Perinatal and childhood outcomes of children born to female cancer survivors in South Korea

To our knowledge, this population-based study is the most extensive study conducted on this topic. This is the first nationwide population-based study to investigate the perinatal and childhood outcomes of children born to mothers with cancer in South Korea. We found that cancer in mothers is associated with increased the risk of preterm birth, low birth weight, NICU admission, and death in their children. The rates of cerebral palsy diagnosis and delayed development among children of mothers with cancer were higher than those among children of mothers without cancer; however, the HR was not statistically significant after adjustment for gestational age and birth weight.

The findings of this study are consistent with previous findings showing an increase in the rates of preterm birth and low birth weight in the offspring of cancer survivors^9,10,15. There have been reports that offspring of female survivors of adolescent and young adult cancer had an increased risk of admission to a special care unit in population-based cohort studies from Western Australia¹⁶ and Finland¹⁷. Survivors are more likely to have delivery complications, such as labor dystocia, prolonged labor, fetal malpresentation, imminent fetal asphyxia, and rupture of uterus. A deteriorating uterine environment may contribute to adverse outcomes in newborns at birth, thereby increasing the need for intensive care^11,18.

Our study showed that mortality rate in offspring born after maternal cancer diagnosis during the first year of life did not significantly increase. A previous study reported results consistent with our findings that cancer survivors did not have an elevated risk of death in their children within the first year of life¹⁷. However, when mortality over the entire follow-up period (5.86 ± 2.81 years in the offspring of female cancer survivors) was compared between both groups, a 1.3-fold increased risk was observed in children of cancer survivors, even after adjusting for gestational age and birth weight. A Swedish population-based study evaluated mortality risk in the offspring of women with a history of cancer at any point in their lives¹⁹. They reported that the overall mortality risk in the offspring of mothers diagnosed with cancer was the same as that in the background population (standardized mortality ratio [SMR] = 1.00, 95% CI 0.97–1.03). However, in this Swedish study, the relative risk of death in offspring born between 1 year before and 1 year after their mothers’ cancer diagnosis doubled during the first 4 years after birth (SMR = 2.03, 95% CI 1.46–2.68). Offspring born 1 year after maternal cancer diagnosis had significantly increased mortality risk only if the mother had hematopoietic cancer (SMR = 2.07, 95% CI 1.10–3.35). We were unable to perform further analyses because the NHIS database did not include causes of death. Other studies have reported that the main causes of death among offspring of cancer survivors are prematurity, delivery complications, and congenital anomalies¹⁷. Based on these results, further analyses are needed to investigate the risk factors of offspring death by dividing the subgroups according to the type of cancer, type of treatment, and timing of pregnancy.

We found that the higher risk of cerebral palsy and delayed development in children born to mothers with cancer was due to preterm birth or low birth weight. The major risk factors for cerebral palsy and delayed development are preterm birth and low birth weight^20,21. Preventing preterm birth and low birth weight could be a fundamental intervention to improve the health outcomes of children born to cancer survivors. We also assessed the risk of epilepsy, language disorder, and hearing impairment, which are known to be increased in children born preterm²²; however, these diseases did not show a significant increase among children of female cancer survivors. We followed the children for approximately 6 years, but a longer follow-up study would be able to evaluate other diseases whose prevalence rate increase with age.

In our study, the proportion of children with chromosomal anomalies was similar between mothers with and without cancer (0.15% vs. 0.16%). Contrary to our findings, two cohort studies conducted in Sweden reported that the risk of congenital malformation in children of female cancer survivors was significantly increased^11,23. While our study included only chromosomal abnormalities in the analysis (Q90–99), the studies from Sweden differed by including malformations and deformities in addition to chromosomal abnormalities (Q00–99). The risk of congenital malformation among offspring was elevated in mothers diagnosed with bladder, kidney, and nervous system tumors^23,24. However, another study in Denmark, which included only abnormal karyotypes, reported no increase in chromosomal abnormalities among children of cancer survivors¹², which is consistent with the findings of our study.

The risk of cancer in offspring is a major concern for cancer survivors during pregnancy²⁵. In a large Nordic study, the overall standardized incidence ratio (SIR) for non-retinoblastoma cancer among the offspring of cancer survivors was small but statistically significant (SIR = 1.6, 95% CI 1.1–2.4) ²⁶. However, when only sporadic tumors were analyzed, the increase in SIR was not statistically significant (SIR = 1.3, 95% CI 0.8–2.0) ²⁶. Another study reported that cancer risk was not high among offspring of cancer patients after the exclusion of hereditary cancer syndrome²⁷. Although our study did not exclude hereditary cancers, there was no significant increase in cancer risk among offspring of cancer survivors. Given the average follow-up period of 5.86–6.05 years for children in our study, the risk of some cancers, such as lymphoma and epithelial tumors, may not have been accurately reflected. Additional research is needed on the outcomes of children born to cancer survivors with longer follow-up into adulthood.

This study has several notable strengths, including its large number of participants from a nationwide database. The NHIS is a mandatory coverage system for all citizens residing in South Korea, allowing for a thorough investigation of cancer survivors and their offspring born after cancer diagnosis. Our study was free from recall bias, as we acquired claims data of children over time rather than relying on self-reported information, providing a more in-depth understanding of long-term disease diagnosis.

We believe that our study is of interest to a broad international audience, as it provides valuable insights into the perinatal and childhood outcomes of children of female cancer survivors. However, we acknowledge that the high prevalence of thyroid cancer in the study population is a limitation that should be considered when interpreting the findings.

Despite the comprehensive nationwide coverage provided by the South Korean NHIS, the use of diagnostic codes from the NHIS claims data posed limitations in assessing disease severity. Although these codes indicate whether a disease has been diagnosed, they do not provide detailed information on the extent or severity of the condition. Additionally, incomplete or inaccurate data may result when physicians report or file claims. Regarding mothers, the NHIS database lacks important information concerning cancer, such as stage and pathology. Furthermore, the absence of detailed information on the radiotherapy location and extent of surgery precluded us from stratifying the observed findings according to maternal cancer characteristics and treatment.

Another limitation of this study is that the time of onset for some secondary outcomes, such as chromosomal anomalies or cerebral palsy, may be unclear, as we used the time of the first claim as the time of event. This is because these conditions can manifest at different times during childhood, and it may not always be possible to determine exactly when they first occurred. Despite this limitation, we believe that this study provides valuable insights into the childhood outcomes of children born to mothers with cancer.

Finally, we were unable to evaluate all potential risk factors that could influence adverse medical outcomes in this study, such as assisted reproductive technologies and pre-pregnancy chronic diseases in cancer survivors. However, we matched the study population with controls based on maternal age and adjusted for other potential confounders, such as sex, delivery method, maternal age at delivery, income, and pregnancy complications including gestational hypertension and diabetes. Additionally, we adjusted for highly correlated variables in the analysis of hazard ratios for medical outcomes among children of female cancer survivors to minimize the potential for bias.

Our study indicated that the offspring of female cancer survivors had an increased risk of preterm birth, low birth weight, NICU admission, and total death. Our findings also suggested that increased risk of cerebral palsy and delayed development may be attributed to preterm birth or low birth weight. Pregnant female cancer survivors should be closely monitored and supported with hospital access to reduce preterm birth through effective strategies, such as increased access to regular hospital checkups, immediate contact with medical staff through applications, and financial support. Healthcare professionals should also provide supportive counseling to cancer survivors who wish to conceive. When survivors prepare for pregnancy, they should be informed of the high risk of preterm birth, educated about the signs of preterm birth, and referred to centers with a NICU. Further studies are needed to identify the risk factors and underlying mechanisms that contribute to increased rates of NICU admission and mortality.