Season of Delivery and Risk of Hypertensive Disorders of Pregnancy in Los Angeles, California

doi:10.21203/rs.3.rs-4114184/v1

Background:

Environmental risk factors such as seasonal changes have been shown to be linked to hypertensive disorders of pregnancy. However, the effects of season of conception and delivery have been inconsistent and poorly studied in moderate climates such as Los Angeles. We aimed to study the effects of the season of delivery on the risk of hypertensive disorders of pregnancy. Results were verified via assessment of season of conception.

Methods:

We conducted a retrospective cohort study among 24,843 predominantly Hispanic women (2,360 clinically-confirmed cases of hypertensive disorders of pregnancy who delivered at the Los Angeles County + University of Southern California Women’s and Children’s Hospital between 1995 and 2008. The dry season was defined as April to October and the wet season as November to March. Logistic regression models were fit to estimate odds ratios for season of conception and delivery and risk of hypertensive disorders of pregnancy. Multivariable multinomial logistic regression models were then fitted to estimate odds ratios of season of conception/delivery and disease severity.

Results:

Mothers who delivered in the wet season had a significantly increased risk of developing hypertensive disorders of pregnancy compared to those who delivered in the dry season (OR=1.11, 95% CI: 1.02, 1.21). These mothers were also significantly more likely to be nulliparous (OR= 2.43, 95% CI: 2.21, 2.68), 25 years of age or older (OR=1.24, 95% CI: 1.12, 1.38), have diabetes (OR=1.62, 95% CI: 1.43, 1.85), have hypertension (OR=4.99, 95% CI: 4.14, 6.00), be diagnosed with infection (OR=2.14, 95% CI: 1.21, 3.81), or have premature deliveries (OR=2.11, 95% CI: 1.90, 2.33) when compared to controls. When stratifying based on disease severity, only mild preeclampsia indicated an association with season of delivery (OR=1.12, 95% CI: 1.01, 1.25). The effect for severe preeclampsia (OR=1.12, 95% Cl: 0.96, 1.31) and eclampsia/HELLP syndrome (OR=0.80, 95% CI: 0.49, 1.31) did not reach statistical significance, though power was limited in the more severe categories. Results examining the season of conception confirmed the results for the season of delivery.

Conclusions:

Among the predominantly Hispanic women who delivered at Los Angeles County + University of Southern California between 1995 and 2008, deliveries in the wet, winter season were associated with an increased risk of hypertensive disorders of pregnancy.

Dry season

wet season

eclampsia

HELLP syndrome

preeclampsia

Hispanic

Preeclampsia is a multisystem hypertensive disorder of pregnancy that affects approximately 4% of pregnancies in the United States, and continues to be a leading cause of maternal and neonatal morbidity and mortality.¹ Complications include maternal eclampsia, placental abruption, cerebrovascular and cardiovascular issues, fetal intrauterine growth restriction, preterm birth, and stillbirth. Despite this, the pathogenesis of disease is still unclear. Several risk factors for preeclampsia have been identified including obesity, pregestational diabetes, hypertension, nulliparity, and multiple gestation pregnancies, although more recently environmental risk factors such as seasonal changes have been indicated as a potential factor contributing to preeclampsia risk.²

Specifically, studies in temperate regions have observed an increased risk of preeclampsia in the winter, while studies conducted in tropical regions have found an increased risk during the rainy season.^{3, 4} This can be further evaluated according to the season of conception rather than the season of delivery. Studies that tracked the season of conception found that there was an increased risk of preeclampsia in conception during the summer months,^{2, 5} while studies that tracked the season of delivery found an increased risk of preeclampsia among those who delivered in the winter months.^{4, 6} These studies were performed in regions such as Norway, Bangkok, Texas, Australia, and Japan; however, there is a paucity of research examining the effect of seasonality in Mediterranean climates such as Los Angeles.

In addition, previous studies conducted in the United States examined primarily Caucasian populations. Studies that examined more diverse populations found that seasonal trends differed when data was stratified by race and ethnicity.⁷ There is a scarcity of research in patient populations with a demographic similar to those in East Los Angeles, which is primarily Hispanic. Data that factor in this population can be used to inform physician practice and counseling of patients at higher risk of preeclampsia.

Our objective was to study the seasonal variation of hypertensive disorders of pregnancy in Los Angeles. Given the unique climate in Los Angeles, we hypothesize that among the predominantly Hispanic women delivering at the Los Angeles County + University of Southern California (LAC+USC) Women’s and Children’s Hospital between 1995 and 2008, the risk of hypertensive disorders of pregnancy will be highest for deliveries in the wet months (November - March) compared to the dry months (April - October).

Predominantly Hispanic women delivering singleton infants at the LAC+USC Women’s and Children’s Hospital between January 1995 and August 2008 were included in the study population. Only the first delivery at the LAC+USC Women’s and Children’s Hospital was used for the analysis. Records for each delivery were recorded in the delivery log which included information on timing of labor and delivery, antenatal and perinatal procedures and medications, medical history, pregnancy complications, mode of delivery, infant birth weight, and Apgar scores.

Demographics and clinical characteristics of the study population are summarized as mean standard deviation for numeric variables and tested using a t-test while categorical variables are presented as count (frequency) and tested using a Pearson’s Chi-Square.

We defined the dry season as being from April to October and the wet season as November through March, in keeping with Los Angeles’ weather patterns.⁸ We used logistic regression to assess the relationship between season of delivery and any hypertensive disorders of pregnancy diagnosis. The following variables were considered for inclusion in the multivariable model: nulliparity, diabetes, hypertension renal disease, lupus, infection status, induction of delivery, cardiac disease, asthma, anemia, HIV status, bleeding disorders, thyroid disease, seizure disorders, and post-date delivery. Maternal age was dichotomized as <25 years and ≥25 years, based upon a lowess curve indicating nonlinearity. Only confounders and variables with p<0.05 were included in the final model. A confounder was defined as any variable which alters the effect of season on hypertensive disorders of pregnancy by >15% when included in the model. Model fit was tested using the Hosmer-Lemeshow goodness-of-fit test and via inspection of residuals, leverage, and deviance. A link test was performed to assess the appropriateness of the model specification. We likewise evaluated the season of conception. To evaluate the relationship between disease severity (mild eclampsia, severe eclampsia, and eclampsia/HELLP Syndrome) and season of delivery, we used multivariable multinomial logistic regression. All analyses were conducted using Stata 17 (Statacorp, College Station, TX) and p<0.05 was considered statistically significant.

There were 24,843 singleton pregnancies occurring during the study period. However, due to missing data on some covariates, 24,802 were included in the analysis population. Specifically, 16 patients were missing both hypertension and diabetes status, 6 were missing information on prematurity, 8 were missing maternal age, and 11 were missing infection status. The analytic population included 22,442 controls, 1,607 mild preeclamptics, 682 with severe preeclampsia, and 71 with eclampsia/HELLP Syndrome (Figure 1).

Demographics and clinical characteristics of the analysis population are presented in Table 1. Women with hypertensive disorders of pregnancy were slightly older than controls (27.7 ± 7.5 vs. 27.4 ± 6.6, p=0.021), delivered earlier (37.3 ± 3.2 vs. 38.2 ± 3.0, p<0.001), were more likely to be nulliparous (50.6% vs. 33.2%, p<0.001), had a lower gravidity (2.7 ± 2.2 vs. 3.1 ± 3.2, p<0.001), and a lower infant birth weight (3047.6 ± 815.0 vs. 3242.1 ± 681.9, p<0.001). Women with hypertensive disorders of pregnancy were also more likely to deliver infants with intrauterine growth restriction (4.1% vs. 2.0%, p<0.001) and more likely to have diabetes (15.0% vs. 9.3%, p<0.001), renal disease (1.4% vs. 0.8%, p=0.001), hypertension (8.8% vs. 1.7%, p<0.001), or thyroid disease (2.5% vs. 1.3%, p<0.001). Controls were more likely to deliver vaginally (76.3% vs. 63.5%, p<0.001), but there were no differences with respect to proportion of male infants (p=0.583) or rates of cardiac disease (p=0.889).

There was a statistically significant independent association between season of delivery and hypertensive disorders of pregnancy, with those delivering in the wet season having an increased risk of developing hypertensive disorders of pregnancy compared to those delivering in the dry season (OR=1.11, 95% CI: 1.02, 1.21, Table 2). Additionally, women with hypertensive disorders of pregnancy were 2.43 (95% CI: 2.21, 2.68) times more likely to be nulliparous compared to controls and were more likely to be at least 25 years of age or older (OR=1.24, 95% CI: 1.12, 1.38), independent of all other variables modeled. Cases were more likely to have diabetes (OR=1.62, 95% CI: 1.43, 1.85), hypertension (OR=4.99, 95% CI: 4.14, 6.00), or be diagnosed with infection (OR=2.14, 95% CI: 1.21, 3.81) compared to controls. Premature delivery was more than twice as common in the cases than in controls (OR=2.11, 95% CI: 1.90, 2.33). We also evaluated the season at conception but found no difference in effect size from season of delivery (data not shown).

When stratifying on hypertensive disorders of pregnancy severity, only mild preeclampsia indicated an association with season of delivery (OR=1.12, 95% CI: 1.01, 1.25, Table 3). Nulliparity was most common among those who developed severe disease but was statistically significantly associated with all severities (p<0.001 for all). Increased maternal age was significantly associated with both mild and severe preeclampsia (p<0.05 for both), but not with eclampsia/HELLP Syndrome (p=0.164). Likewise, diabetes was associated with mild and severe forms of preeclampsia (p<0.001 for both), but not with eclampsia/HELLP Syndrome (p=0.749). All levels of severity were associated with hypertension and prematurity (p0.002 for all), but only severe preeclampsia was associated with infection (p=0.004). All models indicated acceptable fit to the data.

In this study we found that deliveries in the wet season (November to March) had a significantly increased risk of developing hypertensive disorders of pregnancy compared to deliveries in the dry season (April to October). However when stratified by disease severity, only cases of mild preeclampsia showed a significant association with season of delivery. The effect of the season of conception was not substantively different from the season of delivery and is therefore not presented herein.

Several previous studies have explored seasonal variation in respect to preeclampsia with similar findings. Two large population-based studies in Norway reviewing births spanning two distinct epochs (1967–1998 and 1999–2009) both found that incidence of preeclampsia upon delivery was highest in the wet season (winter) and lowest in the dry season (summer).⁶ A systematic review by TePoel et al. echoed these findings in tropical climates such as India, Thailand, and Colombia, where preeclampsia rates were elevated during the wet season.⁴

Conversely, there are studies with results that are inconsistent with our findings. TePoel et al., while affirming the wet season's association with elevated preeclampsia rates in tropical regions, delineated higher incidence during the dry season in non-tropical environments such as Australia, China, and South Africa.⁴ Verburg et al. augmented this relationship in Australia through a large population study during 2007-2014 revealing a peak incidence (8.0%) of hypertensive disorders of pregnancy for deliveries in August (dry season) and a trough (6.2%) for deliveries in February (wet season).⁹ Similarly, Wellington et al.’s expansive study of women who delivered in Texas in 2007 found minimal seasonal variation of preeclampsia: a nadir for deliveries (3.89%) in the wet season (fall) and a zenith (4.1%) in the dry season (winter).¹⁰ In Bangkok, Pitakkarnkul et al. investigated seasonal impact on deliveries in the author’s institution between 2008 and 2009, revealing the rates were not significantly different: 5.0% in the dry season vs. 4.3% in the monsoon.¹¹ In Japan, Morikawa et al. retrospectively studied hypertensive disorders of pregnancy in women between 2005 and 2009.¹² The prevalence was higher for deliveries in the dry season (winter/early spring) and was lowest (3.6%-4.6%) in the wet season (July-August).

These differences may be attributable to the climate variation in each region. Under the modified Köppen classification system, Los Angeles is classified as a Mediterranean climate with increased rainfall in winter months with moderate fluctuations in temperature.¹³ In 2020, data from the National Weather Service shows that Los Angeles only had a 16 degree difference in average temperature between the coolest month and the warmest month.⁸ Given the moderate fluctuations in temperature, seasonality in Los Angeles may be better characterized by changes noted in precipitation, with heightened rainfall reported in winter months compared to summer months. Per the National Weather Service, between 2000-2021 the wettest month in Los Angeles was historically February with a mean 3.17” of precipitation, and the driest month being August with a mean 0.005” of precipitation.⁸ Under this classification, we observed an increased risk of hypertensive disorders of pregnancy with deliveries in the wet, winter months of Los Angeles.

Exploring the racial differences of hypertensive disorders of pregnancy, a study of 20,794 White women and 18,916 Black women in the United States found the incidence of preeclampsia was lowest with delivery in summer among White women, but no significant association of preeclampsia risk among Black women.⁷ This difference may reflect the reported racial variation in the rates of preeclampsia. A broader study looking at data collected from the National Inpatient Sample between 2005-2014 (N=177,000), highlighted notable racial disparities of reported preeclampsia and eclampsia: 69.8 per 1000 deliveries in Black women, 43.3 per 1000 deliveries in White women, and 46.8 per 1000 deliveries in Hispanic women.¹⁴ The overall increased incidence of hypertensive disorders of pregnancy in Black women may affect the observed seasonal variation in hypertensive disorders of pregnancy, or may underscore divergent environmental risk factors contributing toward the hypertensive disorders of pregnancy pathogenesis in different subpopulations. Nonetheless, a dearth of data impedes a comprehensive description of seasonal variation among different ethnic cohorts, including the predominantly Hispanic demographic residing in East Los Angeles.

Many mechanisms have been proposed to explain the association between seasonality and risk of hypertensive disorders of pregnancy. Specifically, the effect of melatonin levels, vitamin D status, pollutants, infections, and temperature-related changes in plasma volume and vascular tone have all been suggested as possible mechanisms.^{5, 15, 16} Specifically, some investigators have suggested that reduced levels of melatonin in preeclamptics may lead to abnormal placental development,¹⁵ or that seasonal variation in vitamin D and calcium metabolism may lead to an increased inflammatory state and vascular reactivity in the pathogenesis of preeclampsia.¹^{7, 18}There are also indications that air pollution, which varies according to season, can induce systemic inflammation and oxidative stress, resulting in vascular endothelial injury and thereby contributing to placental dysfunction in hypertensive disorders of pregnancy.¹⁹ A study based in Shenzhen, China found a positive association between preeclampsia risk and increased particulate matter and sulfur dioxide exposure during pregnancy, with effects modified by humidity.²⁰ Additionally, seasonal variation in rate of infection may play a role. Arechavaleta-Velasco et al. found that viral infection early in pregnancy can impair trophoblast function, which can lead to placental dysfunction and its associated complications.²¹ Other investigators examined the effect of temperature related changes, where cold stimulus causes vasospasm of the uterine artery and may lead to placental insufficiency,²² while warmer weather at the beginning of pregnancy may be related to an impaired placental bed and affect blastocyst implantation.²³ Nonetheless, additional studies are needed to elucidate the mechanisms behind seasonal variations for hypertensive disorders of pregnancy.

As there is a dearth of data in this population, we were specifically interested in estimating the seasonal variation of hypertensive disorders of pregnancy in the predominantly Hispanic population living in the moderate climate of Los Angeles.

This retrospective cohort study has several strengths and limitations. It is limited by the generalizability to women living in Los Angeles, which are predominantly Hispanic, who deliver at safety net hospitals. Additionally, the retrospective nature of the study results in failure to collect data that may be important for assessing the relationship between season and preeclampsia, though we could not think of any confounding variables for which we did not have data for. Nevertheless, it would have been interesting to evaluate neonatal outcomes in relation to season of delivery, but this data was not available. Missing data prevented the inclusion of 41 individuals from the analytic population. However, this only represents 0.2% of the analytic population and thus is not likely to have impacted the results. The study population was heterogeneous in terms of hypertensive disorders of pregnancy diagnoses. Thus, we stratified on severity and evaluated the relationship between season and hypertensive disorders of pregnancy, albeit with limited power among the more severe diagnoses. Strengths of the study include the large sample size, the novelty of the study population, and the large percentage of complete data.

In summary, we observed an 11% increase in the risk of hypertensive disorders of pregnancy among women delivering in the wet season compared to the dry season among predominantly Hispanic women living in Los Angeles. Additional studies are needed to confirm these results.

LAC+USC: Los Angeles County + University of Southern California

Ethics approval and consent to participate: This study was approved by the University of Southern California Institutional Review Board (USC IRB): HS-08-00228. The data accessed was part of an EMR database which the USC IRB granted permission to access. There was no identifying information available to us so all patients remained anonymous.

Consent for publication: Not applicable

Availability of data and materials: Dataset is available by contacting Dr. Melissa Wilson: [email protected]

Competing interests: The authors declare that they have no competing interests

Funding: The authors did not receive any funding

Authors' contributions:

HC: Writing - Original Draft, Literature Review

KG: Writing - Review & Editing, Literature Review

BG: Writing - Review & Editing

MW: Conceptualization, Supervision, Formal analysis, Data curation

Acknowledgements: We would like to thank the participants for being in the study which made this project possible.

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Table 1: Demographics and Clinical Characteristics of the Study Population, Stratified by Presence or Absence of Hypertensive Disorders of Pregnancy (HDP)

Variable¹	N	No HDP	N	HDP	p-value
Maternal Age at Delivery (years)	22407	27.4 ± 6.6	2360	27.7 ± 7.5	0.021
Gestational Age at Delivery (weeks)	22250	38.2 ± 3.0	2357	37.3 ± 3.2	<0.001
Nulliparous	22407	7449 (33.2)	2360	1195 (50.6)	<0.001
Gravity	22407	3.1 ± 3.2	2360	2.7 ± 2.2	<0.001
Birthweight (g)	22404	3242.1 ± 681.9	2358	3047.6 ± 815.0	<0.001
Baby’s Gender Female Male Undetermined	22405	11417 (51.0) 10791 (48.2) 197 (0.9)	2360	1225 (51.9) 1112 (47.1) 23 (1.0)	0.583
IUGR No Yes	22407	21965 (98.0) 442 (2.0)	2360	2263 (95.9) 97 (4.1)	<0.001
Vaginal Delivery No Yes	22407	5322 (23.8) 17805 (76.3)	2360	862 (36.5) 1498 (63.5)	<0.001
Apgar Score One Minute Five Minutes	22407	8.0 ± 2.4 8.8 ± 2.9	2360	7.5 ± 1.9 8.5 ± 1.4	<0.001 <0.001
Diabetes No Yes	22407	20326 (90.7) 2081 (9.3)	2360	2007 (85.0) 353 (15.0)	<0.001
Cardiac Disease No Yes	22407	22153 (98.9) 254 (1.1)	2360	2334 (98.9) 26 (1.1)	0.889
Renal Disease No Yes	22407	22227 (99.2) 180 (0.8)	2360	2327 (98.6) 33 (1.4)	0.003
Hypertension No Yes	22407	22038 (98.4) 369 (1.7)	2360	2153 (91.2) 207 (8.8)	<0.001
Thyroid Disease No Yes	22407	22112 (98.7) 295 (1.3)	2360	2300 (97.5) 60 (2.5)	<0.001

¹Numeric variables are presented as mean standard deviation and testing using an independent t-test while categorical variables are presented as count (percentage) and testing using a chi-square test.

Table 2: Independent Association Between Season of Delivery with Hypertensive Disorders of Pregnancy (n=24,802)

Variable

OR (95% CI)

p-value¹

Season

Dry

Wet

Referent

1.11 (1.02, 1.21)

0.017

Nulliparous

No

Yes

Referent

2.43 (2.21, 2.68)

<0.001

Maternal Age

<25 years

≥25 years

Referent

1.24 (1.12, 1.38)

<0.001

Diabetes

No

Yes

Referent

1.62 (1.43, 1.85)

<0.001

Hypertension

No

Yes

Referent

4.99 (4.14, 6.00)

<0.001

Infection

No

Yes

Referent

2.14 (1.21, 3.81)

0.009

Premature

No

Yes

Referent

2.11 (1.90, 2.33)

<0.001

¹P-values were obtained using multivariable logistic regression. Results presented are mutually adjusted for all variables shown.

Table 3: Association Between Season of Delivery with Severity of Hypertensive Disorders of Pregnancy (n=24,802)

Mild Preeclampsia

(n=1,608)

Severe

Preeclampsia

(n=682)

Eclampsia

or HELLP

(n=71)

Variable

OR (95% CI)

p-value¹

OR (95% CI)

p-value¹

OR (95% CI)

p-value¹

Season

Dry

Wet

Referent

1.12

(1.01, 1.25)

0.027

Referent

1.12

(0.96, 1.31)

0.153

Referent

0.80

(0.49, 1.31)

0.372

Nulliparous

No

Yes

Referent

2.37

(2.12, 2.66)

<0.001

Referent

2.55

(2.14, 3.03)

<0.001

Referent

2.75

(1.64, 4.60)

<0.001

Maternal Age

<25 years

25 years

Referent

1.23

(1.09, 1.38)

0.001

Referent

1.26

(1.05, 1.52)

0.013

Referent

1.47

(0.85, 2.55)

0.164

Diabetes

No

Yes

Referent

1.61

(1.38, 1.87)

<0.001

Referent

1.77

(1.42, 2.20)

<0.001

Referent

0.88

(0.39, 1.95)

0.749

Hypertension

No

Yes

Referent

3.90

(3.09, 4.92)

<0.001

Referent

7.47

(5.79, 9.64)

<0.001

Referent

4.26

(1.89, 9.58)

<0.001

Infection

No

Yes

Referent

1.57

(0.71, 3.48)

0.264

Referent

3.13

(1.43, 6.83)

0.004

Referent

2.79

(0.37, 20.88)

0.319

Premature

No

Yes

Referent

1.25

(1.09, 1.44)

0.002

Referent

4.48

(3.81, 5.27)

<0.001

Referent

10.72

(6.57, 17.49)

<0.001

¹p-values were obtained using multivariable multinomial logistic regression. Results presented are mutually adjusted for all variables shown.

No competing interests reported.

Season of Delivery and Risk of Hypertensive Disorders of Pregnancy in Los Angeles, California

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Abstract

Figures

BACKGROUND

METHODS

RESULTS

DISCUSSION

CONCLUSIONS

LIST OF ABBREVIATIONS

DECLARATIONS

REFERENCES

TABLES

Additional Declarations

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