1
Title Page
2
3
Revisiting the Link Between Preeclampsia, Eclampsia and Seasonal Variation: An
4
Analysis of over 39,000 Deliveries in West Michigan from 2005 to 2010
5
None of the authors of the paper have any personal financial interest in the work or with
6
a commercial sponsor.
7
8
9
INTRODUCTION
10
Preeclampsia (PreE) and eclampsia (E) is a syndrome affecting multiple organ systems with
11
symptoms including severe headache, vision changes, right upper-quadrant pain, nausea and
12
vomiting, dizziness, and edema. In the United States, preeclampsia and eclampsia complicate
13
2–7% of first-time pregnancies and are characterized by new-onset hypertension with
14
concurrent proteinuria after 20 weeks gestation [1]. In Canada, women who immigrated from
15
Hispanic, Sub-Saharan African or Caribbean countries were three times more likely than women
16
from industrialized nations to develop PreE/E [2]. This disorder causes significant fetal and
17
maternal morbidity and its basic pathophysiology is not well understood [3-5]. As a result,
18
preeclampsia and eclampsia present significant challenges to clinicians who seek to provide the
19
best outcomes for both their patients and their infants.
20
21
Studies have emerged that analyze the role vitamin D deficiency plays in the development and
22
progression of PreE/E [6]. Low serum vitamin D levels in pregnant women have been found to
23
increase the risk of PreE/E and vitamin D deficiency may be an independent risk factor for
24
developing PreE/E [7,8]. Similarly, studies have shown that serum Vitamin D levels fluctuate
25
with exposure to sunshine. In a group of women of childbearing age, sunlight exposure during
26
May-October were significantly and independently associated with lower prevalence ratios of
27
vitamin D deficiency and inadequacy [9]. Vitamin D levels of healthy Canadians were highest in
28
the summer and lower in the fall and spring [10]. Additionally, vitamin D levels of people living
29
in West Michigan tend to follow the same trend during the winter. A random sample of patients
30
who had their blood drawn over 12 weeks from January to April had an average vitamin D level
31
of 17.43 ng/ml, Males had a level on average of 16.3 ng/ml and women had an average of 17.6
32
ng/ml. Both of these averages are well below the accepted total vitamin D reference values of
33
25-80 ng/ml. [11]
34
35
Weather Patterns in West Michigan
36
Out of 174 U.S. cities and towns listed by the National Climatic Data Center, Grand Rapids in
37
West Michigan is number 161 in percent of annual available sunshine received (46%) [12]. The
38
area’s weather is determined by its latitude and eastern proximity to Lake Michigan; this location
39
receives lake effect snow, rain, and heavy cloud coverage. Because there is less sunshine
40
received in this region, we wanted to evaluate whether there is a strong correlation between
41
available sunlight and pregnancy complications.
42
43
This report describes the outcomes of over 39,000 births in West Michigan in relation to the total
44
available minutes of sunshine in the preceding trimester prior to the births. A strong correlation
45
between PreE/E rates and total amount of sunshine was observed. We briefly describe the
46
methods and results of the findings in this report.
47
Pathophysiology
48
Vitamin D deficiency has been implicated in many disorders including hypertension, end-stage
49
renal disease (ESRD), diabetes, heart disease, inflammatory disorders, and increased cancer
50
risk [6, 13-16]. Because the vitamin D receptor (VDR) modulates transcription of hundreds of
51
genes and is expressed in many cells in the human body [6,17], it affects multiple organ
52
systems. Low serum vitamin D levels is associated with many disease processes, including
53
those affecting the cardiovascular and renal systems.
54
55
Vitamin D deficiency is a well-established marker for cardiovascular disease [18-28] and
56
hypertension [25, 29-32]. Studies examining the link between vitamin D and cardiovascular
57
disease show an increase in cardiovascular mortality during seasons in which Ultra Violet B
58
radiation exposure is low [28, 33, 34], that there is an increase in thromboembolic events during
59
the winter months [36, 37]. Hypovitaminosis D is associated with elevated mortality from
60
cardiovascular illness [20-24, 26, 27]. Furthermore, multiple studies have linked vitamin D
61
deficiency to hypertension by vitamin D’s effect on renin [32, 38-41]. In 2007, Yuan et al.
62
showed vitamin D suppresses expression of a renin promoter gene indicating that low Vitamin D
63
levels could activate the renin angiotensin system [31]. Vitamin D’s renal effects extend beyond
64
the renin-angiotensin system. Extensive study of patients with ESRD has established low
65
Vitamin D is associated with the development of albuminuria and inflammation. .
66
Vitamin D Deficiency and the Development of Preeclampsia/Eclampsia
67
The combination of renal protein wasting and systemic inflammation is a hallmark of PreE/E and
68
has led to the hypothesis that vitamin D deficiency may be involved in the pathogenesis of
69
PreE/E [49]. Research shows that a correlation exists between hypovitaminosis D and PreE/E
70
as well as other complications of pregnancy [50-54] This relationship is supported by studies
71
that show that decidual and trophoblastic cells both make and respond to vitamin D and that
72
vitamin D aids in implantation. [55-67]. Furthermore, a Norwegian survey study indicated that
73
women who take vitamin D supplements have substantial reduction in PreE/E; however,
74
because vitamin D intake in this population is correlated with omega-3 intake it was not possible
75
to rule out a benefit from long chain fatty acids in the diet [68].
76
77
MATERIALS AND METHODS
78
79
Using de-identified data, and adhering to IRB protocols the electronic medical record database
80
of Spectrum Health, a multi-hospital network in West Michigan predominantly serving Kent
81
County, was searched from June of 2005 through May of 2010 to construct the PreE/E rate. The
82
five most current years were used because after mid 2005, deliveries reached steady state as
83
labor and delivery was concentrated at one of the Spectrum Health hospitals. A rate was
84
calculated for each calendar month over those five years using diagnostic codes for PreE/E and
85
their ICD-9 (see table 1) derivatives from the hospital system’s medical record database.
86
Because the ICD-9 codes for both preeclampsia and eclampsia contain the 642 code number
87
series, it was not possible to reliably distinguish between the two diagnoses. The PreE/E codes
88
in each month during the five-year period were compared to total deliveries per month over the
89
same time frame to construct a PreE/E rate.
90
The PreE/E rate from this data was then compared to minutes of available sunlight in West
91
Michigan using public domain information from the National Weather Service. Specifically, the
92
total number of minutes of actual sunshine received at the Grand Rapids, Michigan weather
93
station for each month in the five-year period being examined as well as the three months prior
94
to the diagnosis of Pre/E was recorded and analyzed. This allowed for the comparison of
95
PreE/E rates in any month to the potential influence of vitamin D from accumulated sunlight
96
exposure in prior months. In order to work with positive integers, minutes of darkness were
97
derived from the sunlight data by subtracting the minutes of sunlight from the total minutes in
98
each month. The minutes of darkness for the month were then divided by the number of days in
99
each month to obtain the average minutes of darkness per day in each month. A similar
100
calculation was performed to find the average minutes of darkness per day in the three months
101
prior to the month of the PreE/E rate.
102
103
Vitamin D precursor molecules have half-lives of many weeks, which can lead to significant
104
accumulation over an extended period of sun exposure [69]. The correlation between available
105
sunlight and PreE/E rate was examined using the average minutes of darkness per day for the
106
one-month period and the three-month period prior to the month of the PreE/E rate. In order to
107
have a more powerful dataset the PreE/E rate of each month of each year was used
108
individually, giving 60 data points.
109
110
The Pearson product moment correlation coefficient was calculated as a measure of the linear
111
relationship between the of PreE/E rate for each month and the aforementioned corresponding
112
1 month and 3 month prior period’s average minutes of darkness. PreE/E rate was calculated
113
as the total of PreE/E cases in each month divided by the total live births in that month. A p
114
value <0.05 was considered to be significant. Correlations were calculated using SPSS, version
115
19, and checked for accuracy in Microsoft Excel. The 95% confidence intervals for rates were
116
calculated in Excel using the Normal Approximation Method. Graphical representations of the
117
data were created in Microsoft Excel 2003 (Bar Charts) and SPSS, version 19 (Scatter plot). A
118
confidence interval graph was created with Open Office, version 1.1.
119
120
RESULTS
121
122
There were 39,337 total live births during the five-year period under observation and 2,607
123
cases recorded as preeclampsia or eclampsia with delivery for a global rate of 6.63% (95% CIs
124
[.0638, .0688]). The rate varied from a high of 7.76% (95% CIs [.0681, .0871]) in December to a
125
low of 5.30% in September (95% CIs [.0455, .0605]); a 32% reduction from peak to trough.
126
Inversely this represents a 46% increase from September to December. The difference between
127
the peak and trough rates is statistically significant at the 95% level. The average rate from the
128
five low sun months of December through April was 7.32% (95% CIs [.0691, .0772]) and for the
129
high sun months of July through September was 5.64% (95% CIs [.0525, .0603]); these
130
numbers yield a relative increase of 30%, which is also statistically significant at the 95% level.
131
These confidence intervals can be seen in Figure 1.
132
133
Figure 1
134
135
136
The general pattern of the PreE/E rate from 2005 through 2010 and the average minutes of
137
darkness in the preceding three-month period can be seen in Figure 2.
138
Figure 2
139
140
141
There was a significant positive correlation (.r = 0.364, p = 0.004) between the PreE/E rate and
142
the prior three months’ average minutes of darkness per day. This correlation can be seen in
143
Figure 3.
144
Figure 3
145
146
147
There was also a significant positive correlation (r = 0.358, p = 0.005) between the PreE/E rate
148
and the prior month’s average minutes of darkness per day.
149
150
151
152
153
154
DISCUSSION
155
Our findings suggest a strong relationship between available sunlight in the three months and 1
156
month prior to delivery and the rate of PreE/E and further distinguish the differences in the
157
PreE/E rate when comparing summer to winter. There have also been reports of regional
158
variation around the world with reductions in pre-eclampsia the closer the region is to the
159
equator. Grand Rapids, Michigan where the data was collected is on the 43rd latitude north and
160
had an overall prevalence of 6.63%. In Beijing, China, at the 39th latitude north, the prevalence
161
of pre-eclampsia is 5.7%. [70] In Hong Kong at the 22nd latitude north the risk of pre-eclampsia
162
has been reported to be 1.6%. [71] We found a 32% increase in the PreE/E rate for births in
163
December compared to births in September. Although vitamin D levels were not obtained in
164
this study, these findings may support current theories that hypovitaminosis D plays a role in the
165
pathogenesis of PreE/E and hypovitaminosis D peaks in the fall and winter months, providing a
166
different perspective on the vitamin D connection [6-12]. Because sunshine is associated with
167
vitamin D production, vitamin D serum levels are highest in months where sunshine is most
168
prevalent, and vitamin D has been implicated in the development of hypertension and PreE/E, it
169
is likely that increased sunshine reduces the risk of preeclampsia and eclampsia.
170
Similar to findings of seasonal variation in hypertension rates in pregnant women, our findings
171
lend credence to the importance of obtaining sufficient sun exposure in the second and third
172
trimesters to help reduce a woman’s risk of PreE/E. A meta-analysis of the literature examining
173
the relationship between seasonal variation and hypertension, preeclampsia and eclampsia
174
rates reported 11 out of 14 studies showed an increase in preeclampsia in the winter months in
175
non-tropical climates [72]. Furthermore, a large Australian study has shown that the amount of
176
sunlight during the time closest to birth is a better predictor of the onset of hypertension in
177
pregnancy than the amount of sunlight at conception [73].
178
Potential confounders
179
Future studies to evaluate the correlation between seasonal variation and PreE/E should report
180
vitamin D levels, and address potential confounders such as race, obesity, and levels of
181
exercise, depression and migraine, or maternal infection all of which may contribute to
182
hypovitaminosis D. Research so far has found considerable support for the role of diet in
183
preventing PreE/E. Studies show that the high intake of vegetables, fiber, milk, and foods rich in
184
potassium reduce the risk of PreE/E while a diet high in processed meat, calorie-rich foods,
185
sweet drinks, and salty snacks increase the risk of PreE/E [64,74-78]. Other morbidities such as
186
depression and migraine, which could have an effect on behavior, have also been examined
187
and are also associated with an increased risk of PreE/E [79]. As a consequence, while the
188
results of this study suggest an inverse association between sunlight exposure and PreE/E, this
189
may be just one factor of many contributing to this disease.
190
191
Recommendations
192
These findings suggest that pregnant women in cloudier climates may be more likely to develop
193
Pre/E in the fall and winter seasons. Due to the potentially life-threatening effects of PreE/E, it
194
may be necessary to test serum Vitamin D levels in all women at the end of the first trimester or
195
at 20 weeks gestation. Alternatively, women who have an increased risk of developing PreE/E
196
due to obesity, race, or cloudier climates should have their Vitamin D levels checked at the end
197
of the first trimester and all pregnant women should take Vitamin D supplements daily along
198
with their prenatal vitamins to help prevent hypovitaminosis D leading up to PreE/E. While the
199
cost-effectiveness of drawing vitamin D levels on pregnant women is yet to be determined,
200
lifestyle changes that promote outdoor physical activity and sun exposure may reduce the
201
morbidity associated with PreE/E. We should educate our patients to “live summer year round”
202
by encouraging pregnant women to exercise during the winter, eat more fruits and vegetables,
203
and in a region with as little sunshine as West Michigan, take a vitamin D supplement with
204
consumption guided by repeated serum blood levels.
205
206
The Institute of Medicine stated that while substantial evidence exists linking levels of vitamin D
207
with bone health, current evidence does not support other benefits of vitamin D supplementation
208
[77]. While this statement may hold true for many Americans, we believe that sufficient evidence
209
exists for the monitoring and treatment of hypovitaminosis D in specific populations. Examples
210
of such populations include African Americans, Hispanics, those with chronic kidney disease
211
and pregnant women living in areas of little sun exposure especially in the winter. Further
212
research into the role of vitamin D deficiency in the risk of PreE/E is needed.
213
214
CONCLUSION
215
216
PreE/E was 32% more common during the winter in West Michigan when compared to the
217
average during the summer. There was a moderately strong correlation with the number of
218
minutes of darkness in the three months preceding the ensuing month’s PreE/E rate. This
219
suggests a possible link to vitamin D status, but other life style influences cannot be ruled out.
220
Future studies should be carried out to assess potential confounders like race, and pregnant
221
women should be encouraged to take Vitamin D supplements daily, particularly in the fall and
222
winter seasons.
Acknowledgements
Ted Kuik, Kuik Computer Services
Allen Shoemaker, Grand Rapids Medical Education Partners
Abbreviations:
ESDR = end-stage renal disease
PreE/E = preeclampsia/eclampsia
VDR = vitamin D receptor
References:
1. Sibai BM: Hypertension. In Gabbe SG, Niebyl JR, Simpson JL. (eds): “Normal and
Problem Pregnancies,” 5th ed. Philadelphia: Churchill Livingstone, pp 864-901, 2007.
2. Urquia ML, Ying I, Glazier RH, Berger H, De Souza LR, Ray JG: Serious Preeclampsia
Among Different Immigrant Groups. J Obstet Gynaecol Can 34:348–352, 2012.
3. Khan KS, Wojdyla D, Say L, Gülmezoglu AM, Van Look PF: WHO analysis of causes of
maternal death: a systematic review. Lancet 367:1066-1074, 2006.
4. Duley L: The global impact of pre-eclampsia and eclampsia. Semin Perinatol 33:130137, 2009 .
5. MacKay AP, Berg CJ, Atrash HK: Pregnancy-related mortality from preeclampsia and
eclampsia. Obstet Gynecol 97:533-553, 2001.
6. Bikle D: Nonclassic actions of vitamin D. J Clin Endocrinol Metab 94:26-34, 2009.
7. Bodnar LM, Catov JM, Simhan HN, Holick MF, Powers RW, Roberts JM: Maternal
vitamin D deficiency increases the risk of preeclampsia. J Clin Endocrinol Metab
92:3517-3522, 2007.
8. Baker AM, Haeri S, Camargo CA Jr, Espinola JA, Stuebe AM. A nested case-control
study of midgestation vitamin D deficiency and risk of severe preeclampsia. J Clin
Endocrinol Metab. 95(11):5105-9 2010.
9. Zhao G, Ford ES, Tsai J, Li C, Croft JB. Factors Associated with Vitamin D Deficiency
and Inadequacy among Women of Childbearing Age in the United States. Obstet
Gynecol 2012: 691486 2012.
10. Rucker D, Allan JA, Fick GH, Hanley DA. Vitamin D insufficiency in a population of
healthy western Canadians. CMAJ 166:1517-24 2002.
11. Gostine ML, Davis FN. Vitamin D deficiencies in pain patients. Prac Pain Mgmt.
(July/August): 16-19, 2006.
12. Ranking of Cities based on % annual possible sunshine in descending order from most
to least average possible sunshine. 2004 [cited 2012 Feb 9]; Available from:
http://www.ncdc.noaa.gov/oa/climate/online/ccd/pctposrank.txt.
13. Chambers JC, Fusi L, Malik IS, Haskard DO, De Swiet M, Kooner JS: Association of
maternal endothelial dysfunction with preeclampsia. JAMA 285:1607-1612, 2001.
14. Bikle D: Nonclassic actions of vitamin D. J Clin Endocrinol Metab 94:26-34, 2009.
15. Gorham ED, Garland CF, Garland FC, Grant WB, Mohr SB, Lipkin M, Newmark HL,
Giovannucci E, Wei M, Holick MF: Optimal vitamin D status for colorectal cancer
prevention: a quantitative meta analysis. Am J Prev Med 32:210-216, 2007.
16. Garland CF, Garland FC, Gorham ED: Calcium and vitamin D. Their potential roles in
colon and breast cancer prevention. Ann N Y Acad Sci 889:1207-1221, 1999.
17. Mizwicki MT, Norman AW: The vitamin D sterol-vitamin D receptor ensemble model
offers unique insights into both genomic and rapid-response signaling. Sci Signal 2:re4,
2009.
18. Anderson JL, May HT, Horne BD, Bair TL, Hall NL, Carlquist JF, Lappé DL, Muhlestein
JB; Intermountain Heart Collaborative (IHC) Study Group: Relation of vitamin D
deficiency to cardiovascular risk factors, disease status, and incident events in a general
healthcare population. Am J Cardiol 106:963-968, 2010.
19. de Borst MH, de Boer RA, Stolk RP, Slaets JP, Wolffenbuttel BH, Navis G: Vitamin D
deficiency: universal risk factor for multifactorial diseases? Curr Drug Targets 12:97-106,
2011.
20. Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, Lanier K, Benjamin EJ,
D'Agostino RB, Wolf M, Vasan RS: Vitamin D deficiency and risk of cardiovascular
disease. Circulation 117:503-511, 2008.
21. Giovannucci E, Liu Y, Hollis BW, Rimm EB: 25-hydroxyvitamin D and risk of myocardial
infarction in men: a prospective study. Arch Intern Med 168:1174-1180, 2008.
22. Pilz S, Dobnig H, Fischer JE, Wellnitz B, Seelhorst U, Boehm BO, März W: Low vitamin
d levels predict stroke in patients referred to coronary angiography. Stroke 39:26112613, 2008.
23. Pilz S, März W, Wellnitz B, Seelhorst U, Fahrleitner-Pammer A, Dimai HP, Boehm BO,
Dobnig H: Association of vitamin D deficiency with heart failure and sudden cardiac
death in a large cross-sectional study of patients referred for coronary angiography. J
Clin Endocrinol Metab 93:3927-3935, 2008.
24. Pilz Pilz S, Dobnig H, Nijpels G, Heine RJ, Stehouwer CD, Snijder MB, van Dam RM,
Dekker JM: Vitamin D and mortality in older men and women. Clin Endocrinol (Oxf)
71(5):666-672, 2009.
25. Pilz S, Tomaschitz A, Ritz E, Pieber TR: Vitamin D status and arterial hypertension: a
systematic review. Nat Rev Cardiol 6:621-630, 2009.
26. Dobnig H, Pilz S, Scharnagl H, Renner W, Seelhorst U, Wellnitz B, Kinkeldei J, Boehm
BO, Weihrauch G, Maerz W: Independent association of low serum 25-hydroxyvitamin d
and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality. Arch
Intern Med. 168:1340-1349, 2008.
27. Ginde AA, Scragg R, Schwartz RS, Camargo CA Jr: Prospective study of serum 25hydroxyvitamin D level, cardiovascular disease mortality, and all-cause mortality in older
U.S. adults. J Am Geriat 57:1595-1603, 2009.
28. Zittermann A, Gummert JF, Börgermann J: The role of vitamin D in dyslipidemia and
cardiovascular disease. Curr Pharm Des 17:933-942, 2011.
29. Martini LA, Wood RJ: Vitamin D and blood pressure connection: update on
epidemiologic, clinical, and mechanistic evidence. Nutr Rev 66:291-297, 2008.
30. Wu SH, Ho SC, Zhong L: Effects of Vitamin D supplementation on blood pressure.
South Med J 103:729-737, 2010.
31. Yuan W, Pan W, Kong J, Zheng W, Szeto FL, Wong KE, Cohen R, Klopot A, Zhang Z, Li
YC: 1,25-dihydroxyvitamin D3 suppresses renin gene transcription by blocking the
activity of the cyclic AMP response element in the renin gene promoter. J Biol Chem
282:29821-29830, 2007.
32. Xiang W, Kong J, Chen S, Cao LP, Qiao G, Zheng W, Liu W, Li X, Gardner DG, Li YC:
Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and
cardiac renin-angiotensin systems. Am J Physiol Endocrinol Metab 288:E125-132, 2005.
33. Scragg R: Seasonality of cardiovascular disease mortality and the possible protective
effect of ultra-violet radiation. Int J Epidemiol 10:337-341, 1981.
34. Barnett AG, de Looper M, Fraser JF: The seasonality in heart failure deaths and total
cardiovascular deaths. Aust NZ J Public Health. 32:408-413, 2008.
35. cardiovascular deaths. Aust NZ J Public Health. 32:408-413, 2008.
36. Gallerani M, Boari B, de Toma D, Salmi R, Manfredini R: Seasonal variation in the
occurrence of deep vein thrombosis. Med Sci Monit 10:CR191-CR196, 2004.
37. Gallerani M, Boari B, Smolensky MH, Salmi R, Fabbri D, Contato E, Manfredini R:
Seasonal variation in occurrence of pulmonary embolism: analysis of the database of the
Emilia-Romagna region, Italy. Chronobiol Int 24:143-160, 2007.
region, Italy. Chronobiol Int 24:143-160, 2007.
38. Qiao G, Kong J, Uskokovic M, Li YC: Analogs of 1alpha,25-dihydroxyvitamin D(3) as
novel inhibitors of renin biosynthesis. J Steroid Biochem Mol Biol 96:59-66, 2005.
39. Kong J, Li YC: Effect of ANG II type I receptor antagonist and ACE inhibitor on vitamin D
receptor-null mice. Am J Physiol Regul integr Comp Physiol 285:R255-R261, 2003.
40. Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP: 1,25-Dihydroxyvitamin D(3) is a
negative endocrine regulator of the renin-angiotensin system. J Clin Invest 110:229-238,
2002.
41. Li YC: Vitamin D regulation of the renin-angiotensin system. J Cell Biochem
88:327-331, 2003.
42. Bucharles S, Barberato SH, Stinghen AE, Gruber B, Meister H, Mehl A, Piekala L,
Dambiski AC, Souza A, Olandoski M, Pecoits-Filho R: Hypovitaminosis D is associated
with systemic inflammation and concentric myocardial geometric pattern in hemodialysis
patients with low iPTH levels. Nephron Clin Pract. 118:c384-c391, 2011.
43. Schleithoff SS, Zittermann A, Tenderich G, Berthold HK, Stehle P, Koerfer R: Vitamin D
supplementation improves cytokine profiles in patients with congestive heart failure: a
double-blind, randomized, placebo-controlled trial. Am J Clin Nutr 83:754-759, 2006.
44. Tan X, Wen X, Liu Y: Paricalcitol inhibits renal inflammation by promoting vitamin D
receptor-mediated sequestration of NF-kappaB signaling. J Am Soc Nephrol
19:1741-1752, 2008.
45. Alborzi Alborzi P, Patel NA, Peterson C, Bills JE, Bekele DM, Bunaye Z, Light RP,
Agarwal R: Paricalcitol reduces albuminuria and inflammation in chronic kidney disease:
a randomized double-blind pilot trial.. Hypertension 52:249-255, 2008.
46. Wang P, Anderson PO, Chen S, Paulsson KM, Sjögren HO, Li S: Inhibition of the
transcription factors AP-1 and NF-kappaB in CD4 T cells by peroxisome proliferatoractivated receptor gamma ligands. Int Immunopharmacol 1:803-812, 2001.
47. Lu X, Farmer P, Rubin J, Nanes MS: Integration of the NfkappaB p65 subunit into the
vitamin D receptor transcriptional complex: identification of p65 domains that inhibit 1,25dihydroxyvitamin D3-stimulated transcription. J Cell Biochem 92:833-848, 2004.
48. Guijarro C, Egido J: Transcription factor-kappa B (NF-kappa B) and renal disease.
Kidney Int 59:415-424, 2001.
49. Hyppönen E: Vitamin D for the prevention of preeclampsia? A hypothesis. Nutr Rev
63:225-232, 2005.
50. Bodnar LM, Catov JM, Simhan HN, Holick MF, Powers RW, Roberts JM: Maternal
vitamin D deficiency increases the risk of preeclampsia. J Clin Endocrinol Metab
92:3517-3522, 2007.
51. Mannion CA, Gray-Donald K, Koski KG: Association of low intake of milk and vitamin D
during pregnancy with decreased birth weight. CMAJ 174:1273-1277, 2006.
52. Zhang C, Qiu C, Hu FB, David RM, van Dam RM, Bralley A, Williams MA: Maternal
plasma 25-hydroxyvitamin D concentrations and the risk for gestational diabetes
mellitus. PLoS One 3:e3753, 2008.
53. Merewood A, Mehta SD, Chen TC, Bauchner H, Holick MF: Association between vitamin
D deficiency and primary cesarean section. J Clin Endocrinol Metab
94:940-945, 2008.
54. Bodnar LM, Krohn MA, Simhan HN: Maternal vitamin D deficiency is associated with
bacterial vaginosis in the first trimester of pregnancy. J Nutr 139:1157-1161, 2009.
55. Barrera D, Avila E, Hernández G, Halhali A, Biruete B, Larrea F, Díaz L: Estradiol and
progesterone synthesis in human placenta is stimulated by calcitriol. J Steroid Biochem
Mol Biol 103:529-532, 2007.
56. Barrera D, Avila E, Hernández G, Méndez I, González L, Halhali A, Larrea F, Morales A,
Díaz L: Calcitriol affects hCG gene transcription in cultured human syncytiotrophoblasts.
Reprod biol Endocrinol 6:3, 2008.
57. Stephanou A, Ross R, Handwerger S: Regulation of human placental lactogen
expression by 1,25-dihydroxyvitamin D3. Endocrinology 135:2651-2656, 1994.
58. Diaz Díaz L, Noyola-Martínez N, Barrera D, Hernández G, Avila E, Halhali A, Larrea F:
Calcitriol inhibits TNF-alpha-induced inflammatory cytokines in human trophoblasts. J
Reprod Immunol 81:17-24, 2009.
59. Liu N, Kaplan AT, Low J, Nguyen L, Liu GY, Equils O, Hewison M: Vitamin D induces
innate antibacterial responses in human trophoblasts via an intracrine pathway. Biol
Reprod 80:398-406, 2009.
60. Halhali A, Acker GM, Garabédian M: 1,25-Dihydroxyvitamin D3 induces in vivo the
decidualization of rat endometrial cells. J Reprod Fertil 91:59-64, 1991.
61. Du H, Daftary GS, Lalwani SI, Taylor HS: Direct regulation of HOXA10 by 1,25-(OH)2D3
in human myelomonocytic cells and human endometrial stromal cells. Mol Endocrinol
19:2222-2233, 2005.
62. Zehnder D, Evans KN, Kilby MD, Bulmer JN, Innes BA, Stewart PM, Hewison M: The
ontogeny of 25-hydroxyvitamin D(3) 1alpha-hydroxylase expression in human placenta
and decidua. Am J Pathol 161:105-114, 2002.
63. Rigby WF, Stacy T, Fanger MW: Inhibition of T lymphocyte mitogenesis by 1,25dihydroxyvitamin D3 (calcitriol). J Clin Invest 74:1451-1455, 1984.
64. Chen S, Sims GP, Chen XX, Gu YY, Chen S, Lipsky PE: Modulatory effects of 1,25dihydroxyvitamin D3 on human B cell differentiation J Immunol 179:1634-1647, 2007.
65. Lemire JM, Adams JS, Sakai R, Jordan SC: 1 alpha,25-dihydroxyvitamin D3 suppresses
proliferation and immunoglobulin production by normal human peripheral blood
mononuclear cells J Clin Invest 74:657-661, 1984.
66. Lemire JM, Archer DC, Beck L, Spiegelberg HL: Immunosuppressive actions of 1,25dihydroxyvitamin D3: preferential inhibition of Th1 functions J Nutr
125:1704S-1708S, 1995.
67. Piccinni MP, Scaletti C, Maggi E, Romagnani S: Role of hormone-controlled Th1- and
Th2-type cytokines in successful pregnancy. J Neuroimmunol 109:30-33, 2000.
68. Haugen M, Brantsaeter AL, Trogstad L, Alexander J, Roth C, Magnus P, Meltzer HM:
Vitamin D supplementation and reduced risk of preeclampsia in nulliparous women.
Epidemiology 20:720-726, 2009.
69. TePoel MR, Saftlas AF, Wallis AB. Association of seasonality with hypertension in
pregnancy: a systematic review. J Reprod Immunol 89:140-152, 2011.
70. Zhonghua F, Chan K, Za Z. Study on clinical risk of maternal underlying medical
conditions and onset of preeclampsia. 47(6):405-11. 2012
71. Tam WH, Sahota DS, Lau TK, Li CY, Fung TY. Seasonal variation in pre-eclamptic rate
and its association with the ambient temperature and humidity in early pregnancy.
Gynecol Obstet Invest. 66(1):22-6. 2008.
72. Algert CS, Roberts CL, Shand AW, et al. Seasonal variation in pregnancy hypertension
is correlated with sunlight intensity. Am J Obstet Gynecol 203:215.e1-5, 2010.
73. Brantsaeter AL, Haugen M, Samuelsen SO, Torjusen H, Trogstad L, Alexander J,
Magnus P, Meltzer HM: A dietary pattern characterized by high intake of vegetables,
fruits, and vegetable oils is associated with reduced risk of preeclampsia in nulliparous
pregnant Norwegian women. J Nutr 139:1162-1168, 2009.
74. Clausen T, Slott M, Solvoll K, Drevon CA, Vollset SE, Henriksen T: High intake of
energy, sucrose, and polyunsaturated fatty acids is associated with increased risk of
preeclampsia. Am J Obstet Gynecol 185:451-458, 2001.
75. Oken E, Ning Y, Rifas-Shiman SL, Rich-Edwards JW, Olsen SF, Gillman MW: Diet
during pregnancy and risk of preeclampsia or gestational hypertension. Ann Epidemiol
17:663-668, 2007.
76. Qiu C, Coughlin KB, Frederick IO, Sorensen TK, Williams MA: Dietary fiber intake in
early pregnancy and risk of subsequent preeclampsia. Am J Hypertens 21:903-909,
2008.
77. Frederick IO, Williams MA, Dashow E, Kestin M, Zhang C, Leisenring WM: Dietary fiber,
potassium, magnesium and calcium in relation to the risk of preeclampsia. J Reprod
Med 50:332-344, 2005.
78. Cripe SM, Frederick IO, Qiu C, Williams MA: Risk of preterm delivery and hypertensive
disorders of pregnancy in relation to maternal co-morbid mood and migraine disorders
during pregnancy. Paediatr Perinat Epidemiol 25:116-123, 2011.
79. Committee to Review Dietary Reference Intakes for Vitamin D and Calcium; Institute of
Medicine: Summary. In Ross C, Taylor CL, Yaktine AL, Del Valle HB, (eds): “Dietary
Reference Intakes for Calcium and Vitamin D.” Washington DC: National Academies
Press, pp 1-14, 2010.
Table 1
ICD-9a Codes Used to Calculate Preeclampsia/Eclampsia Rate
Code
Description
642.4
Mild or Unspecified Pre-eclampsia
642.5
Severe Pre-eclampsia
642.6
Eclampsia
642.7
Pre-eclampsia or eclampsia superimposed on pre-existing hypertension
a
International Classification of Diseases
Figure Legends
Figure 1
The 95% Confidence intervals for the Preeclampsia/Eclampsia rate over the five-year period of
the study. Comparison of the peak rate in December to the trough rate in September and that in
the low sun months of December through April to the high sun months of July through
September.
Figure 2
Comparison of seasonal pattern of Preeclampsia/Eclampsia rate with that of average minutes of
darkness (no sunlight) per day in prior three-month period.
Figure 3
Scatter plot with best-fit line showing where each of the 60 months in the five-year period
analyzed fall in terms of Preeclampsia/Eclampsia rate and average minutes of darkness (no
sunlight) in the prior three-month period.