Maternal Migraines And Associated Pediatric Cancers
Overview
Maternal migraines are seen to be associated with unfavorable birth outcomes such as congenital malformations in babies, preterm births and infant low birth weight. It has been hypothesized that these unfavorable or adverse birth outcomes may be due to the intake of certain medications during pregnancy, in addition to genetics, hormonal effects, lifestyle and neurochemical factors.
There is sufficient evidence backing the incidence of cancers among adults suffering from migraines. In this study, we examined the association or link between the risk of cancer in offspring and maternal diagnosis of migraines using data obtained from the Denmark national registries.
Several cases were identified by the Cancer Registry among patients aged below 20 years diagnosed with cancer between the years 1996 to 2016. The control group was obtained from the Central Population Register, and participants were matched based on their sex and year of birth to cases.
Mothers who had a diagnosis of migraines were identified using the International Classification of Diseases from the National Patient Register. In the National Pharmaceutical Register versions 8 and 10, migraine prophylactic or acute treatment were recorded and used for this study.
Logistic regression was used to assess the risk of childhood malignancies in relation to maternal migraines.
Maternal migraines were seen to have a positive association with increased risk of non-Hodgkin’s lymphoma, osteosarcoma and central nervous system tumors such as gliomas.
Several pediatric cancers such as neuronal tumors were assessed to determine their association with maternal migraines. Other possible associations of note include genetics, lifestyle factors, hormonal factors and neurochemical factors are seen to play a role in the correlation between maternal migraines and pediatric cancers.
Introduction
Migraine
Migraine is a neurologic disorder commonly affecting adults within the age of childbearing. It affects 10% to 25% of Danish females within reproductive age, i.e. from the age of adolescence to age of menopause (40 years). Migraines were also seen to occur in 9% of Danish children irrespective of their gender. The frequency and prevalence of migraines in women is notably influenced by hormonal factors. Migraine prevalence dramatically rises with onset of menstruation (menarche) and reduces notably following menopause. The frequency of migraines varies at different phases of the menstrual cycle and decreases with pregnancy.
Women who suffer from maternal migraines are most likely smokers and at a higher risk of obesity compared to women who do not have migraines. Comorbidities like asthma, allergies, hypertension and other cardiovascular pathologies were seen to have a higher prevalence among people with migraines.
Maternal migraines have been seen to affect pregnancies as it is closely linked to adverse birth outcomes such as prematurity and low birth weight. Also, congenital anomalies have been linked to migraines and are speculated to be as a result of medical therapy during pregnancy. Furthermore, maternal migraines have been shown to be associated with complications during pregnancy such as severe vomiting and nausea and preeclampsia. In certain studies, these factors were shown to be associated with an increased risk of pediatric cancer.
Maternal migraines were shown to be related to some pediatric disorders such as psychiatric disorders, asthma and colic.
On the contrary, migraines reduces alcohol intake due to the fact that alcohol triggers migraine attacks, and as such, may reduce pediatric cancer related to alcohol intake in their offspring. There is a reduced risk of progesterone-receptor positive and estrogen-receptor positive breast cancer among women who suffer from migraines, which further buttresses the effect of hormones on migraines. Several hypotheses which aimed to link hormone levels to the risk of pediatric cancers were targeted on osteosarcoma and germ cell tumors. Estrogen mediates the effect of androgens on skeletal maturation, pubertal growth, and bone mass. Additionally, estrogen also induces apoptosis of osteoclasts. In an animal study involving mice, administration of estrogen led to the formation of testicular cancer.
Higher estriol levels were seen to increase the risk of testicular germ cell tumors in early childhood as seen in a Californian study of pediatric testicular tumors and newborn hormone levels. Also, the study showed that the effects of androgen and estriol varied based on age as there was a decreased risk of cancer in adolescence compared to early childhood.
Children of mothers suffering from maternal migraines were noted to have a higher incidence of central nervous system tumors and other cancers as seen in two studies.
Children with neurofibromatosis 1 were also reported to have a higher incidence of migraines. Neurofibromatosis is a disease of genetic origin which sets the stage for other pediatric cancers such as optic pathway glioma and rhabdomyosarcoma.
Migraines, as demonstrated by a study in Denmark, were seen to be increased among pediatric cancer survivors. However, some authors reported that this statistic may have been due to the effects of increased medical surveillance and therapies.
Method
The human subjects protection boards of the Danish Data Protection Agency, the University of North Texas and University of California, Los Angeles gave approval for this study. Data for this study was obtained from the Cancer Registry which involved patients aged below 20 years and diagnosed between the years 1996 to 2016. Data on the diagnoses of migraines were obtained from the Danish extended version of the National Patient Register using International Classification of Disease with ICD-10 coding established in 1993, following the previous International Classification of Disease version 8 (ICD-8).
28 cancer patients were recruited from the Cancer Registry. The cancer patients recruited for this study were linked to healthy controls obtained from the Central Population Register via a unique identification code which was given to all residents since the year 1968. This identification code provided information such as details of the parents of each child and their demographic information. These controls were matched to cancer patients on the basis of their age, sex and birth date with a 25:1 matching rate. These controls were selected randomly from the Central Population Register. Their files were then linked to the Medical Births Registry to report information on their gestational period, the National Pharmaceutical Register for information on their drug prescriptions and the National Patient register to obtain information on their medical conditions. Patients with migraine were also identified by their prescriptions of migraine specific prophylactic or acute treatment medications. The link or relationship between maternal migraines and migraines in their offspring was assessed as headaches may be an early sign of a tumor. A lagged analysis could not be carried out owing to the small sample size of 9 children diagnosed with migraines at least a year before their cancer diagnosis.
In this study, the association of migraines with other cancers was assessed. Unconditional logistic regression was used to evaluate the risk of pediatric cancer related to maternal migraines.
Eligibility Criteria
Children included in the study were born in Denmark to ensure that detailed and accurate information is gotten with regards to their gestation and birth.
Results
Mothers suffering from maternal migraines were seen to be younger in age and likely to have been born in Denmark when compared to mothers who do not have migraines.
Mothers with migraines were seen to most likely have a history of epilepsy or asthma, with a majority likely having a diagnosis of ischemic heart disease during or prior to the index pregnancy.
4% of children with congenital malformations had mothers with a history of suffering from maternal migraines.
Maternal migraines were seen in the logistic regression analysis to be positively linked with an increased risk of central nervous system tumors especially gliomas and neuroblastomas, non-Hodgkin lymphoma and osteosarcoma. Some leukemias and retinoblastoma also exhibited an elevated point estimate with wide confidence intervals.
Differences in the cancer risk in offspring of mothers suffering from migraine who take and who do not take medications was not considered when stratifying mothers suffering from migraine via their use of migraine-specific medications.
Conclusion
This study is one of the first to assess the relationship between a diagnosis of maternal migraines and the risk of pediatric cancers. Increases in the prevalence of osteosarcoma was observed to be associated with a maternal migraines diagnosis. Higher risk of pediatric central nervous system tumors, non-Hodgkin lymphoma and neuroblastoma were seen to be related to a maternal migraines diagnosis in exploratory analysis.
Childhood cancer survivors were seen to have increased migraine rates in a study in Denmark. However, considering that headache is a common sign of tumors, it is not clear if migraines led to the tumor or if the tumor led to the migraines. Hormones were also hypothesized to be a migraine trigger. Females with maternal migraines were seen to have higher levels of gonadotropin releasing hormone, low testosterone levels and higher prolactin levels (which may further lower estrogen levels) throughout their menstrual cycle compared with controls. In the follicular phase of the menstrual cycle, estrogen levels are higher than that of controls compared with cases, while in the luteal phase, estrogen levels are lower than that of controls. Lower estrogen levels were associated with higher severity of migraine.
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