1977 and the ICD, 10th revision hereafter), anatomical localization, and histology (ICD, oncology, third edition) since 1978.4 Before 2004, cancers were reported to the registry on paper forms sent by hospitals and clinics. From 2004 and onward, cancers are reported electronically mainly through the National Patient Registry.
Before 2004, only month and year of diagnosis was reported, and the date of diagnosis was set to the 15th of the month.
The authors would like to thank senior statistician Vanna Albieri from the Danish Cancer Society Research Center for statistical advice.
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