Research Article

Difference of Cervical Nitric Oxide Levels in Pregnancy between Postdate in Labor

and not in Labor
Perbedaan Kadar Nitrit Oksida Serviks pada Kehamilan Postdate Inpartu dan
belum Inpartu

Anggun Pratissa, Ermawati, Joserizal Serudji, Roza Sri Yanti

Department of Obstetrics and Gynecology

Faculty of Medicine Universitas Andalas
Dr. M. Djamil General Hospital, Padang
Abstract
Objective: To determine the difference of nitric oxide levels in postdate in labor pregnancy and not in
labor.
Method: This research was quantitative research using analytic study and cross sectional comparative
study design which compared nitric oxide levels between two groups of study, postdate in labor
pregnancy and not in labor. The number of samples were 24 people which consisted of 12 people who
was diagnosed postdate in labor pregnancy and 12 people postdate not in labor. The sampling
technique was consecutive sampling. This research was conducted on May 2018 until samples was
fulfilled in Obstetric and Gynecology Division of RSUP Dr. M. Djamil, Network Hospitals, and Biomedical
Laboratory of Medical Faculty of Universitas Andalas. Independent T test was used to determine the
difference of NO levels between 2 groups with 95% CI (p≤0,05).
Results: There was difference of NO levels (p=0.0001) between postdate in labor pregnancy and not in
labor. Average of nitric oxide levels in postdate in labor pregnancy was higher (75,1 ± 26,6 µmol/L) than
postdate not in labor (8,7 ± 5,7 µmol/L).
Conclusions: There was difference of NO level between postdate in labor pregnancy and not in labor.
Keywords: cervix, labor, no, postdate, pregnancy

Abstrak
Tujuan: Mengetahui perbedaan kadar NO serviks pada kehamilan postdate inpartu dengan postdate
belum inpartu.
Metode: Penelitian ini merupakan penelitian kuantitatif dengan jenis penelitian studi analitik dan desain
penelitian studi banding potong lintang yang membandingkan kadar nitrit oksida serviks pada dua
kelompok penelitian yaitu kehamilan postdate inpartu dan belum inpartu. Jumlah sampel sebanyak 24
orang yang terdiri dari 12 orang kehamilan postdate inpartu dan 12 orang postdate belum inpartu.
Teknik pengambilan sampel consecutive sampling. Penelitian dimulai pada bulan Mei 2018 hingga
jumlah sampel terpenuhi di Bagian Obstetri dan Ginekologi RSUP Dr. M Djamil, Rumah Sakit Jejaring,
dan Laboratorium Biomedik Fakultas Kedokteran Universitas Andalas. Untuk mengetahui perbedaan
rerata kadar NO serviks pada kedua kelompok digunakan uji T Independen dengan 95% CI (p≤0,05).
Hasil: Terdapat perbedaan rerata kadar NO serviks (p=0,0001) antara kehamilan postdate inpartu dan
belum inpartu. Rerata kadar NO serviks pada kehamilan postdate inpartu lebih tinggi (75,1 ± 26,6
µmol/L) dibandingkan postdate belum inpartu (8,7 ± 5,7 µmol/L).
Kesimpulan: Terdapat perbedaan rerata kadar NO serviks pada kehamilan postdate inpartu dan belum
inpartu.
Kata kunci: inpartu, kehamilan, no, postdate, serviks

Correspondence author: Anggun Pratissa; anggunpratissa@gmail.com

1
 INTRODUCTION

Postdate pregnancy occurs within a period of > 40 weeks to 42 weeks. Pregnancy of

more than 41 weeks that has not shown signs of childbirth will continue to be a month-long
pregnancy (posterm). The reported incidence of posterm pregnancy varies between 4-14% of
all pregnancies with an average of 10%.1
The American College of Obstetricians and Gynecologists (ACOG) predicts that 6% of 4
million babies born in the United States during 2006 were born at 42 weeks or more.2
According to the World Health Organization (WHO), the incidence of pregnancy through the
date in the world ranges from 4-19%.3 Whereas in Indonesia, according to the results of data
from Riskesdas (Basic Health Research) in 2010, the incidence of pregnancy through the date;
in Indonesia approximately 10%, varies between 10.4–12% if the 42-week deadline is taken and
3.4–4% when a 43-week deadline is taken.4
Postdate pregnancy is often associated with an increased risk of perinatal morbidity and
mortality. The perinatal mortality rate at 40 weeks 'gestation is 2–3 neonates every 1,000 births,
while at 42 weeks' gestation it is 2-fold, even reaching 4-6 times in 44 weeks.5 This happens
because at postdate pregnancy there is a decrease in the supporting function of fetal welfare,
namely the placenta so that it has a higher risk of perinatal death associated with meconium
aspiration and asphyxia so that postdate pregnancy will affect fetal output.6
Several theories have been tried to explain the occurrence of childbirth, namely the
theory of oxytocin, the theory of progesterone, the theory of fetal cortisol, the theory of
prostaglandins, uterine structure, nutrition, circulation and nerves, the mechanism of decreased
fetal head.1 One theory that is thought to underlie the occurrence of labor is the theory of
progesterone reduction. This theory states that labor begins when there is a decrease in
progesterone levels. This decrease in progesterone levels causes the release of nitric oxide (NO)
in the endometrium and cervix and cytokine activation. Cytokine activation via the cyclo-
oxygenase (COX) II pathway will cause an increase in prostaglandin E2 (PGE2). NO release and
increase in PGE2 will cause collagen degeneration of the cervix and cervical tissue remodeling
so that cervical ripening occurs.7
The cervical ripening process is a multifactorial and multilevel process that can be started
on a different path. In this case, Nitric Oxide (NO) is the final metabolic mediator in the cervical
ripening process that works in the last cascade of the ripening process. NO activates the
advanced stages of cervical ripening, also works with prostaglandin pathways by inducing
COX-II. This interaction will strengthen the pro-inflammatory effect of NO. NO plays a multi-
functional role in the inflammatory process and various pro-inflammatory effects in the form
of increased vascular permeability, cytotoxicity, tissue damage, changes in the synthesis of
glycosaminoglycans and apoptosis. Various metalloproteins are also known to be potential
targets for NO.8
In a Finland study in 2004, there was a lower NO cervical pregnancy rate over months
(19.4 μmol / L) than a month-long enough pregnancy (106 μmol / L). Low levels of NO cervix
will inhibit the ripening of the cervix so that labor does not occur and continues into pregnancy
through months.9 Conducted a study using NO donors in 3rd trimester pregnancy for cervical
ripening performed from 2000-2005, found that the NO drug does not cause uterine
hyperstimulation so it is safe and has no major side effects on the fetus or mother.10 This proves
how important the presence of NO is in the labor process, so it is important to know how many
levels of NO can trigger the parturition process.

2
 This study measures and compares NO cervical levels in postdate in labor and not in
labor pregnancy. It is expected that by knowing the levels of NO at the time of this postpartum
pregnancy and not yet inpartu, it can be predicted that the occurrence of pregnancy over
months, so that proper management can be carried out which results in a decrease in maternal
and neonatal morbidity and mortality due to months of pregnancy.

METHOD

This research was quantitative research using analytic study and cross sectional comparative
study design which compared nitric oxide levels between two groups of study, postdate in
labor pregnancy and not in labor.
This research was conducted on May 2018 until samples was fulfilled in Obstetric and
Gynecology Division of RSUP Dr. M. Djamil, Network Hospitals, and Biomedical Laboratory of
Faculty of Medicine Universitas Andalas.
The population of this study were patient who diagnosed postdate in labor pregnancy
and not in labor with the inclusion criteria for postdate (> 40 weeks) gestational age in labor
and not in labor condition, the first day of the last menstruation was clear, willing to be the
research sample. The number of samples were 24 people in which 12 people postdate in labor
and 12 people postdate not in labor. The sampling technique was consecutive sampling. Each
sample will be explained about Information for consent and sign an informed consent.
Independent T test was used to determine the difference of cervical NO levels between
postdate in labor pregnancy and not in labor with 95% CI (p≤0.05). Data was analyzed by
computer program.
RESULTS

Table 1. Characteristics of Research Subject

Postdate in Labor Postdate Not in p–

Characteristics (n=12) Labor (n=12) value

Mother’s age (year) 27.5 ± 7 31.3 ± 6.3 0.2

BMI 27.1 ± 3.1 26.1 ± 1.9 0.4
Parity
Multipara 7 (41.2%) 10 (58.8%) 0.4
Primipara 5 (71.4%) 2 (28.6%)
Leukocytes (mm3) 11260.3 ± 2162.7 10739.2 ± 1974.5 0.5

Based on Table 1 it can be concluded that there is no difference in the characteristics of

the research subjects between patients with postdate in labor and not in labor (p> 0.05).

Table 2. Difference of Cervical NO Levels between Postdate in Labor and Not in Labor

Groups
Postdate in Postdate Not
Variable
Labor in Labor P
(Mean ± SD) (Mean ± SD) value
Nitric Oxide 75.1 ± 26.6 8.7 ± 5.7 0.0001
levels (µmol/L)

Based on Table 2, it can be concluded that there is a difference in the mean of NO cervical
levels between groups with postdate in labor pregnancy and not in labor, p = 0.0001 (p <0.05).
DISCUSSION

3
The results of this study showed that there were no differences in respondent characteristics
(maternal age, BMI, parity, and leukocyte levels) between postdate in labor and not in labor
pregnancy. The results of this study are almost the same where there is no age difference
between individual patients and not yet in part but based on the characteristics of parity shows
a significant difference.11 That obesity is a risk factor for postterm pregnancy based on the
results of their study but in this study there was no significant relationship between BMI and
postdate pregnancy.12 That risk factors for postterm pregnancy in general are parity (tend to
be more in primiparous) and a history of postterm pregnancy, whereas in this study more than
half of the subjects of postdate have not yet been multiparous.13
The risk of perinatal death in postdate increases with increasing age of pregnancy.
Postdate pregnancy causes a decrease in intra uterine fetal well-being. The process of the birth
of postdate is not known with certainty, but the causative factor that is considered to contribute
to the occurrence of postdate pregnancy is maternal age and parity.11
Postdate pregnancy is associated with incomplete maturity of reproductive organs in
mothers aged <19 years and decreased organ function of mothers at the age of >30 years.14
According to Endjun, the best age for pregnancy and childbirth for women is age 20-30 years,
because at that age psychologically and biologically are ready to experience pregnancy and
childbirth.15 According to Cunningham's theory, the age group of 20-35 years is a healthy
reproductive age group and most pregnancies will occur in this age group.1 According to
Simkin, that ages 20 to 35 are the most favorable age for women.16 This is in accordance with
this study where the age of mother in postdate in labor and not in labor between 27-33 years
old.
Postdate pregnancy is rare in multiparous because women with parity> 3 have frequently
stretched the uterus.17 Ninety five percent postdate pregnancy occurs in mothers with a first
pregnancy.1 Agree with Sloane, who stated that the prone category for pregnancy is the
pregnancy of the first child (primipara). One problem that is often encountered in postdate
pregnancy management is the difficulty in determining the age of pregnancy which cannot
always be determined precisely so that the fetus may not be as mature as expected.18, 19
The results of the analysis showed that there were significant differences in mean NO
cervical levels in which the mean NO cervical levels among postdate in labor patients were
higher (75.1 µmol/L) than postdate not in labor patients (8.7 µmol/L). The results of this study
are in line with Mochtar (2008) research in Semarang, which showed a significant difference in
NO levels and mean of cervical NO levels among postdate in labor mothers were higher (120.5
µmol/L) than postdate not in labor (45.1 µmol/L).11 Likewise with the study in Finland where
there was a lower cervical NO in postdate patients (19.4 µmol / L) than in labor aterm
pregnancy (106 µmol / L).9
Based on this study, NO cervical levels were significantly higher in postdate in labor
pregnancy and this was supported by two previous studies. This shows that NO has an
important role in the delivery process, where NO levels are positively correlated with labor. The
study is in accordance who found that NO concentrations were positively correlated with
cervical thinning and increased bishop scores among in labor patients.20. Low cervical NO levels
can inhibit the ripening process of the cervix so that labor does not occur and can cause
postdate.
One of the inflammatory chemical mediators that play a role in the ripening process of
the cervix is prostaglandin which is synthesized using enzyme cyclo-oxygenigen (COX) II.
Prostaglandins are formed through the reaction of arachidonic acid oxidation with the help of

4
COX II enzyme. NO plays a role in COX II stimulation which will cause the formation of
prostaglandins. Prostaglandins induce the release of NO uterine cervix of pregnant women,
and furthermore the NO release response to prostaglandins increases with gestational age.
The NO, prostaglandin and COX-2 sequences are important and interconnected in cervical
ripening.10
Prostaglandin has a stimulating effect on iNOS which will trigger a larger NO formation,
so that the more mature the cervix, the higher the NO level. The foregoing can explain the
higher levels of NO among in labor pregnancy compared to unborn pregnancy.10
Several experimental studies conducted on animals have shown that NO is an important
mediator in cervical ripening and the use of NO in the induction of cervical maturation is still
debated.21 In studies conducted in humans, iNOS became a cervical stimulating compound
during vaginal birth.22 Excessive production of NO can result in cervical ripening, membrane
fragility and premature birth.10
High cervical NO levels may be a major factor in ripening the cervix. The cervical ripening
process begins with a decrease in the Progesterone-B receptor. Decreased Progesterone-B
receptors in myometrial cells will induce iNOS which will synthesize NO which causes ripening
of the cervix. NO works to ripen the cervix by increasing vascular permeability, increasing
regulation of MMP, cytokine secretion, and inducing apoptosis of cervical tissue. In the cervical
ripening process there is a breakdown of the cervical collagen and an increase in water content,
so that the cervical tissue becomes soft and the ostium opens. The cervical ripening process is
a multifactorial and multilevel process that can be started on a different path. In this case, NO
is the final metabolic mediator in the cervical ripening process that works in the last cascade
of the ripening process. NO activates the advanced stages of cervical ripening, also works with
prostaglandin pathways by inducing COX-II. This interaction will strengthen the pro-
inflammatory effect of NO. NO plays a multi-functional role in the inflammatory process and
various pro-inflammatory effects in the form of increased vascular permeability, cytotoxicity,
tissue damage, changes in the synthesis of glycosaminoglycans and apoptosis. Various
metalloproteins are also known to be potential targets for NO.8
In women with pregnancies over months who have low NO levels, the duration of labor
will be more frequent until the birth process fails compared to women with high NO. The more
mature the cervix, the higher the levels of NO.10
In multiparous women, the levels of NO released are higher than nulliparous. The release
of NO cervix can be induced by uterine contractions and manipulation of the cervix (6.6 times).
Placental perfusion is partly controlled by NO. NO transdermal donor reduces the index of
uterine pulsatility and uterine resistance index. Oxytocin will stimulate the release of NO in the
membrane of a fetus that is rich in NO during term pregnancy. NO release can be stimulated
for cervical maturation both physiologically and pharmacologically.10

CONCLUSION

Based on the results of the study, it can be concluded that there is a significant difference in
the mean of NO cervical levels among postdate in labor pregnancy and not in labor.
Examination of NO cervical levels can be used as an examination to predict postdate
pregnancy, thereby reducing maternal and neonatal morbidity and mortality due to pregnancy
postdate.
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