SHORT REPO R T

Eclampsia is more prevalent during the winter season in Sweden

ASA RYLANDER1 & PELLE G. LINDQVIST2
IVF Clinic, Queen Sophia Hospital, Stockholm, and 2 Department of Obstetrics and Gynecology, Clintec, Karolinska University Hospital, Huddinge, Sweden
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Key words Eclampsia, season, sunlight, vitamin D, incidence, smoking Correspondence Pelle G. Lindqvist, Department of Obstetrics and Gynecology, Clintec, Karolinska University Hospital, Huddinge, Kvinnokliniken K 57, SE-14186 Stockholm, Sweden. E-mail: Pelle.Lindqvist@ki.se Conict of interest The authors have stated explicitly that there are no conicts of interest in connection with this article. Received: 04 June 2010 Accepted: 21 September 2010 DOI: 10.1111/j.1600-0412.2010.01010.x

Abstract Hypertensive pregnancy conditions have shown seasonal variations and have been related to low levels of vitamin D. In Sweden, the hours of sunlight per day are few in winter. We hypothesized that eclampsia would be more common in the winter season. We performed a population-based cross-sectional study of all singleton deliveries in Sweden during a 5-year period (n = 482,759 women). All parturients with eclampsia were included as cases and those without formed control group. The incidence of eclampsia was nearly doubled during winter season (odds ratio 1.9, 95% condence interval 1.42.6) as compared to other seasons. The incidence of eclampsia during the period studied (19901994) was four in 10,000 pregnancies. We found that eclampsia was twice as common in winter and we introduce the alternative hypothesis that lack of sunlight exposure increases womens susceptibility to eclampsia, possibly due to vitamin D insufciency.

Introduction
Eclampsia is a maternal complication of preeclampsia occurring in two to ten of 10,000 pregnancies. It is related to both fetal and maternal morbidity and mortality. There are many epidemiological reports of different incidences of eclampsia depending on season (for references) (1). Environmental factors, such as low temperature, high humidity/rainy season and reduced barometric pressure have been suggested to be related to an increased risk, but results are not consistent (1). Preeclampsia has also been related to an increased inammatory response with increased levels of IL-6, IL-8 and TNF , and lower levels of modulator cytokines such as IL-10 (2). Regarding eclampsia, presumably the time span in close relation to delivery is most important for triggering seizures. Therefore, in this study, we focus on eclampsia. Low maternal vitamin D level in both early and late pregnancy has been related to preeclampsia (3). The major source of vitamin D is sunlight ultraviolet B radiation (wavelength between 290 and 315 nm), which converts previtamin D to vitamin D. In the Nordic countries, the levels of vitamin D

vary widely with season, with normal levels during summer and low or subnormal levels during winter (4,5). The hydroxylation of 25-OHVitD into its active form 1 ,25(OH)2 vitamin D3 (1,25VitD) takes place in a number of systems, such as the endothelium, intestines and brain, but mainly in the kidney (5). Whether eclampsia is related to the amount of sunlight, however, is unknown. We hypothesized that eclampsia would be more common in the winter season in Sweden, when the hours of sunlight are few.

Material and methods

This study is an analysis comprising all singleton pregnancies recorded at the National Birth Registry of Sweden over a 5-year period (19901994) (n = 482,759). All singleton parturients with eclampsia were included as cases; and those without eclampsia formed a control group. The diagnosis of eclampsia was that which was obtained from the National Birth Registry. Preeclampsia was dened as pregnancy-induced hypertension (140/90 mmHg) and

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c 2010 The Authors Acta Obstetricia et Gynecologica Scandinavica c 2010 Nordic Federation of Societies of Obstetrics and Gynecology 90 (2011) 114117

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proteinuria 0.3 g/l. Eclampsia was dened as preeclampsia in combination with general convulsions. Season of birth was categorized into: winter (December to February), spring (March to May), summer (June to August) or autumn (September to November). Because odds ratios (ORs) were similar in analysis of eclampsia, season was dichotomized into winter or other seasons (reference). Parity was classied as nulli- (no previous birth) or multiparous (at least one previous birth = reference). Smokers were characterized by daily cigarette consumption into smokers or 0 (non-smokers or occasional smokers = reference). Maternal age was classied as either 34 years (reference), or 35. Region of the country was categorized into north, middle and south. ORs were determined with multiple logistic regression analysis of the outcome variable eclampsia compared to combinations of the independent (explanatory) variables season, smoking, maternal age, parity, region and fetal gender. Crosstabulations with the chi-squared test were used for bivariate analysis. By using 0.05 two-sided signicance level and including 480,000 women, assuming the incidence of eclampsia to be 4/10,000, we would have 70% power to identify a 50% increased risk during winter season. We did not include missing data in the analysis. The Statistical Package for the Social Sciences (SPSS Inc., Chicago, IL, USA) software was used. p-Values less than 0.05 were considered signicant.

95% CI 0.40.9), while nulliparous women were at a fourfold increased risk (OR 3.6, 95% CI 2.55.2). High maternal age (35) was related to a 60% increased risk (OR 1.6, 95% CI 1.032.6). There were no differences depending on part of the country. The number of sun-hours per day and the number of eclampsia cases per 10,000 deliveries are shown in Figure 1.

Discussion
In this study, we found the risk of eclampsia being almost doubled during winter season as compared to other seasons. There was no difference between north and south Sweden regarding eclampsia. Our nding gives epidemiological support for the hypothesis that lack of sunlight exposure and vitamin D insufciency is involved in the pathogenesis of eclampsia. However, our ndings may only be hypothesis generating. The large population-based study design is a strength of the present study. However, the retrospective design may have introduced biases. If some eclampsia cases were missed, it would only have had a minor effect on the risk estimates and the incidence in our material was similar to that usually reported for the period (4/10,000 pregnancies). These results may only be valid in countries with large differences in the amount of sunlight between seasons, that is at high latitudes and in populations with subnormal vitamin D levels. Swedes in general have a sun-seeking behavior. The daily exposure to ultraviolet radiation (sun exposure) has been shown to inuence the vitamin D status (4). We recognize it as a limitation that we have only data on the amount of sun in relation to season, and not personal data on sun habits. Several other climatic/environmental factors, which

Results
The results of bivariate and multivariate analysis of eclampsia are presented in Table 1. The incidence of eclampsia was nearly doubled during the winter season as compared to other seasons. Smoking lowered the risk by 40% (OR 0.6,

Table 1. Risk of eclampsia in relation to season and part of the country. Eclampsia (n = 182) Season Spring Summer Fall Winter Winter season Yes No Part of the country South Middle North Control group (n = 482,477) OR Bivariate analysis 95% CI Multivariate analysis OR 95% CI

43 36 36 67 67 115 68 82 32

133,576 123,500 109,712 115,666 115,666 366,811 176,378 225,416 80,599

1.1 1.0 1.1 2.0 1.8 1.0 1.0 0.9 1.0

0.71.7 Reference 0.71.8 1.33.0 1.42.5 Reference Reference 0.71.3 0.71.6

1.1 1.0 1.1 1.9 1.9 1.0 1.0 0.9 1.0

0.71.7 Reference 0.61.7 1.33.0 1.42.6 Reference Reference 0.61.3 0.71.6

OR = odds ratio, 95% CI = 95% condence interval. We give the total numbers and the number with data present. Those with missing data were not included. Adjustment in multivariate analysis: smoking, fetal gender, parity and age groups.

c 2010 The Authors Acta Obstetricia et Gynecologica Scandinavica c 2010 Nordic Federation of Societies of Obstetrics and Gynecology 90 (2011) 114117

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Eclampsia and season

A . Rylander and P. G. Lindqvist

Figure 1. Mean number of daily hours of sunlight and incidence of eclampsia per 10,000 deliveries.

have not been adjusted for might confound the results, such as humidity, altitude, physical activity, infections, nutritional factors and social behavior. Our hypothesis is not in opposition to the theory of seasonal variation (with increased risk in cold and humid/rainy weather) (1) or the results of risk reduction of eclampsia with calcium supplementation (6). Lack of sunlight will result in colder weather and also an impaired calcium metabolism. In addition, our hypothesis is in agreement with the shown brinolytic and the cytokine changes in severe preeclampsia (2,7,8). Eclampsia has generally been described as an endothelial disease. The tissue plasminogen activator antigen (tPA Ag) level is useful as a marker of endothelial dysfunction, and levels of 25-OHVitD have been shown to be inversely related to tPA Ag levels in vivo (8). The tPA level is also related to preeclampsia (8). Endothelial cells show 1,25VitD receptor activity together with a 1 -hydroxylas enzyme for local 1,25vitD production from 25-OHVitD. Supplementing patients with Type 2 diabetes mellitus and low 25-OHVitD status with vitamin D, improves endothelial function (9). It has been estimated that among those living at high latitudes almost no vitamin D is produced in winter from sunlight (10). Since both food and food supplements are generally low in vitamin D, a large proportion of the childbearing population may also be affected by an insufcient vitamin D status in winter (4).

There are several possible mechanisms by which the winter season may have doubled the risk of eclampsia. It may be caused by (a) increased blood pressure (5), (b) increased vascular resistance (5), (c) excessive expression of inammatory cytokines (TNF , IL6) and by decreasing IL10 (5). Thus, we speculate that less sun exposure during winter season will provoke vitamin D insufciency, which is more unfavorable for a normal pregnancy. There are several epidemiological data indicating that preeclampsia is related to low vitamin D levels. Our epidemiological study cannot rule out cold as the predisposing condition. There was, however, no difference between north and south Sweden regarding risk of eclampsia. Other possible causes are infections or other nutritional factors that differ between seasons. Insufciency or deciency of vitamin D will cause parathyroid hormones to rise, leading to hypocalciuria. A thorough, large-scale study in the USA did not nd any difference in urinary calcium levels between normal and preeclamptic women (6). This might be explained by adequate food and sun exposure habits in north America. Recently, women taking multivitamin preparations upon conception have been shown to be at lower risk of preeclampsia, fetal growth restriction and preterm birth (11). However, the authors of those studies mainly considered the vitamin E and folic acid supplementation. Supplementation with vitamin D has been reported to lower the risk of preeclampsia (12). A randomized

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controlled trial of vitamin D supplementation may separate the effects of sun exposure and cold as predisposing mechanisms. If the patophysiological mechanisms of eclampsia could be determined better, it would have a large impact on surveillance of women at risk. As eclampsia was twice as common in winter, we introduce the alternative hypothesis that lack of sunlight exposure increases womens susceptibility to eclampsia, possibly due to vitamin D insufciency.

5. 6.

Funding
No specic funding.

7.

Acknowledgements
We acknowledge the help provided by the National Board of Health and Welfare in extracting data from the National Birth Registry. The study was supported by Karolinska University Hospital, Huddinge, Karolinska Institute fund, and Queen Sophia Hospital, Stockholm. References
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