Dairy food, calcium and vitamin D intake in pregnancy, and wheeze and eczema in infants

Epidemiological studies of the relationship of intake of dairy products with asthma, wheeze, and/or eczema have provided mixed results 1–8. Some studies found a protective relationship between dairy food intake and any symptoms of such conditions 1–3 whereas others reported a null association 4–7. Only one cross-sectional study of young Australian adults showed a significant positive association between intake of dairy products other than milk and the prevalence of asthma 8.

The role of intra-uterine exposure in the development of allergic disorders has gained interest. A birth cohort study in Germany showed no associations between maternal intake of milk, yoghurt or cheese during pregnancy and the risk of doctor-diagnosed eczema in the children at 2 yrs old 9. In a birth cohort study in the Netherlands, maternal dairy intake (average of milk and milk product consumption) during pregnancy was not related to the risk of childhood wheeze during the first 8 yrs of life 10. A significant inverse exposure–response relationship between maternal vitamin D intake during pregnancy and the risk of recurrent wheeze but not eczema, was found in 3-yr-old children in the USA 11. A prospective study in the UK found that higher maternal vitamin D consumption during pregnancy was significantly associated with a decreased risk of wheeze in children aged 5 yrs whereas such an inverse association was not observed in children at 2 yrs old 12. Prenatal deficiency of vitamin D may affect fetal lung and immune system development 13. Dairy foods are a rich source of calcium. To our knowledge, no epidemiological study has investigated the association between maternal calcium intake during pregnancy and the risk of childhood allergic disorders.

In this investigation, we examined the association between maternal consumption of dairy products, calcium, and vitamin D during pregnancy and the risk of wheeze and eczema in Japanese children at 16–24 months old, using data from the Osaka Maternal and Child Health Study (OMCHS).

METHODS

RESULTS

In the third survey, the prevalence of wheeze and eczema based on the ISAAC criteria was 22.1% and 18.6%, respectively, among 763 infants. About 75% of infants had been breastfed for 6 months or longer (table 1⇓). Slight or substantial changes in diet in the previous 1 month were reported by 551 mothers due to nausea gravidarum (n = 453), maternal and fetal health (n = 89) and other reasons (n = 9). Maternal mean daily total energy consumption and energy-adjusted intake of total dairy products, calcium and vitamin D during pregnancy were 7628.6 kJ, 168.8 g, 542.3 mg, and 6.2 μg, respectively (table 2⇓).

Compared with maternal total dairy product intake during pregnancy in the first quartile, consumption in the fourth quartile was significantly associated with a decreased risk of wheeze in the offspring, showing a clear inverse exposure-response relationship: the adjusted OR for comparison of the highest with the lowest quartile was 0.45 (95% CI: 0.25−0.79, p for trend 0.007) (table 3⇓). Likewise, higher maternal intake of milk and cheese during pregnancy was independently related to a reduced risk of wheeze in the children: the adjusted ORs for the highest versus lowest quartiles were 0.50 (95% CI: 0.28−0.87, p for trend 0.02) and 0.51 (95% CI: 0.31−0.85, p for trend 0.02), respectively. With regard to different types of milk, maternal consumption of full-fat, but not low-fat, milk was significantly inversely related to the risk of infantile wheeze. No evident relationship was observed between maternal yoghurt consumption during pregnancy and the risk of wheeze in the offspring. Maternal calcium intake during pregnancy was independently inversely associated with the risk of wheeze: the adjusted OR between extreme quartiles was 0.57 (95% CI: 0.32−0.99, p for trend 0.04). Compared with maternal vitamin D intake during pregnancy in the first quartile, only its consumption in the second quartile was independently related to a decreased risk of wheeze in the children.

Maternal intake of total dairy products, milk, yoghurt, cheese and calcium during pregnancy was not measurably associated with the risk of eczema in the offspring. There was an inverted J-shaped association between maternal vitamin D intake during pregnancy and the risk of eczema in the children although adjusted ORs for the second and third quartiles were of borderline significance.

Because all adjusted ORs for infantile wheeze and eczema associated with maternal vitamin D intake during pregnancy in the second, third and fourth quartiles were below unity, maternal vitamin D consumption during pregnancy was categorised into two groups using a cut-off point at the 25th percentile (<4.309 and ≥4.309 μg·day⁻¹). The consumption of ≥4.309 μg·day⁻¹ (≥172.4 IU·day⁻¹) was significantly associated with a decreased risk of both wheeze and eczema in the offspring: the adjusted ORs were 0.64 (95% CI 0.43−0.97) and 0.63 (95% CI 0.41−0.98), respectively. No interaction was found in the association of maternal calcium intake during pregnancy with infantile wheeze between children whose mothers had consumed 4.309 μg or more of vitamin D daily during pregnancy and those whose mothers had consumed <4.309 μg daily (p = 0.77 for homogeneity of OR for the highest quartile).

Maternal intake of total dairy products, milk and cheese was correlated with maternal calcium consumption: Pearson's correlation coefficients were 0.85 (p<0.0001), 0.74 (p<0.0001) and 0.39 (p<0.0001), respectively. The significant inverse relationships between maternal consumption of total dairy products, milk and cheese in the highest quartile and the risk of wheeze in the children were completely attenuated by further adjustment for maternal calcium intake during pregnancy as a continuous variable; the further-adjusted ORs were 0.68 (95% CI 0.30−1.53), 0.74 (95% CI 0.36−1.50) and 0.63 (95% CI 0.37−1.07), respectively.

Maternal intake of calcium and vitamin D was correlated with maternal consumption of docosahexaenoic acid and vitamin E (table 4⇓). Our previous findings using data from the OMCHS showed significant inverse associations between maternal intake of α-linolenic acid, docosahexaenoic acid 22 and vitamin E 23 during pregnancy and the risk of wheeze in the infants aged 16–24 months. Additional adjustment for maternal intake of α-linolenic acid, docosahexaenoic acid or vitamin E during pregnancy did not materially alter the significant inverse relationships between maternal intake of total dairy products, milk and cheese during pregnancy and the risk of wheeze in children. However, the inverse associations between maternal intake of calcium in the highest quartile and ≥4.309 μg·day⁻¹ of vitamin D and infantile wheeze were not statistically significant after further control for maternal intake of docosahexaenoic acid (further adjusted ORs (95% CIs) were 0.60 (0.34−1.04) and 0.76 (0.47−1.25), respectively) or vitamin E (further adjusted ORs (95% CIs) were 0.62 (0.35−1.08) and 0.71 (0.47−1.08), respectively) whereas the significant inverse associations remained after additional adjustment for maternal α-linolenic acid intake. According to our previous findings regarding eczema, additional adjustment for maternal intake of n-6 polyunsaturated fatty acids 22, green and yellow vegetables, citrus fruit, or β-carotene 23 did not materially change the significant inverse association between maternal intake of 4.309 μg·day⁻¹ or more of vitamin D and infantile eczema whereas the inverse association had disappeared after further control for maternal vitamin E intake (further adjusted OR (95% CI) was 0.68 (0.44−1.06)).

DISCUSSION

To the best of our knowledge, the current birth cohort study is the first to find that maternal intake of total dairy products, milk, especially full-fat milk, cheese and calcium during pregnancy was independently related to a decreased risk of wheeze in infants aged 16–24 months although such an inverse association with maternal yoghurt intake was not observed. On the other hand, no material associations were observed between maternal consumption of total dairy products, milk, yoghurt, cheese and calcium during pregnancy and the risk of eczema in the offspring. Children whose mother had consumed daily 4.309 μg or more of vitamin D during pregnancy had a significantly reduced risk of wheeze and eczema, suggesting a threshold effect rather than a monotonic trend. This is the first study in a non-Western population to examine the relationship of maternal vitamin D intake to allergic disorders in the offspring.

The potential protective effects of maternal consumption of total dairy products, milk and cheese during pregnancy on wheeze in infants essentially disappeared when we additionally controlled for maternal calcium intake during pregnancy in this study. Thus, the beneficial associations with dairy foods might be attributable to some extent to calcium or unmeasured constituents associated with calcium. Unknown factors in yoghurt might have interfered with the expected benefit of maternal calcium intake during pregnancy in the development of wheeze in the offspring in our population. All calcium in bodily fluids, whether in blood, in interstitial spaces or within the cell cytosol or organelles, originates from the diet 24. Several routes of Ca²⁺ influx may be implemented at various stages of the development and maturation of lymphocytes 25. Hammond et al. 26 observed that increases in extracellular calcium caused Ca²⁺ to be released from intracellular stores in human B cells, activated signalling cascades and resulted in increased cluster of differentiation (CD)83 expression and responsiveness to Toll-like receptor, B-cell receptor and cytokine receptor signals. Local changes in extracellular calcium may be sensed by nearby B cells and prepare them to interact with T cells 26. Thus, higher maternal calcium intake during pregnancy might be expected to moderate extracellular calcium fluctuations in a fetus and modulate antenatal immune responses via downregulation of the calcium-sensing mechanism on B cells, resulting in a decreased risk of allergic disorders in the child. However, no association was found between maternal calcium intake during pregnancy and the risk of eczema in infants in the current study.

The average vitamin D intake by pregnant females participating in a previously cited UK birth cohort study and in a US birth cohort study was 137 IU·day⁻¹ and 548 IU·day⁻¹, respectively 11, 12. The corresponding figure for the current study was 248 IU·day⁻¹. Milk fortified with vitamin D is the main source of vitamin D intake in the US diet 11. Fish and eggs are major sources of vitamin D intake among Japanese people. An inverse relationship between maternal vitamin D intake during pregnancy and the risk of childhood wheeze was observed in the three different populations regardless of the amount of vitamin D intake. The main source of vitamin D is the cutaneous synthesis induced by sunlight exposure irrespective of populations 27. The two previous birth cohort studies 11, 12 and our study did not take sunlight exposure status into consideration. Another UK prospective study reported that children whose mothers had higher serum concentrations of 25 (OH)-vitamin D in late pregnancy had a significantly increased risk of visible eczema on examination at 9 months and asthma at age 9 yrs 28. The effects of vitamin D on allergic disorders might depend on the timing of vitamin D exposure. In a birth cohort study in Finland, subjects who had received vitamin D supplementation regularly during the first year compared to others had a marginally significantly increased risk of asthma at age 31 yrs 29. Higher vitamin D intake at 5 months old was significantly positively related to the risk of eczema at the age of 6 yrs in Swedish children 30.

The present study had methodological strengths. Study subjects were homogeneous in terms of having the same residential background. We incorporated extensive information on potential confounding factors. The prospective design was likely to reduce the possibility of recall bias. The definition of wheeze and eczema was based on the ISAAC questions although validation tests of the ISAAC questions have not been performed for Japanese infants. No attempt was made to ascertain outcome status through reviews of medical records. Moreover, the outcomes under study were measured at varying ages between 16 and 24 months and, additionally, wheeze in infancy is known not to be a good predictor of asthma over the longer term. These disadvantages could bias the magnitude of the observed effects towards the null.

There are other limitations in this study that deserve recognition. Our DHQ could only approximate consumption although the correlation between the DHQ and dietary records was reasonable, as described above. The consequence would have been an underestimation of values in our results. Our DHQ was designed to assess recent dietary intake, i.e. for 1 month prior to completing the questionnaire. This disadvantage is likely to be alleviated after adjustment for the season when data were collected, however. Changes in diet in the past 1 month were controlled for because pregnant females are likely to change their diet. Information on unpasteurised milk or raw milk was not included in our DHQ; however, Japanese people rarely consume raw milk even in rural areas. We did not include data on whether any of the participants lived on a farm, where consumption of raw milk might be more likely than in urban areas. At baseline, almost all of the participants lived in the Osaka Prefecture, an urban area that has the population density with 4,655 people per square kilometre; thus minimising the inclusion of farm families. The observed inverse associations with maternal intake of calcium and ≥4.309 μg·day⁻¹ vitamin D were attenuated by further adjustment for maternal consumption of docosahexaenoic acid or vitamin E. Thus, maternal consumption of docosahexaenoic acid or vitamin E might have confounded the inverse associations. Although we adjusted for a variety of potential confounders, we cannot eliminate the possibility that the observed inverse associations are a consequence of residual confounding by uncontrolled dietary or nondietary factors.

The follow-up rate was not good. Of the 1,002 participants at baseline, 239 mother–child pairs did not take part in the third survey. There were no material differences between the 239 nonparticipants and the 763 participants in the third survey with regard to distribution of maternal age, maternal and paternal history of asthma, atopic eczema and allergic rhinitis, and maternal intake of total energy, milk, yoghurt, cheese and calcium. Compared with non-participants in the third survey, participants were less likely to report low family income and a low maternal and paternal educational level and were more likely to have a high intake of vitamin D. Moreover, at baseline, the participation rate in Neyagawa City was only 17.2% and in other areas the participation rate could not be calculated because the exact number of eligible subjects among the sources from which participants were recruited was not available. Thus, the mother–child pairs in this study were likely not representative of Japanese mother–child pairs in the general population. In fact, educational levels were higher in the mothers in our study than in the general population. According to the year 2000 population census of Japan, the proportions of females aged 30–34 yrs in the Osaka Prefecture with <13, 13−14, ≥15 yrs and unknown number of years of education, were 49.2, 32.3, 13.6 and 4.9%, respectively 31. The present population might have had a greater awareness about health than the general population.

In summary, findings from this prospective study suggest that higher maternal consumption of total dairy products, milk, cheese, calcium and vitamin D during pregnancy may reduce the risk of infantile wheeze. Also, higher maternal vitamin D intake during pregnancy may be protective against eczema in the children. Our data, however, did not provide evidence that yoghurt intake during pregnancy is preventive against infantile wheeze and eczema. Because of a lack of inverse relationships between maternal intake of total dairy products, milk, cheese and calcium during pregnancy, and the risk of infantile eczema, we cannot rule out the possibility that such intake might be preventive against respiratory infections, rather than atopy. Further confirmation of these findings is required.

Support statement

The study was supported by a Grant-in-Aid (13770206, 16790351) for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology and Health and Labour Sciences Research Grants, Research on Allergic Disease and Immunology from the Ministry of Health, Labour, and Welfare, Japan.

Statement of interest

Statements of interest for Y. Miyake and K. Tanaka can be found at www.erj.ersjournals.com/misc/statements.dtl