Maternal autoimmune disease is not associated with cancer in the offspring

1 INTRODUCTION

Autoimmune diseases, such as connective tissue or inflammatory bowel disease, affect women in their reproductive ages. In 0.7% of pregnancies ending in delivery in Finland, the mother receives reimbursement for drug therapy costs of a connective tissue disease. According to the Finnish Institute of Health and Welfare, inflammatory bowel disease is equally common among pregnant women.¹

In Finland, up to 200 cancers are diagnosed annually among children and adolescents under 20 years of age. Cancer remains the most common, non-accidental cause of death among children in developed countries. The aetiology of childhood cancer is unclear with only 5–10% of cases linked to hereditary cancer predisposition syndromes and the same proportion possibly to yet undefined environmental factors.²

Autoimmune disease, especially rheumatoid arthritis, appears to increase the risk of cancer among adult patients.^3-6 Also, therapies used to treat autoimmune disease, such as TNF-alpha-inhibitors, have been associated with an increased risk. Both rheumatoid arthritis and its treatment have been associated with lymphoma.^{7, 8} There is speculation that the risk is positively associated with increasing severity of the disease.⁵

The relationship between a familial autoimmune disease and the risk of childhood cancer has been previously studied, mostly in case-control settings with the exposure data being based either on recall ^{3, 9-11} or population-based registries.^12-15 Only one study reported a significant association between a maternal autoimmune disease, that is exposure in utero to the mother's condition, and childhood Hodgkin´s lymphoma.³ The rest found positive but non-significant^{11, 12, 14, 15} associations or no association^{9, 10, 13} between a maternal autoimmune disease and childhood acute lymphoblastic leukaemia (ALL) and lymphomas. The definition of autoimmune disease varied widely among the studies warranting a population-based approach with specific subgroups.

We investigated whether a maternal autoimmune disease or its medication are associated with the risk of cancer in the offspring up to the age of 20 years using national, population-based, registry data.

2 MATERIALS AND METHODS

A unique personal identity code given to each Finnish citizen since 1967 allows for the linkage of information recovered from the health and vital statistics registries. Permanent residents of Finland are covered through the Finnish National Health Insurance and eligible for reimbursement for the cost of prescription medicines. People with certain chronic diseases are eligible for special reimbursement for their prescription medicine costs, and they are assigned a special reimbursement code.

The Finnish Cancer Registry started systematic, nationwide registration of cancer in 1953 and includes data on treatments and causes of death. It has a 95% coverage for all cancers.¹⁶ The completeness for childhood cancer is 92% for solid tumours and 97% for leukaemia.¹⁷

The Finnish Medical Birth Register, run by the Finnish Institute for Health and Welfare, was founded in 1987. The Medical Birth Register contains data on all mothers who have delivered a child in Finland, and the obstetric and neonatal outcomes are available until seven days after delivery or at hospital discharge.

The Register of Reimbursed Drug Purchases is maintained by the Social Insurance Institute of Finland and retains data on all prescription drugs reimbursed since 1993. The database includes personal information on the Anatomic Therapeutic Chemical code of the drug, date of purchase, package size, drug cost and refund category.

The Care Register for Health Care is maintained by The Finnish Institute of Health and Welfare since 1969 and contains information on patients, hospital admissions and discharges, diagnoses and treatment given in secondary and tertiary health care.

Research permits were obtained from The Finnish Institute of Health and Welfare (THL/252/5.05.00/2016), Social Insurance Institute of Finland (15/52272016) and Helsinki University. No ethical board review was required as this study was based on national statutory registries, and no study participants were contacted.

2.1 Study population

We identified all 2037 individuals with a first cancer diagnosis before the age of 20 years in the FCR for the years 1996–2014. We also identified five population-based controls for every case (n = 10,185) matched on sex and birth year from the Medical Birth Register. Due to missing data on birth weight, eight cases and 82 controls were excluded (Figure 1), resulting in 2029 cases and 10,103 controls being included in the analysis. For the descriptive characteristics of the cases and controls, see Table 1.

TABLE 1. Maternal and offspring characteristics of childhood cancer cases and controls, 1996–2014

	Number of cases 2029	Percentage of cases	Number of controls 10,103	Percentage of controls
Maternal characteristics
Maternal age (years)
<25	355	17.5	1872	18.5
25–29	639	31.5	3246	32.1
≥30	1035	51.0	4985	49.3
Parity
Primiparous	847	41.7	4098	40.6
Multiparous	1182	58.3	6005	59.4
Maternal smoking
Yes	291	14.3	1447	14.3
No	1680	82.8	8404	83.1
Unknown	58	2.9	252	2.5
A diagnosis of autoimmune disease prior to delivery	19	0.9	134	1.3
Any autoimmune disease medication purchase 3 months before/during pregnancy (ATC-code)	169	8.3	888	8.8
Inflammatory bowel disease medication (A07E)	13	0.6	65	0.6
Systemic corticosteroids (H02)	21	1.0	107	1.1
Immunosuppressants (L04)	3	0.1	13	0.1
Anti-inflammatory and antirheumatic products (M01)	141	6.9	761	7.5
Inflammatory bowel disease	12	0.6	61	0.6
Inflammatory bowel disease diagnosis, no medication	2	0.1	12	0.1
Connective tissue disease	7	0.3	74	0.7
Connective tissue disease diagnosis, no medication	1	0.05	38	0.4
Offspring characteristics
Offspring sex
Male	1092	53.8	5431	53.8
Female	937	46.2	4672	46.2
Multiple pregnancy
No	1962	96.7	9784	96.8
Yes	67	3.3	319	3.2
Gestational age
<37 weeks	141	6.9	537	5.3
≥37 weeks	1888	93.1	9566	94.7
Weight for gestational age (size at birth)
Small for gestational age	55	2.7	217	2.1
Appropriate for gestational age	1881	92.7	9587	94.9
Large for gestational age	93	4.6	299	3.0
Delivery type
Vaginal birth	1675	82.6	8470	83.8
Caesarean section	354	17.4	1627	16.1
Unknown	0	0.0	6	0.5

3 RESULTS

A total of 172 (8.5% of 2029) cases with cancer and prenatally exposed to any maternal autoimmune disease and the medication used as disease therapy were included. Sixteen cases (0.8% of all cases) had a mother with an autoimmune disease diagnosis and used medication, three (0.1% of all cases) had a diagnosis but no medication, and 150 (7.4% of all cases) had medication but not a diagnosis. In the control group, there were 938 (9.3% of 10,103 controls) offspring exposed to maternal autoimmune disease and, or, its medication. Eighty-five mothers (0.8% of all controls) had a diagnosis of autoimmune disease and used medication, 50 mothers (0.5% of all controls) had a diagnosis but no medication, and 753 (7.5% of all controls) had medication but not a diagnosis.

The maternal autoimmune diseases included in the analyses were not associated with an increased risk for offspring cancer (crude OR 0.70, 95% CI 0.43–1.14) when compared to the offspring of mothers with no autoimmune disease. This result was similar after adjusting for maternal age, parity and smoking status (OR 0.76, 95% CI 0.47–1.23) or when further adjusted for birth weight for gestational age (OR 0.76, 95% CI 0.47–1.24). For inflammatory bowel disease, the adjusted OR was 1.08 (95% CI 0.56–2.01) and 0.50 (95% CI 0.23–1.08) for the connective tissue diseases (Table 2).

The results remained unaltered in an unmatched analysis stratified by birth year and sex (adjusted OR for any autoimmune disease 0.70, 95% CI 0.43–1.15), except for a maternal connective tissue disease showing a lower risk for childhood cancer (OR 0.41, 95% CI 0.18–0.94) (Table S1). There was no change in the results in a sensitivity analysis with further adjustment for the birthweight (data not shown).

Any maternal medication used to treat the autoimmune disease and purchased up to three months before or during the pregnancy was not associated with an increased risk of childhood cancer (adjusted OR 0.95, 95% CI 0.80–1.14). The results by the class of drugs were similar: maternal inflammatory bowel disease medication (adjusted OR 1.08, 95% CI 0.59–1.97), systemic corticosteroids (adjusted OR 1.01, 95% CI 0.64–1.63), immunosuppressants (adjusted OR 1.28 with 95% CI 0.36–4.60) or anti-inflammatory and antirheumatic products (adjusted OR 0.92, 95% CI 0.76–1.11) compared with no medication (Table 2). In a sensitivity analysis for any maternal autoimmune disease medication excluding the anti-inflammatory and antirheumatic products, the adjusted OR was 1.06 (95% CI 0.72–1.56, data not shown).

Analyses by cancer subtype (Table 3) also generally showed results compatible with no association between a maternal autoimmune disease and childhood cancer in the offspring. We found no association with acute lymphoblastic leukaemia (adjusted OR for maternal autoimmune disease 0.72, 95% CI 0.30–1.71, for medication OR 0.93, 95% CI 0.66–1.32) nor for lymphomas (adjusted OR for autoimmune disease medication 0.80, 95% CI 0.09–6.80). However, an increased, but not statistically significant OR for lymphomas with autoimmune disease medication was observed (adjusted OR 1.32, 95% CI 0.70–2.48).

In analyses by trimester, the adjusted OR was 0.89 (95% CI 0.73–1.09) for cancer risk associated with autoimmune disease medication before and/or during the first trimester, and 1.32 (95% CI 0.74–2.44) for the second and/or third trimesters (Table S2). The same pattern was observed in subgroup analyses for the use of corticosteroids or anti-inflammatory and antirheumatic products Table S3 and Table S4.

4 DISCUSSION

We found no definitive evidence of increased cancer risk among the offspring of women with an inflammatory bowel disease or connective tissue disease during pregnancy, compared with mothers with no autoimmune disease. These results are in line with previous publications.^{9, 10, 13}

Maternal connective tissue diseases, including rheumatoid arthritis, however, appeared to be associated with a lower risk of childhood cancer as shown in stratified analysis. A lower risk for childhood acute lymphoblastic leukaemia has been demonstrated only for rheumatoid arthritis in one previous study with self-reported data,¹⁰ but the underlying biology remains unclear. This warrants repeating the analysis for rheumatoid arthritis in a larger study and possibly further exploring the biology.

Our findings were not consistent with an increased risk of childhood leukaemia or lymphomas following maternal autoimmune disease exposure as previously shown by some,^{3, 23} but not all studies.^{9-12, 14, 15} The impact on risk for cancers other than leukaemia or lymphomas also remains inconclusive, with positive associations in other studies possibly due to varying definitions of autoimmune disease, for example, including maternal diabetes which is known to be associated with childhood cancer.^{24, 25} This emphasises the need for prospective collection of detailed and standardised data for future analyses.

Biological, including genetic, explanations for the associations of maternal autoimmune disease or its medication with the risk of cancer in the offspring are unknown. Yet, there is an established risk of cancer, particularly the lymphomas, among the adult patients with an autoimmune disease.^{5, 6, 12, 26} The cases were younger than 20 years of age in our study, so we cannot rule out a possible increase in cancer risk later in life.

Maternal autoimmune disease and resulting glucocorticoid stress was not a risk factor for childhood cancer in our study.²⁷ Autoimmune disease medication can partially cross the placenta and is associated with an elevated risk of malformations. Despite this, it was not associated with childhood cancer in the offspring.^{7, 28} Our subgroup analysis by trimester, however, suggested a potentially harmful impact rendered by autoimmune medication later in pregnancy, for corticosteroids as well as anti-inflammatory and antirheumatic products. Unfortunately, we lacked data on steroids administered antenatally at the hospital, shown previously to be associated with an increased childhood cancer risk.²⁹ In our sensitivity analysis without the anti-inflammatory medication, the OR for autoimmune disease medication was slightly higher, indicating a need for more detailed analysis on the different autoimmune disease medication groups. Medication used to treat autoimmune disease changed markedly during the study period and thereafter with targeted biological therapies being currently available. In addition, we were unable to separate the immunosuppressive medication into subgroups. This and the trimester-specific impact of autoimmune disease medication on cancer risk of the offspring warrants further investigation also including therapy given in the hospital (antenatal steroids) and the other maternal autoimmune diseases not covered in this study.

5 CONCLUSION

In our population- and registry-based, nationwide dataset, we did not find the risk of childhood cancer, or its key subtypes, to be increased following exposure to a maternal autoimmune disease and, or, its medication. Whether the risk is impacted by the status of the foetal development (trimester) remains unclear. The possible protective association with connective tissue disease, especially rheumatoid arthritis, warrants confirmation.

CONFLICT OF INTEREST

The authors report no conflict of interest.