p-ISSN: 2980-4302
e-ISSN: 2980-4310
Vol.
2 No. 6 June 2023
DIFFERENCES IN
AVERAGE SERUM CORTISOL LEVELS AND SERUM 25 HYDROXYVITAMIN D LEVELS IN
PREECLAMPSIA AND NORMAL PREGNANCY
Imelda Ganeza, Defrin, Rika Susanti
Faculty of
Medicine, Universitas Andalas, West Sumatera, Indonesia
Email: imeldaganeza@gmail.com
Abstract
According to
the World Health Organization, hypertension ranks second as the direct cause of
maternal death in pregnancy; namely gestational hypertension (14%). Causes of
maternal death in 2021 related to hypertension in pregnancy totaling 1,077
cases. Preeclampsia involves a number of biological processes that affect
immune dysfunction, placental implantation, abnormal angiogenesis, excessive
inflammation and high oxidative stress reactions and diseases related to
maternal vascularization or blood vessels are possible contributing causes. Research
with a case-control design was conducted at RSUP Dr. M. Djamil,
RSIA Siti Hawa, and RSIA Cicik
Padang from February 2021–August 2022. Preeclampsia and normal pregnancy
research samples consisted of 27 case samples and 27 control samples. Serum
cortisol levels and serum 25-hydroxyvitamin D levels were examined by the ELISA
method. The Independent Sample T-Test was used to analyze the data. The mean
difference in serum cortisol levels in preeclampsia was 48.70 ± 15.23 µg/dL,
higher than that in normal pregnancy, 38.62 ± 8.27 µg/dL (p-value = 0.004, p
<0.05). Differences The mean serum level of 25 Hydroxyvitamin D in
preeclampsia was 13.63 ± 6.12 ng/ml, lower than that in normal pregnancy, 14.49
± 3.94 ng/ml (p-value =0.539, p>0.05). The study
concluded that there were differences in cortisol levels in preeclamptic
pregnancies with normal pregnancies and there were no differences in serum
levels of 25 Hydroxyvitamin D in preeclamptic pregnancies with normal
pregnancies.
Keywords: Serum
cortisol levels; Levels of 25 Hydroxyvitamin D Serum; Preeclampsia and Normal
Pregnancy;
INTRODUCTION
Pregnancy is part of the
physiological processes of human reproduction, which in the course of which can
become pathological. Preeclampsia is one of the pathological conditions in
pregnancy that is one of the leading causes of maternal death. Preeclampsia is
hypertension in pregnancy characterized by systolic blood pressure of 140 mmHg
or more or diastolic blood pressure of 90 mmHg or more on two examinations with
a minimum distance of 4 hours, Preeclampsia after 20 weeks gestation,
accompanied by proteinuria ≥ 30 mg / mmol (Chappell et al., 2021).
Preeclampsia is associated with 2% to 8% of
pregnancy-related complications worldwide. Preeclampsia causes 9% to 26% of
maternal deaths in low-income countries and 16% in high-income countries.
Preeclampsia causes more than 50,000 maternal deaths, and more than 500,000
fetal deaths worldwide (Karrar & Hong, 2022)
MMR in West Sumatra Province
increased from 2017 to 2018, which was 16 cases to 17 cases. The annual report
of the Padang City Health Office found that the causes of maternal death in
2017 were Preeclampsia consisting of 6 cases (37.5%), bleeding 5 cases (31.25%),
bronchial asthma 2 cases (12.5%), sepsis 1 case (6.25%), carcinoma recti 1 case
(6.25%), and hyperemesis gravidarum 1 case (6.25%). Preeclampsia is the most
important cause of maternal and perinatal death in obstetrics (Usman, 2021).
Preeclampsia can cause
interference for both the fetus and the mother. Preeclampsia can lead to
various severe complications in the mother such as post
partum hemorrhage, placental abruption, kidney disorders, edema and
pulmonary embolism, Elevated Liver Enzymes Low Platelet Count (HELLP) hemolysis
syndrome to death. Preeclampsia and eclampsia conditions will adversely affect
fetal health due to decreased placental utero perfusion, hypovolemia,
vasospasm, and placental vascular endothelial cell damage so that it can affect
the growth and development of the baby (Prawirohardjo, 2014).
In research Salustiano et al., (2013) stated that the involvement of several hormonal systems in the
pathogenesis of preeclampsia, one of which is the hormone cortisol. Cortisol is
the primary glucocorticoid secreted by the adrenal cortex. In addition to
having metabolic, anti-inflammatory and immunosuppressive effects, the hormone
cortisol also has a permissive effect on the activity of another hormone,
namely epinephrine. Cortisol can increase epinephrine activity so that it can
cause vasoconstriction (narrowing of blood vessels) so that this can trigger an
increase in blood pressure (Black & Hawks, 2014; Sherwood, 2014)
Cortisol is the primary
glucocorticoid secreted by the adrenal cortex. Cortisol plays an important role
in the regulation of blood pressure. In addition to having metabolic,
anti-inflammatory and immunosuppressive effects, the hormone cortisol also has
a permissive effect on the activity of other hormones. Cortisol hormone levels
and gestational hypertension have a significant relationship with p value =
0.000 (p < 0.05) (Sherwood, 2014; Usman, 2021)
According to research Purswani et al., (2017) stated that preeclampsia is also caused by vitamin D deficiency. Vitamin
D deficiency can indirectly result in an increase in blood pressure in the body
of pregnant women. Renin Angiotensinogen System (RAS) plays an important role
in blood pressure regulation (Purswani et al., 2017).
Various studies show the
relationship of vitamin D with hypertension, Vitamin D deficiency conditions
are proven to be associated with increased blood pressure through impaired
mechanisms in renin transcription, parathyroid hormone imbalance, vascular
vasoconstriction, and increased sympathetic nerve activity. Various
epidemiological studies have proven the effect of vitamin D in preventing and
treating chronic diseases such as hypertension in pregnancy. Various clinical
trial results show that vitamin D has an inconsistent effect on blood pressure
in mothers during pregnancy (Farapti & Fadilla, 2021).
Research conducted by Dror et al., (2012) shows supporting evidence that vitamin D levels play a role in the early
part of pregnancy in regulating risk factors for complications in pregnancy,
supporting fetal growth, bone development and immune maturity. Vitamin D
deficiency, as measured by serum levels of 25-hydroxyvitamin D [25(OH)D] is
common in pregnant women. Many studies have shown that the risk of preeclampsia
increases when serum vitamin D levels are low. A significant association
between vitamin D deficiency and preeclampsia has been previously reported
(odds ratio, 4.2; confidence interval 95%, 1.4-12.8; p value 0.04).10
Cortisol and vitamin D have
been thought to play a role in the development of complications during
pregnancy. High cortisol levels mediate the association between stressful
conditions during pregnancy, hypertension, and increased risk of preeclampsia.
An increase in cortisol during pregnancy is caused by a 2-3-fold increase in
cortisol-binding globulin. Vitamin D-binding proteins also increase 2-fold
during pregnancy. Both the increase in cortisol-binding globulin and vitamin
D-binding proteins are believed to be driven by increased estrogen production
during pregnancy. Variations in serum diurnal cortisol have also been observed
for 25(OH)D.10
Dr. M. Djamil
Padang Central General Hospital (RSUP) is a government general hospital in
Padang City and as a referral center for West Sumatra Province and its
surroundings. According to data obtained from the Medical Record of Dr. M. Djamil Padang Hospital, in 2018 preeclampsia patients
treated in obstetric, gynecological and outpatient inpatient installations were
169 people, in 2019 there were 92 people and again increased in 2020 by 174
people. The high number of preeclampsia cases handled at Dr. M. Djamil Padang Hospital and cases that have been categorized
as preeclampsia. For this reason, it is important during pregnancy to pay
attention to blood pressure during pregnancy, as well as vitamin D and cortisol
so as to prevent preeclampsia in pregnancy, based on the background above,
researchers are interested in discussing the "Differences in Average Serum
Cortisol Levels and Serum 25 Hydroxyvitamin D Levels in Preeclampsia Pregnancy
and Normal Pregnancy at Dr. M. Djamil Hospital, Siti Hawa Hospital and RSIA Cicik
Padang.
RESEARCH METHODS
This study used an
observational analytical research design with the research design used was a
retrospective case control, namely by identifying a group of cases (patients
suffering from the effects or disease being studied) compared to a control
group (those who did not suffer from the disease or effects).
This research was carried
out at the Midwifery Department of Dr. M. Djamil
Padang Hospital, Siti Hawa Padang Hospital and Cicik
Padang Hospital with sample collection starting from February 2021 to August
2022. Examination of serum cortisol levels and serum 25-hydroxyvitamin D levels
was carried out at the Biomedical Laboratory of the Faculty of Medicine, Andalas University using the Enzyme Linked Immunosorbent
Assay (ELISA) method.
The population in this study
was all pregnant women who experienced Preeclampsia and normal pregnant women
at RSUP M.Djamil, RSIA Siti Hawa and RSIA Cicik Padang. The
sample is part of the population that meets the inclusion and exclusion
criteria from research at RSUP Dr. M. Djamil, RSIA
Siti Hawa and RSIA Cicik
Padang. The inclusion criteria in this study were willing to participate in the
study by signing informed consent, patients with a diagnosis of Preeclampsia
based on clinical symptoms and laboratory examination results and mothers with
normal pregnancies, and maternal age 20-35 years. The exclusion criteria in
this study were mothers with a history of chronic diseases based on history /
in treatment such as heart, diabetes, kidney and mothers with a history of
chronic hypertension. Sampling in this study was carried out using consecutive
sampling techniques until it met the required number of samples, namely 27
pregnant women with a diagnosis of Preeclampsia (cases) and 27 normal pregnant
women (controls) at Dr. M. Djamil Hospital, Siti Hawa Hospital and Cicik Padang
Hospital. The independent variables in this study were Serum Cortisol levels
and 25 Serum Hydroxyvitamin (25(OH)D) Levels. The dependent variables in this
study were Preeclampsia pregnant women and normal pregnant women. All
preparations and examinations of serum cortisol levels and serum 25
Hydroxyvitamin D are carried out at the Biomedical Laboratory of Andalas University. The examination was assisted by
officers of the Biomedical Laboratory of Andalas
University.
The entire population of
Preeclampsia mothers and normal pregnant women at RSUP Dr M. Djamil, RSIA Cicik and RSIA Siti
Hawa were determined by inclusion criteria according to the number of samples
determined both case samples and normal samples. Case samples were obtained
through the Emergency Department (IGD) of RSUP M. Djamil,
RSIA Cicik and RSIA Siti Hawa, while normal samples
were obtained at the polyclinics of RSUP M. Djamil,
RSIA Cicik and RSIA Siti Hawa.
The blood
collection process is carried out 1 time for Preeclampsia pregnant women who
come to the Emergency Department (IGD) of RSUP M. Djamil,
RSIA Cicik and RSIA Siti Hawa who have not received
MgSO4 treatment, while normal pregnant women also take blood 1 time at the
polyclinic. Researchers check blood pressure first, before taking blood. The researcher explained informed consent to
respondents, respondents signed informed consent that had been read and
approved then the researcher conducted interviews and filled out questionnaires
related to respondent characteristic data. Blood sampling is taken as much as 3
cc to check serum cortisol levels and serum levels of 25 (OH) D. Blood taken is
stored in EDTA tubes (yellow color) and / or heparin. Then, the serum sample
was brought and sent to the Biomedical Laboratory of FK Unand
immediately. Serum samples of subjects that have been put into a microtube are
put into a cool box which has been prepared ice cold
pack to maintain the temperature in the cool box is still safe in the range of
2-6ºC on the way to the Biomedical Laboratory of FK Unand.
Blood that has been taken is then centrifuge to obtain the subject's blood
serum so that it has a longer resistance and is not damaged quickly. Using the
25-hydroxyvitamin D ELISA kit (25(OH)D) from Biochem
Diagnosis Canada (DBC). After the sample entered the Biomedical Laboratory of
FK Unand, the subject's serum sample was stored at a
temperature of less than -100 C to be stored for a longer time (± 6 months).
Each micro tube of serum samples is given a code according to the respondent
code. After laboratory analysis tests, data analysis was carried out using
statistical tests Independent sample T test if normally distributed and Mann
Whitney test if not normally distributed to obtain the final results of the
study.
RESULT AND DISCUSSION
This research has been carried out from
February 2021 to August 2022 with research sites at Dr.
M Djamil Padang Hospital, RSIA Cicik
Padang and Siti Hawa Padang Hospital and the Biomedical Laboratory of the
Faculty of Medicine, Andalas University. The sample
studied amounted to 54 respondents consisting of 27 respondents with a
diagnosis of preeclampsia and 27 respondents with a diagnosis of normal
pregnancy.
This study used Kolmogorov Smirnov's
normality test (data ≥ 50 samples). At serum cortisol levels and serum 25
hydroxyvitamin D levels, the results obtained p = 0.200 (p> 0.05) so that
data on serum cortisol levels and serum 25 hydroxyvitamin D levels can be
concluded normally, the data can be continued with bivariate analysis using the
Independent Sample T test.
The most characteristic results of
respondents with high school education level were 17 people (63.0%) in the
preeclampsia pregnancy group and 15 people (55.6%) in the normal pregnancy
group. In employment status, 21 (77.8%) mothers did not work in the
preeclampsia pregnancy group and 20 (74.1%) mothers did not work in the normal
pregnancy group. A total of 8 people (29.6%) mothers with second and third
pregnancies as many as 9 people (33.3%) in the preeclampsia pregnancy group,
and 10 people (37.0%) mothers with third pregnancies in the normal pregnancy
group.
In this study, it was known that pregnant
women in the preeclampsia group had the most BMI of obesity (≥27.5 kg / m2) as
many as 13 people (48.1%), as well as normal pregnancy groups had the most BMI
of obesity (≥27.5 kg / m2) as many as 11 people (40.7%). Most family members in
the preeclampsia pregnant women group smoked as many as 24 people (88.9%), as
well as the normal pregnancy group also known to many family members smoke, as
many as 21 people (77.8%).
In this study it was also known that in the
pre-eclampsia pregnancy group did the most activities outside the home less
than one hour as many as 17 people (63%), as well as in the normal pregnancy
group did the most activities outside the home less than one hour, which was as
many as 11 people (40.7%). The average age of pregnant women in the
preeclampsia pregnancy group was (33.30 ± 5.84) years and in the normal
pregnancy group was (31.11 ± 4.76) years. Average blood pressure in the preeclampsia
pregnancy group was (162.78 ± 12.62) mmHg and in the normal pregnancy group was
(117.85 ± 11.04) mmHg.
Based on the results of the study, the
average serum cortisol levels in preeclampsia and normal pregnancies can be
seen in table 2. Based on Table 2. The average results of serum cortisol levels
in preeclampsia pregnancy were (48.70 ± 15.23) μg / dL. Average normal pregnancy serum cortisol levels were
(38.62 ± 8.27) μg/dL
Table 1. Average Serum Cortisol Levels Preeclampsia Pregnancy and Normal
Pregnancy
Average
Serum Levels |
Preeclampsia
Pregnancy Group (Mean
± SD) |
Normal
Pregnancy Group (Mean
± SD) |
Kortisol (µg/dL) |
48,70 ± 15,23 |
38,62 ± 8,27 |
Based on the results of the
study, the average level of 25 serum Hidroxyvitamin D
in preeclampsia and normal pregnancy can be seen in table 3. Based on Table 3.
The average results of 25 serum Hidroxyvitamin D in
preeclampsia pregnancy were (13.63 ± 6.12) ng / ml. Average levels of 25 normal
pregnancy serum Hidroxyvitamin D were (14.49 ± 3.94)
ng/ml.
Table 2. Average Serum
Hydroxyvitamin D Levels in Preeclampsia and Normal Pregnancy
Average Serum Levels |
Preeclampsia Pregnancy Group (Mean
± SD) |
Kelompok
Kehamilan Normal (Mean ± SD) |
25 Hydroxyvitamin D (ng/ml) |
13,63±6,12 |
14,49 ± 3,94 |
Based on the results of the
study, differences in serum cortisol levels in preeclampsia and normal
pregnancy can be seen in table 4. Based on Table 5.4, the results of
differences in serum cortisol levels of preeclampsia pregnancy were (48.70 ±
15.23) μg / dL
and normal pregnancy serum cortisol namely (38.62 ± 8.27) μg / dL
with a difference in values of 10.08 μg / dL.
Based on the results of statistical tests using the Independent T-test, the
result of p-value = 0.004 (p< 0.05) means that there is a difference in
serum cortisol levels between preeclampsia pregnancy and normal pregnancy.
Table 3. Differences in
Serum Cortisol Levels in Preeclampsia Pregnancy and Normal Pregnancy
Up to Serum |
Preeclampsia Pregnancy Group (Mean ± SD) |
Normal Pregnancy Group (Mean ± SD) |
Difference (Δ) |
p-value |
Kortisol (µg/dL) |
48,70 ± 15,23 |
38,62 ± 8,27 |
10,08 |
0,004 |
Based on the results of the
study, the difference in serum levels of 25 Hidroxyvitamin
D in preeclampsia and normal pregnancy can be seen in table 5. Based on Table
5., the results of differences in serum levels of 25 Hidroxyvitamin
D in preeclampsia pregnancy were (13.63 ± 6.12) ng / ml and 25 Hidroxyvitamin D serum normal pregnancy namely (14.49 ±
3.94) ng / ml with a difference in values of 0.86 ng / ml. Based on the results
of statistical tests using the Independent T-test, the result of p-value =
0.539 (p> 0.05) means that there is no difference in serum levels of 25 Hidroxyvitamin D between preeclampsia pregnancy and normal
pregnancy.
Table 4. Differences in
Serum 25 Hydroxyvitamin D Levels in Preeclampsia and Normal Pregnancy
Up
to Serum |
Preeclampsia Pregnancy Group (Mean ± SD) |
Normal Pregnancy Group (Mean ± SD) |
Difference
(Δ) |
p-value |
25 Hidroxyvitamin D (ng/ml) |
13,63 ± 6,12 |
14,49 ± 3,94 |
0,86 |
0,539 |
The results showed that the characteristics of respondents based on
education were the most with high school education level, namely 17 people
(63.0%) in the preeclampsia pregnancy group and 15 people (55.6%) in the normal
pregnancy group. According to research by Fairbrother et al., (2017) the education factor of pregnant women affects the occurrence of
preeclampsia.
The level of education also determines whether or not a person absorbs
and understands pregnancy knowledge and the risks of complicating it that they
get. This can be used as a basis for distinguishing methods in proper absorption.
Education is needed so that a person is responsive to nutritional problems in
the family and can take action as soon as possible (Suhardjo et al., 1985).
In employment status, 21 people (77.8%) were non-working mothers / IRT
(Housewives) in the preeclampsia pregnancy group and 20 people (74.1%) were not
working mothers / IRT in the normal pregnancy group. Work is related to the
physical activity load of mothers who work as housewives tend to do activities
and spend time at home.
Activities that are often done by housewives such as starting from
cleaning the house, preparing school children, ironing clothes, cooking,
washing clothes and various other activities that often trigger stress due to
monotonous or repetitive activities every day. This can be seen from the
statistical results that serum cortisol levels are higher in housewives with
preeclampsia pregnancy with average serum cortisol levels of 49.7 (μg / dL)
while serum cortisol levels in housewives with normal pregnancy groups are
37.66 (μg / dL).
Mothers who work as housewives are busy with work inside the house
causing mothers to rarely move outside the home so that little sun exposure.
This can be seen from the statistical results in this study it is known that
most mothers with work as housewives have an average level of 25 serum
hydroxyvitamin D (25 (OH)D) lower than working mothers, where the average level
of 25 serum hydroxyvitamin D in housewives of normal pregnancy group is 12.79
ng / ml, while the average level of 25 serum hydroxyvitamin D in housewives
with preeclampsia pregnancy group is 10.93 ng / ml.
Research has been conducted by Wulandari, R
and Firnawati, A (2012), which states that there is a
significant relationship between maternal work and the incidence of
preeclampsia with p = 0.001; OR = 4.173 (CI = 1.709-10.188). Research by Indriani et al., (2012), also proved that employment status
has a significant relationship with preeclampsia. In addition, there is also a
significant relationship between work and stress levels in pregnant women.3
In this study, it is known that pregnant women in the preeclampsia group
have the most obesity BMI (≥27.5 kg / m2) as many as 12 people, while in the
group of normal pregnant women mothers with obesity BMI (≥27.5 kg / m2) only as
many as 4 people. Based on the statistical results of the research conducted,
it is known that mothers with obesity can increase the average serum cortisol
levels where the average serum cortisol levels in pregnant women in the normal
group are 50.5 μg / dl, while serum cortisol levels in the preeclampsia pregnancy group are
56.8 μg / dl. Conversely, pregnant
women with obesity can reduce serum levels of 25 hydroxyvitamin D, where the
average vitamin D levels in the normal pregnancy group are 10.16 ng / ml, while
the average vitamin D levels of the preeclampsia pregnancy group are 9.47 ng /
ml.
Women who were overweight and obese were 1.4 and 1.8 times more likely
to have preeclampsia than women with normal BMI, while women who were
underweight were likely to have preeclampsia 0.7 times. There was a positive
association between increased body mass index before pregnancy and the risk of
developing preeclampsia, with an odd ratio of 1.8 for obese women with a BMI
above 30 compared to women of normal weight, a BMI between 20 and 24.9 (Mrema et al., 2018).
In this study also found most family members in the group of
preeclampsia pregnant women smoked as many as 24 people, as well as the normal
pregnancy group also known to many family members smoke, as many as 21 people.
In research states that smoking during pregnancy causes oxidative stress which
has an impact on the occurrence of vitamin D deficiency and secondhand
smoke during pregnancy has a synergistic impact on gestational hypertension.
Vitamin D deficiency and smoking are important interrelated factors for
hypertension in pregnancy or preeclampsia. Mothers exposed to secondhand smoke had significantly higher systolic,
diastolic and proteinuria blood levels (Yıldız et al., 2022).
In this study, both in the preeclampsia pregnancy group and the normal
pregnancy group, pregnant women mostly experienced exposure to high cigarette
smoke. In this study, from statistical results it was proven that exposure to
cigarette smoke can reduce serum hydroxyvitamin D levels where, the average
serum hydroxyvitamin D levels in mothers exposed to normal pregnancy cigarette
smoke were 12.81 ng / ml, while the average vitamin D levels in mothers who
were not exposed to cigarette smoke in normal pregnancy was 20.37 ng / ml.
Similarly, the average serum level of 25 hydroxyvitamin D in the preeclampsia
group exposed to cigarette smoke was 12.11 ng / ml, while the level of 25 serum
hydroxyvitamin D in preeclampsia mothers who were not exposed to cigarette
smoke was 25.72 ng / ml.
In this study, it was also known that in the preeclampsia pregnancy
group did the most activities outside the home for less than one hour as many
as 17 people (63%), as well as in the normal pregnancy group the most did
activities outside the home for less than one hour, which was as many as 11
people (40.7%). According to research, high daily exposure to solar radiation
during pregnancy is associated with a reduced risk of hypertension in pregnancy
(Preeclampsia).
Clinical studies have shown that sunlight, especially UVB, has a direct
effect on vascular health and reduces blood pressure through the release of
nitric oxide from the skin. UVB exposure for 20 minutes led to a reduction of
3.5 mmHg in mean systolic artery pressure and 4.9 mmHg in diastolic blood
pressure in healthy adults. Best exposed to sunlight at 10.00 to 13.00 wib. Lack of sun exposure is associated with reduced serum
levels of 25 hydroxyvitamin D (Botyar & Khoramroudi, 2018).
In line with the results of research that has been conducted where
statistical results obtained the levels of 25 serum hydroxyvitamin D were lower
in respondents with activities outside the home less than one hour in the
normal pregnancy group at 11.9 ng / ml while serum 25 hydroxyvitamin D levels
in the normal pregnancy group with activities outside the home for more than
one hour at 18.14 ng / ml. The average serum hydroxyvitamin D level in the
group with preeclampsia pregnancy with less than one hour activity was 9.95 ng
/ ml, while the average serum 25 hydroxyvitamin D levels in preeclampsia
pregnancy with activity more than one hour was 19.87 ng / ml.
A significant correlation was found between maternal serum 25
hydroxyvitamin D levels and exposed body surface area (r = 0.36, p <0.002)
or percentage of body surface exposed (r = 0.39, p <0.001) and radiation
intensity (r = 0.15, p = 0.029).3 The body surface area that must be minimally
exposed to the sun is sun exposure on the face, arms, and hands (15-20% of the
body surface area). There are significant differences in vitamin D synthesis
between full-body exposure versus face-to-foot sun exposure (Judistiani et al., 2019).
Pregnant women without hijab are advised to have continuous exposure for
approximately 37.5 minutes per day, while for hijabi
women the recommended duration is about 64.5 minutes per day.15 Skin exposure
to sunlight for 7-25 minutes from 10.00 am to 3 pm, at least twice a week,
where the face, arms, and legs are exposed without sunscreen application should
be sufficient to induce vitamin D synthesis (Ilmiawati et al., 2020). The characteristics of the fabric used, such as color,
thickness, and weaving mode, can affect its effectiveness in blocking UVB
absorption by the skin. Dark cloth is twice as effective at absorbing UVB
radiation as white cloth.16
The average age of pregnant women in this study in the preeclampsia
pregnancy group was (33.30 ± 5.84) years and in the normal pregnancy group was
(31.11 ± 4.76) years. Average blood pressure in the preeclampsia pregnancy
group was (162.78 ± 12.62) mmHg and in the normal pregnancy group was (117.85 ±
11.04) mmHg. Age is one of the dominant risk factors associated with the
incidence of preeclampsia.16
Pregnant women aged 35 years or older have a four times greater chance
of developing preeclampsia than those aged 25-29 years. Likewise, those women
aged 30-34 were about three times more likely to develop preeclampsia than
those aged 25-29. Mothers aged >35 years experience
changes in their bodies such as impaired aging of organs, decreased kidney
function, decreased liver function, increased blood pressure and diabetes
mellitus, so the likelihood of finding diseases during pregnancy such as
preeclampsia will increase (Yıldız et al., 2022).
In this study, most respondents found multigravida pregnant women with
the same number of gravids more than two, both in the
normal pregnancy group of 24 respondents (88.8%) and in multigravida mothers in
the preeclampsia pregnancy group of 23 respondents (85.18%). Based on the
results of research conducted by Brunton, et al (2020) stated that parity was
identified as a predictor of anxiety and psychological disorders.17
According to research by Madhavanprabhakaran et al., (2015) states that primiparous mothers with younger ages have higher levels of
pregnancy-related anxiety compared to older multiparous mothers. Stress during
pregnancy is common in mothers who give birth for the first time (primipara)
due to lack of adaptation to physical (biological) and psychological changes
during pregnancy.18
In contrast to research conducted by Polo‐Kantola et
al.,( 2017) states that older age
during pregnancy causes depression and higher psychological disorders.
Psychological disorders lead to an increase in cortisol levels. Stress in
multiparous mothers can arise due to experiences through the previous process
of pregnancy and childbirth. In addition, stress levels can occur because
multigravida mothers have an older age during pregnancy is significantly
associated with worsening sleep quality and insomnia during pregnancy. Polo‐Kantola et
al., (2017) also reported that
multiparous mothers had poorer sleep quality than primiparous mothers. Sleep
disorders and psychological disorders cause elevated cortisol levels (Bublitz et al., 2018; Polo‐Kantola et al., 2017)In this study, it was found that multigravida mothers had a higher
average cortisol than mothers with primigravida where the average cortisol
levels in primigravida mothers in the normal pregnancy group were 33.08 μg / dL
while the average cortisol levels in multigravida were 39.31 μg / dL.
While in the preeclampsia pregnancy group with primigravida had an average
cortisol level of 48.01 μg / dL,
then in the preeclampsia pregnancy group with multigravida the average cortisol
level was 48.82 μg / dL.
Based on Table 2. The average results of serum cortisol levels in
preeclampsia pregnancy were (48.70 ± 15.23) μg / dL.
The average serum cortisol level of normal pregnancy is (38.62 ± 8.27) μg / dL.Based
on the results of statistical tests using the Independent T-test, the result of
p-value = 0.004 (p< 0.05) which means there is a difference in serum
cortisol levels between preeclampsia pregnancy and normal pregnancy. In this
study, it was seen that the difference in average serum cortisol levels in the
preeclampsia pregnancy group and the normal pregnancy group looked much
different, namely 10.08 μg / dL.
From these results, it can be seen that there are differences in cortisol
levels, where serum cortisol levels are higher in the preeclampsia group than
in the normal pregnancy group.
This result is in line with the results of research by Bärebring et al., (2019) which reported that there is a significant positive correlation or
relationship between cortisol and the incidence of preeclampsia. Where the
higher cortisol levels, the higher the risk of preeclampsia. In this study, the
average cortisol level in the group of hypertensive pregnant women or
preeclampsia was 111.50 μg / dL.
An increase in serum cortisol of 16.9 μg / dL
was associated with an increase in systolic and diastolic 0.7 and 0.4 mmHg.21
Research by Liu et al., (2020) also states that cortisol levels in the preeclampsia pregnancy group
are higher than in the normal pregnancy group.22 Prenatal glucocorticoid
exposure is associated with higher increases in systolic and diastolic blood
pressure. High cortisol levels can be a risk factor for cardiovascular disease,
with elevated plasma glucose and triglyceride levels and elevated systolic
blood pressure (Eberle et al., 2021; Wang et al., 2013)
High exposure to glucocorticoids/cortisol during prenatal activity can
cause regulation of Lipoxin A (LXA 4) levels to decrease in preeclampsia
patients. Cortisol levels are negatively correlated with LXA4 levels. Where the
higher cortisol levels, LXA 4 levels will also decrease, this can suppress the
expression of 11β-HSD2 which is a
glucocorticoid inhibitor enzyme in the placenta. Lipoxin A4 (LXA4) is one of
the most important endogenous anti-inflammatory, derived from arachidonic acid
(AA) which involves enzymatically double lipoxygenase of arachidonic acid by
lipoxygenase (LOXs), serving as a "stop signal" in inflammation. LXA
4 provides an important role in the recovery of hemostasis
and the cessation of inflammation (Liu et al., 2020).
Preeclampsia can occur due to systemic inflammatory conditions in which
oxidative stress and endothelial dysfunction and spiral artery remodeling can inhibit fetal
growth, but it can also be caused by a deficiency of polyunsaturated fatty
acids (PUFAs) and mediator anti-inflammatory products including lipoxins, resolvin, protectin, and maresin (Liu et al., 2020).
This is in line with research conducted by Leff-Gelman et al., (2020) which states that high cortisol is associated with psychological
disorders such as anxiety disorders or chronic stress. Psychological disorders
such as major anxiety disorder have a positive correlation during pregnancy.
Where the higher the level of anxiety and stress levels, the serum cortisol
levels will also increase (Zhang et al., 2018).
A lot of evidence suggests that preeclampsia is also associated with
glucocorticoid/cortisol exposure caused by stress and anxiety disorders.
Preeclampsia can increase stress and trigger elevated cortisol levels.26
This is in line with the research that has been done, where this study
limits normal cortisol levels based on the standard cortisol kit used. The
normal limits of cortisol are related to the division of AM and PM time. If
sampling in the morning (AM) time range, the normal limit value range of
cortisol is 3.95-27.23 μg/dL
with an average value of 15.59 μg/dL. Meanwhile, if sampling in the day-night (PM)
range, the normal limit range of cortisol is 1.45-10.41 μg / dL
with an average value of 5.93 μg / dL
The results of the study that the researchers have conducted obtained
samples in the normal pregnancy group in the morning range (AM) as many as 11
respondents with an average cortisol level of 41.77 μg / dL,
while sampling normal pregnant women during the day to night (PM) as many as 16
respondents with an average cortisol level of 36.46 μg / dL.
Then in the preeclampsia pregnancy group in the morning range (AM) as many as
16 respondents with an average cortisol level of 54.83 μg / dL,
while sampling of normal pregnant women during the day to night (PM) as many as
11 respondents with an average cortisol level of 39.78 μg / dL
This shows that pregnant women in the normal pregnancy group and the
preeclampsia pregnancy group have cortisol levels higher than normal limits
which is a marker that pregnant women experience stress levels, but the average
cortisol levels are higher in the preeclampsia pregnancy group than the normal
pregnancy group which is a marker that has a higher stress level preeclampsia
group.
Fairbrother et al., (2017) research reported that women with risky pregnancies such as
preeclampsia have 5.2 times greater anxiety and stress than women with normal
pregnancies.27 This is in line with research that researchers have conducted,
mothers with risky pregnancies such as preeclampsia are more easily stressed or
anxious than normal pregnancies because the obstetric problems they experience
require a level of care and doctor visits and medical treatment More often, so this can cause financial
constraints and treatment time which more often triggers psychological
problems.
Therefore, it needs good emotional and instrumental support from family
and health workers for pregnant women so that psychological problems do not
occur both in early pregnancy and before delivery which can increase the
production of cortisol levels in pregnant women. Researchers argue that in this
study, the preeclampsia group had cortisol levels higher than the group with
normal pregnancy because it was triggered by stress that occurred in early
pregnancy and then the stress persisted due to poor obstetric conditions, such
as obesity problems, as well as exposure to cigarette smoke which can increase
the occurrence of oxidative stress, this stress is what causes an increase in
cortisol levels and affects vasoconstriction,
vascularization disorders that have an effect on increasing blood
pressure in mothers
Based on Table 5. The results of differences in serum levels of 25
Hydroxyvitamin D in preeclampsia pregnancy were (13.63 ± 6.12) ng / ml and 25
Hydroxyvitamin D normal pregnancy serum namely (14.49 ± 3.94) ng / ml with a
difference in values of 0.86 ng / ml. Based on the results of statistical tests
using the Independent T-test, p-value = 0.539 (p > 0.05) which means there
is no difference in serum 25 Hydroxyvitamin D levels in preeclampsia pregnancy
with normal pregnancy.
According to guidelines from the Institute of Medicine (IOM) in (Raia-Barjat et al., 2021) recommend vitamin D (25(OH)D)
concentrations for women in pregnancy above 20 ng/mL, then it is said to be
deficient if serum 25 hydroxyvitamin D (25(OH)D) levels are below 20 ng/mL (50
nmol/L). Based on the results of research that researchers have conducted, 25
serum hydroxyvitamin D levels of preeclampsia pregnancy were obtained (13.63 ±
6.12) ng / ml and 25 hydroxyvitamin D levels of normal pregnancy serum namely
(14.49 ± 3.94) ng / ml. This showed that the average vitamin D levels in both
groups of pregnant women were < 20 ng / mL. This
showed that subjects in this study in both normal pregnancy and preeclampsia
groups experienced vitamin D deficiency (Wang et al., 2013).
Vitamin D deficiency during pregnancy is associated with many short- and
long-term problems for both the fetus and the mother.
Vitamin D during pregnancy plays three main roles. First, stimulation of calcium absorption, a
process necessary for the accrual of fetal bone
minerals during the last trimester of pregnancy. Secondly, vitamin D
contributes to fetal tolerance, being an allograft
during pregnancy. A third important role is its involvement in various
transcriptional regulations (Raia-Barjat et al., 2021).
Vitamin D deficiency in mothers during pregnancy is a common and public
health problem at the global level. Vitamin D deficiency (25-hydroxyvitamin D
serum (25(OH)D) < 20 ng/mL) is a major widespread public health problem
among the general population and is particularly prevalent in pregnant women,
The overall average prevalence rate of vitamin D deficiency in pregnant women
and newborns is 54% and 75%, respectively. Globally,
it is estimated that one billion people are deficient in vitamin D (Morales-Suárez-Varela et al., 2022).
In this study it is known that most pregnant women experience vitamin D
deficiency both in the preeclampsia pregnancy group and the normal pregnancy
group. In this study, researchers assumed the cause of vitamin D deficiency in
pregnant women in the city of Padang was caused by lack of sun exposure in
pregnant women where in the pre-eclampsia pregnancy group most did activities
outside the home for less than one hour as many as 17 people (63%), as well as
in the normal pregnancy group did the most activities outside the home for less
than one hour, which was as many as 11 people (40.7%).
In this study, sun exposure was also influenced by employment status as
many as 21 people (77.8%) non-working mothers / IRT (housewives) in the
preeclampsia pregnancy group and 20 people (74.1%) non-working mothers / IRT in
the normal pregnancy group. Work is related to the load of physical activity.
Pregnant women who work as housewives more often spend time and do physical
activities in the house, ranging from cleaning the house, preparing school
children, ironing clothes, cooking, washing clothes and various other
activities so that pregnant women rarely leave the house, especially at
10.00-13.00. In addition, many pregnant women wear hijab when doing outdoor
activities every day, or cover the entire surface of their body when outdoors
even using umbrellas, besides that there are still many pregnant women who are
afraid of exposure to sunlight for fear of black.
In the opinion of researchers in this study found low levels of vitamin
D in pregnant women in the preeclampsia group and normal pregnancy group also
due to other factors such as lack of food intake of vitamin D, nutritional
status or body mass index. It is known that pregnant women in the preeclampsia
group have the most BMI with obesity (≥27.5 kg / m2) as many as 13 people
(48.1%), as well as normal pregnancy groups have the most BMI obesity (≥27.5 kg
/ m2) as many as 11 people (40.7%). Mothers with obesity are prone to vitamin D
deficiency. Vitamin D is a fat-soluble vitamin and fat accumulation throughout
the body will interfere with the transport and conversion of previtamin D3 into vitamin D3. Thus, overweight or obese
individuals experience a decreased capacity for vitamin D synthesis (Morales-Suárez-Varela et al., 2022).
Based on the difference in the average levels of 25 serum hydroxyvitamin
D from the two groups, it was seen that the average difference in serum 25
hydroxyvitamin D levels was not too far with a value of 0.86 ng / ml, so there
was no significant difference between preeclampsia pregnancy and normal
pregnancy with p = 0.539.This result is in line with the research of Serrano et al., (2018) which stated that the concentration of serum 25 hydroxyvitamin D levels
(25(OH)D) was significantly lower in the group
preeclampsia (mean 29.99 ng/mL) compared with normal pregnancy group
(mean 33.7 ng/mL) (Serrano et al., 2018). The study of Gholami et al., (2022) also reported that the average serum hydroxyvitamin D levels of the
preeclampsia case group (16.60 ±5.87 ng/mL) were lower than the normal
pregnancy group (19.06±7.48 ng/mL), in this study found no correlation between
vitamin D deficiency and predictive factors for preeclampsia (H. Gholami et al., 2022). Meanwhile, according to research Raia-Barjat
et al. (2021) reported that pregnant women with vitamin D or 25(OH)D levels of
<12 ng/mL had a 2.4-fold higher risk for early preeclampsia at the age of
<35 weeks than patients with vitamin D or 25(OH)D levels of >30 ng/ml (Raia-Barjat et al., 2021)
In the opinion of researchers, there is no significance of the
difference in serum 25 hydroxyvitamin D levels in the normal pregnant group and
the preeclampsia pregnancy group because nutritional status can be seen from
the Body Mass Index. In this study many pregnant women are obese, and
underweight. Obesity can cause vitamin D to get trapped. Obesity can lead to
increased cytokine-mediated inflammation and oxidative stress, increased shear
stress, dyslipidemia, and increased sympathetic nerve
activity as major pathways that may be involved in the pathogenesis of
preeclampsia, while an underweight BMI can also cause oxidative stress,
endothelial disorders and can also trigger preeclampsia (Raia-Barjat et al., 2021).
In this study, statistical results stated that there was no significance
of vitamin D levels with the incidence of preeclampsia, also related to the
design of research methods and inclusion and exclusion criteria that were still
less strict in considering covariables that could be related to the variables
studied. This is in line with the meta-analysis research of Aguilar-Cordero et al., (2020) which states that there is no significance or relationship between
vitamin D levels and the incidence of preeclampsia due to the design of the
research methodology. We recommend that vitamin D supplementation trials are
well-designed by establishing strict exclusion criteria, studying each
pathology independently and excluding obvious covariables that may affect
research results (Aguilar-Cordero et al., 2020).
This study has several limitations, namely the lack of strictness in
determining exclusion criteria. There are other factors that can affect vitamin
D levels are not assessed such as lifestyle changes, skin pigmentation, season,
culture culture, amount and frequency of consumption
of vitamin D supplements. In addition, this study also did not assess the level
of stress associated with increased cortisol levels
CONCLUSION
There is a difference in serum cortisol levels between preeclampsia and
normal pregnancies. There was no difference in serum 25 hydroxyvitamin D levels
between preeclampsia and normal pregnancies. It is expected that future
researchers will continue this study by assessing the intake of vitamin D
levels, the relationship of cigarette smoke exposure, pre-pregnancy body mass
index with the incidence of vitamin D deficiency and preeclampsia with stricter
inclusion and exclusion criteria. It is expected that future researchers will
use cohort design in assessing the effect of vitamin D supplementation and
psychological stress on pregnancy on the incidence of preeclampsia. It is
expected for health workers to improve the quality of ANC by not only focusing
on obstetric or physical problems but also must pay attention to psychological
problems besides that it is also expected for health workers to provide
education about the importance of vitamin D levels in pregnant women.
BIBLIOGRAPHY
Aguilar-Cordero, M. J., Lasserrot-Cuadrado,
A., Mur-Villar, N., León-Ríos, X. A., Rivero-Blanco, T., & Pérez-Castillo,
I. M. (2020). Vitamin D, preeclampsia and prematurity: A systematic review and
meta-analysis of observational and interventional studies. Midwifery, 87,
102707.
Bärebring, L., O’Connell, M., Winkvist, A., Johannsson, G.,
& Augustin, H. (2019). Serum cortisol and vitamin D status are
independently associated with blood pressure in pregnancy. The Journal of
Steroid Biochemistry and Molecular Biology, 189, 259–264.
Black, J. M., & Hawks, J. H. (2014). Keperawatan
medikal bedah: manajemen klinis untuk hasil yang diharapkan. Elsevier
(Singapore).
Botyar, M., & Khoramroudi, R. (2018). Ultraviolet
radiation and its effects on pregnancy: A review study. Journal of Family
Medicine and Primary Care, 7(3), 511.
Bublitz, M. H., Bourjeily, G., D’Angelo, C., & Stroud, L.
R. (2018). Maternal sleep quality and diurnal cortisol regulation over
pregnancy. Behavioral Sleep Medicine, 16(3), 282–293.
Chappell, L. C., Cluver, C. A., & Tong, S. (2021).
Pre-eclampsia. The Lancet, 398(10297), 341–354.
Dror, R. O., Dirks, R. M., Grossman, J. P., Xu, H., &
Shaw, D. E. (2012). Biomolecular simulation: a computational microscope for
molecular biology. Annual Review of Biophysics, 41, 429–452.
Eberle, C., Fasig, T., Brueseke, F., & Stichling, S.
(2021). Impact of maternal prenatal stress by glucocorticoids on metabolic and
cardiovascular outcomes in their offspring: a systematic scoping review. PLoS
One, 16(1), e0245386.
Fairbrother, N., Young, A. H., Zhang, A., Janssen, P., &
Antony, M. M. (2017). The prevalence and incidence of perinatal anxiety
disorders among women experiencing a medically complicated pregnancy. Archives
of Women’s Mental Health, 20, 311–319.
Farapti, F., & Fadilla, C. (2021). Further Understanding
about the Mechanism of Vitamin D on Blood Pressure. Indonesian Journal of
Pharmacy/Majalah Farmasi Indonesia, 32(3).
Gholami, H., Fayazi, S., Shirshekan, M., Motamed, N., &
Tofighi, S. (2022). Comparison of Serum level of Vitamin D in Pregnant Women
with Preeclampsia and a Control Group in Ayatollah Mousavi Hospital in Zanjan. Journal
of Obstetrics, Gynecology and Cancer Research, 7(4), 335–340.
Gholami, M., Ghaziani, R. K., & Eskandari, Z. (2022).
Three-dimensional fractional system with the stability condition and chaos
control. Mathematical Modelling and Numerical Simulation with Applications,
2(1), 41–47.
Ilmiawati, C., Oviana, A., Friadi, A., & Reza, M. (2020).
Sunlight exposed body surface area is associated with serum 25-hydroxyvitamin D
(25 (OH) D) level in pregnant Minangkabau women, Indonesia. BMC Nutrition,
6(1), 1–7.
Judistiani, R. T. D., Nirmala, S. A., Rahmawati, M.,
Ghrahani, R., Natalia, Y. A., Sugianli, A. K., Indrati, A. R., Suwarsa, O.,
& Setiabudiawan, B. (2019). Optimizing ultraviolet B radiation exposure to
prevent vitamin D deficiency among pregnant women in the tropical zone: report
from cohort study on vitamin D status and its impact during pregnancy in Indonesia.
BMC Pregnancy and Childbirth, 19(1), 1–9.
Karrar, S. A., & Hong, P. L. (2022). Preeclampsia. In StatPearls
[Internet]. StatPearls Publishing.
Leff-Gelman, P., Flores-Ramos, M., Carrasco, A. E. Á.,
Martínez, M. L., Takashima, M. F. S., Coronel, F. M. C., Labonne, B. F., Dosal,
J. A. Z., Chávez-Peón, P. B., & Morales, S. G. (2020). Cortisol and DHEA-S
levels in pregnant women with severe anxiety. BMC Psychiatry, 20(1),
1–14.
Liu, H., Huang, W., Chen, L., Xu, Q., Ye, D., & Zhang, D.
(2020). Glucocorticoid exposure induces preeclampsia via DampeningLipoxin A4,
an endogenous anti-inflammatory and proresolving mediator. Frontiers in
Pharmacology, 11, 1131.
Madhavanprabhakaran, G. K., D’Souza, M. S., & Nairy, K.
S. (2015). Prevalence of pregnancy anxiety and associated factors. International
Journal of Africa Nursing Sciences, 3, 1–7.
Morales-Suárez-Varela, M., Uçar, N., Soriano, J. M.,
Llopis-Morales, A., Sanford, B. S., & Grant, W. B. (2022). Vitamin
D-Related Risk Factors for Maternal Morbidity and Mortality during Pregnancy:
Systematic Review and Meta-Analysis. Nutrients, 14(19), 4124.
Mrema, D., Lie, R. T., Østbye, T., Mahande, M. J., &
Daltveit, A. K. (2018). The association between pre pregnancy body mass index
and risk of preeclampsia: a registry based study from Tanzania. BMC
Pregnancy and Childbirth, 18(1), 1–8.
Polo‐Kantola,
P., Aukia, L., Karlsson, H., Karlsson, L., & Paavonen, E. J. (2017). Sleep
quality during pregnancy: associations with depressive and anxiety symptoms. Acta
Obstetricia et Gynecologica Scandinavica, 96(2), 198–206.
Prawirohardjo, S. (2014). Ilmu kebidanan sarwono
prawirohardjo. Jakarta: PT. Bina Pustaka Sarwono Prawirohardjo.
Purswani, J. M., Gala, P., Dwarkanath, P., Larkin, H. M.,
Kurpad, A., & Mehta, S. (2017). The role of vitamin D in pre-eclampsia: a
systematic review. BMC Pregnancy and Childbirth, 17(1), 1–15.
Raia-Barjat, T., Sarkis, C., Rancon, F., Thibaudin, L., Gris,
J.-C., Alfaidy, N., & Chauleur, C. (2021). Vitamin D deficiency during late
pregnancy mediates placenta-associated complications. Scientific Reports,
11(1), 20708.
Salustiano, R., Neto, E., & Martinez, M. (2013). The
unbalanced load cost on transformer losses at a distribution system. 22nd
International Conference and Exhibition on Electricity Distribution (CIRED
2013), 1–3.
Serrano, N. C., Guío, E., Quintero-Lesmes, D. C.,
Becerra-Bayona, S., Luna-Gonzalez, M. L., Herrera, V. M., & Prada, C. E.
(2018). Vitamin D deficiency and pre-eclampsia in Colombia: PREVitD study. Pregnancy
Hypertension, 14, 240–244.
Sherwood, L. (2014). Fisiologi Manusia; Dari sel ke sistem
(Introduction to Human Physiology). Penerbit Buku Kedokteran EGC.
Suhardjo, L. J. H., Deaton, B. J., & Driskel, J. A.
(1985). Pangan, Gizi dan Pertanian. UI-Pers Jakarta.
Usman, A. S. H. H. (2021). Risiko peningkatan hormon kortisol
pada hipertensi gestasional. Jurnal Ilmiah Obsgin: Jurnal Ilmiah Ilmu
Kebidanan & Kandungan P-ISSN: 1979-3340 e-ISSN: 2685-7987, 13(4),
182–192.
Wang, Z., Lin, Y. S., Dickmann, L. J., Poulton, E., Eaton, D.
L., Lampe, J. W., Shen, D. D., Davis, C. L., Shuhart, M. C., & Thummel, K.
E. (2013). Enhancement of hepatic 4‐hydroxylation of 25‐hydroxyvitamin
D3 through CYP3A4 induction in vitro and in vivo: implications for drug‐induced
osteomalacia. Journal of Bone and Mineral Research, 28(5),
1101–1116.
Yıldız, S., Tammo, Ö., & Tammo Sr, Ö. (2022). Comparison
of Vitamin D Levels and Related Factors in Pregnant Women and Neonates Exposed
to Second-Hand Smoke. Cureus, 14(8).
Zhang, D., Zeng, J., Miao, X., Liu, H., Ge, L., Huang, W.,
Jiao, J., & Ye, D. (2018). Glucocorticoid exposure induces preeclampsia via
dampening 1, 25-dihydroxyvitamin D3. Hypertension Research, 41(2),
104–111.
Copyright holders:
Imelda Ganeza, Defrin, Rika Susanti (2023)
First publication right:
AJHS - Asian Journal of
Healthy and Science
This article is licensed under a Creative
Commons Attribution-ShareAlike 4.0 International