Vitamin D has been suggested to affect the balance between T helper (Th1) and (Th2) type cytokines by favouring Th2 domination. We investigated the association between infant vitamin D supplementation and later pre-eclampsia, a disorder suggested to be dominated by Th1 response. We used data on 2969 women born in the Northern Finland Birth Cohort 1966 of whom 68 (2.3%) had pre-eclampsia in their first pregnancy. Risk of pre-eclampsia was halved (OR 0.49, 95% confidence interval (CI) 0.26–0.92) in participants who had received vitamin D supplementation regularly during the first year of life and this association was not affected by adjustment for own birth order, birth weight, gestational age, social class in 1966 and hospitalizations or pregnancy-induced hypertension of their mothers. Together with earlier observations on a reduced risk of type 1 diabetes after vitamin D supplementation, these data suggest that vitamin D intake in infancy may affect long-term programming of the immune response pattern.
Environmental challenges early in life have been shown to have permanent influences on adult immune system in mammals (Spencer et al., 2006). It has been suggested that the initial establishment and subsequent maintenance of T-cell repertoire may act as a possible focus for early life programming (Prentice et al., 1999). Hormonal vitamin D system has important influences on immune modulation, which include shifting the balance between T helper type 1 (Th1) and Th2 cytokines by favouring Th2 domination (Hayes et al., 2003; Spilianakis et al., 2005).
There is some evidence that early life vitamin D supplementation may have long-term influences on risk of immunological diseases. For example, associations have been reported between infant vitamin D supplementation and a reduced risk of type I diabetes (The EURODIAB Substudy 2 Study Group, 1999; Hyppönen et al., 2001) and an increased risk of allergies (Hyppönen et al., 2004). As type I diabetes is believed to be mediated by upregulation of Th1 type response (Roep, 2003), whereas in allergic conditions Th2 dominates (Romagnani, 2004), these associations could be explained by priming leading to long-term downregulation of Th1 type response pattern. Pre-eclampsia is a serious pregnancy- specific disorder, which has also been suggested to be mediated by overexpression of Th1 type response (Saito and Sakai, 2003; Sibai et al., 2005). As recently summarized (Hyppönen, 2005), there is already some evidence that vitamin D metabolism may influence pre-eclampsia. We investigated whether risk of pre-eclampsia was associated with infant vitamin D supplementation, to obtain further evidence for possible long-term effects of vitamin D supplementation on immune regulation.
Northern Finland Birth Cohort 1966 (NFBC 1966) consists of all births in the two northernmost provinces of Finland (Oulu and Lapland), with expected dates of delivery in 1966 (Rantakallio, 1969). The total number of girls born alive was 5889 of whom 90% (n=5285) participated in the 1-year follow-up study, when information was collected on the use of vitamin D supplementation. Vitamin D recommendation was 2000 IU/day and frequency of supplementation was recorded as regularly/irregularly/none. Information on suspected rickets during the first year was obtained from the child's health records. At the time of the latest follow-up (1997–1998, age 31 years) 5731 daughters were alive (99.2% traced, n=5688). Information on number of pregnancies until 1998 was obtained by a postal questionnaire with 4523 women (80%) responding with an informed consent, and during 1998–2001 from the medical birth register (MBR). There were 3471 women with at least one delivery. After excluding multiple births (n=42), women with pre-existing hypertension (n=45) or gestational hypertension without proteinurea (n=61) and those with no data on infant vitamin D supplementation (n=353), 2969 individuals were left for the current analyses.
Diagnosis of pre-eclampsia on first pregnancy was ascertained by chart review of cases from the MBR and the hospital discharge register (Gissler et al., 1995; Pouta et al., 2004). Pre-eclampsia was diagnosed if there was a blood pressure (BP) of 140/90 mm Hg (Korotkoff phase V for diastolic BP) or greater, measured twice 6 or more hours apart, and consistent proteinuria of 300 mg/day or more after 20th gestational week in a previously normotensive woman (Brown et al., 2001).
χ2 test was used for the associations between background indicators and supplement use/prevalence of pre-eclampsia. Associations with the risk of pre-eclampsia were evaluated using logistic regression. Multiple imputation (10 cycles) was used for missing information background indicators (363 women with at least one missing value) (Royston, 2004). Analyses were carried out using STATA, version 9. Permission to collect outcome data using national registers was obtained from the ministry of social welfare and health. The ethics committee of the faculty of medicine, University of Oulu, approved the study.
Of the 2969 women with children, 68 (2.3%) had pre-eclampsia. Prevalence of pre-eclampsia was greater in women whose mothers had been hospitalized during pregnancy (P<0.05), whereas other background indicators were not significantly associated with pre-eclampsia (Table 1). Women who were first born or pre-term were more likely to have received vitamin D supplementation during the first year of life compared to others (P=0.02), whereas there were no differences by birth weight, maternal hospitalizations during pregnancy or pregnancy-induced hypertension in the mother. Family social class in 1966 and maternal education was associated with the pattern of vitamin D supplementation during the first year (P<0.001), but not with the prevalence of pre-eclampsia.
Prevalence of pre-eclampsia was lower among women who had received vitamin D supplementation regularly during the first year of life compared to those who had received supplementation irregularly or not at all (Table 2). Risk of pre-eclampsia was halved among women who had been supplemented regularly compared to others, but no association was observed for dose of supplementation or suspected rickets.
In the NFBC 1966, regular use of vitamin D supplementation during the first year of life was associated with a 50% reduction in the risk of pre-eclampsia. Hence, our observations on the association between frequency of vitamin D supplementation and pre-eclampsia risk were in line with the initial study hypothesis, proving further support for long-term effects of vitamin D on immune regulation. However, owing to limited power in our study, data on the associations between pre-eclampsia risk with dose of vitamin D supplementation or suspected rickets (i.e. severe vitamin D deficiency) were inconclusive. Therefore, replication is required and these data remain suggestive of rather than providing firm evidence for a causal association between vitamin D and pre-eclampsia risk.
Given the immunomodulatory properties of the active vitamin D metabolite 1,25 (OH)2D (Mathieu and Adorini, 2002; Hayes et al., 2003), it is possible that aside from any long-term effects of infant vitamin D supplementation, current vitamin D status influences immune function and pre-eclampsia risk during pregnancy. There are established differences in vitamin D metabolism in pre-eclamptic compared to normal pregnancies, and some evidence that supplementation with vitamin D or calcium can reduce pre-eclampsia risk (Hofmeyr et al., 2003; Hyppönen, 2005). Regulation of calcium metabolism is the classical function of 1,25 (OH)2D and low calcium intake can lead to secondary vitamin D insufficiency (Wharton and Bishop, 2003). Mechanisms underlying the association between calcium supplementation and pre-eclampsia risk are not well-established and it could be speculated that any beneficial effect may work through increased availability of 1,25 (OH)2D for immune regulation after the correction of inadequate calcium intake.
The main strengths in our study are in the exceptionally large dose of vitamin D typically given to the infants and in the measurement of the main exposures several decades before the onset of the disease. Further, information on pre-eclampsia was based on well-maintained registers with further cross-checking by hospital chart review. The main limitation relates to the small number of women in the main exposure groups and the limited number of women with pre-eclampsia.
To conclude, our data were suggestive of a reduced risk of pre-eclampsia in the first pregnancy in women, who had received vitamin D supplementation during infancy. Combined with our earlier findings on type 1 diabetes, (Hyppönen et al., 2001) and allergies (Hyppönen et al., 2004), these data could suggest that supplementation with large doses of vitamin D in infancy may result in long-term programming of the immune response pattern.
This work was supported by grants from the Academy of Finland, the Ministry of Social and Health Affairs, Oulu University Hospital, and the BUPA Foundation. EH is Department of Health (UK) Public Health Career Scientist. Research at the Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust benefits from R&D funding received from the NHS Executive.
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Revista Colombiana de Cardiología (2016)