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The Effect of 17α-Hydroxyprogesterone Caproate on Prevention of Preterm Labor in High-Risk Pregnant Women

AUTHORS

Shole Shahgheibi 1 , Nazli Hamrah 1 , * , Nasrin Soofizadeh 1 , Aidin Mojtahedzadeh 2 , Fariba Seyedoshohadaei 1 , Masomeh Rezaie 1 , Ghobad Moradi 3

AUTHORS INFORMATION

1 Department of Obstetrics and Gynecology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, IR Iran

2 Department of Pathology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, IR Iran

3 Department of Epidemiology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, IR Iran

How to Cite: Shahgheibi S, Hamrah N, Soofizadeh N, Mojtahedzadeh A, Seyedoshohadaei F, et al. The Effect of 17α-Hydroxyprogesterone Caproate on Prevention of Preterm Labor in High-Risk Pregnant Women, Iran Red Crescent Med J. 2016 ; 18(2):e26150. doi: 10.5812/ircmj.26150.

ARTICLE INFORMATION

Iranian Red Crescent Medical Journal: 18 (2); e26150
Published Online: February 20, 2016
Article Type: Research Article
Received: January 6, 2015
Revised: June 16, 2015
Accepted: January 2, 2016
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Abstract

Background: Preterm labor is referred to as birth before the 37th week of pregnancy. It occurs in 12% of all labors. Prematurity is the cause of 65% of all newborn deaths and despite progressive improvement in gynecological care and extended studies, its prevalence is growing.

Objectives: The aim of this study was to investigate the effect of 17α-hydroxyprogesterone caproate on prevention of preterm labor in high-risk pregnant women.

Materials and Methods: In this double-blinded clinical trial study, 100 pregnant women who were admitted to a high-risk clinic in Besat hospital during the years 2013 - 2014 were block randomized and divided into two groups: intervention (n = 50) and control (n = 50). The intervention group was injected on a weekly basis with 250 mg 17α-hydroxyprogesterone caproate ampoules intramuscularly from the 24th week until the 34th week, and a placebo was given to the control group.

Results: Comparing the effect of 17α-hydroxyprogesterone caproate on prevention of preterm labor in pregnant women aged 18 - 45 years old, this study showed 11 women (22%) with preterm labor at less than 37 weeks and 39 (78%) at more than 37 weeks. However, in the placebo group these figures were 29 (58%) and 21 (42%), respectively. This finding shows that 17α-hydroxyprogesterone caproate had a preventive effect on preterm labor in the intervention group. Using logistic regression analysis, the study showed that there was a significant difference between the intervention and placebo groups, and that 17α-hydroxyprogesterone caproate was effective on patients with a history of congenital uterine malformation, history of preterm labor and age group.

Conclusions: The results showed that 17α-hydroxyprogesterone caproate had a preventive effect on preterm labor.

Keywords

17α-Hydroxyprogesterone Caproate Preterm Labor High-Risk Pregnancy

Copyright © 2016, Iranian Red Crescent Medical Journal. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.

1. Background

Preterm labor is referred to as birth before the 37th week of pregnancy (1) and occurs in 12% of all labors. It is the cause of 65% of neonatal deaths and premature newborns. Despite considerable improvements in obstetrics care and extensive studies, its prevalence is increasing (1, 2). In neonates who survive, there is a high prevalence of acute and long-term complications such as respiratory distress syndrome, body weight at birth less than 2,500 g, a need for mechanical respiration, admission to the NICU and an increased need for supportive oxygen (3).

The survival rate of preterm neonates increases when the duration of pregnancy increases. In addition to mortality and morbidity, preterm neonates are at risk of physical and mental abnormalities and caring for these neonates requires intensive care centers (4-6).

Studies have shown that a mother’s history of preterm labor has a direct relationship with the occurrence of another preterm labor and will be inherited by the next generation (7).

Prevention of preterm labor is inevitable and every one of the prevention methods has its advantages and side effects. Today, for primary treatment of preterm labor, there are various tocolytic drugs, such as beta mimetics, magnesium sulfate and calcium blockers, which inhibit uterine contractions and are used to suppress uterine contractile activities (8). However, there is no evidence supporting the effectiveness of these drugs in preterm labor, and using these medications is not recommended.

Prescribing progesterone for prevention of preterm labor has a 30-year history and its use for prevention of spontaneous abortion or supporting the luteal phase goes back 40 years (9). Progesterone is the main human progestin, and has been used also for the treatment of premenstrual syndrome, post-partum depression, recurrent threat of abortion, prevention of preterm labor, and in recent years, for supporting the luteal phase for in-vitro fertilization (10, 11). Since 1960, 17α-hydroxyprogesterone caproate has been investigated for its safety and efficacy in prevention of preterm labor. Recent studies have shown that progesterone complexes, such as 17α-hydroxyprogesterone caproate, administered intramuscularly decreased preterm labor in women with a history of preterm labor (12).

Recent studies have shown that using progesterone during the second trimester shows a very low risk for teratogenicity (13).

Risks for preterm labor include a history of preterm labor, a woman’s own premature birth or that of her sister and acquired and/or congenital uterine abnormalities. Considering the contradictory results regarding the use of progesterone for prevention of preterm labor, several meta-analyses on published studies have been conducted. All researchers have shown evidence that to some degree suggests the usefulness of progesterone in decreasing preterm labor in special samples. Meanwhile, all researchers recommend the need for further investigation (1).

In many animal studies, uterine deprivation of the inhibitory hormone, progesterone, plays the main role in the beginning of labor. In humans, prescribing anti-progesterone medications, such as RU486, mifepristone or onapristone increases uterine responsiveness and induces cervical changes in 12 - 48 hours. This result shows that progesterone has a role in preventing the onset of labor (14). Very limited studies have been carried out in this regard, for instance, in a study in 2003 by Meis et al. it was proved that weekly injection of 17α-hydroxyprogesterone caproate from the 16th week until the 36th week, in women with history of preterm labor, decreased the rate of preterm labor (15).

2. Objectives

Considering the importance of preterm labor and premature birth with regard to their complications, and the limited number of studies in this regard in Iran, this study investigated the effect of the progesterone complex in prevention of preterm labor in high-risk pregnant women. High risk was categorized as a history of preterm labor, the mother’s own premature birth or that of her sister and acquired and/or congenital uterine abnormalities.

3. Materials and Methods

In this double-blinded study 100 pregnant women who were admitted to a high-risk clinic in Besat hospital during the years 2013 - 2014 and who met the inclusion criteria were block randomized into two groups: intervention (n = 50) and placebo (n = 50). The two groups were similar in age of pregnancy and preterm labor risk factors. After classification and being given an explanation about the study conditions, a written consent was obtained. The study was approved by the ethics committee. Information regarding past history, such as a history of preterm labor, cervical shortness, history of cerclage, history of the mother’s own premature birth or that of her sister, and acquired and/or congenital uterine abnormalities noticed in sonography were documented. Subjects were followed, and 250 mg 17α-hydroxyprogesterone caproate ampoules were injected intramuscularly on a weekly basis from the 24th until the 34th week, and a placebo was given to the control group.

In this double-blinded study, the drug and the placebo were similar in shape, and the clinician who injected the medication was not aware of the contents of the injection. The participants were instructed to admit themselves in a timely manner to the hospital when they felt regular and rhythmic contractions. In the hospital, contractions were monitored by tocodynamometer, and in the case of real contractions, patients were admitted and treated with tocolytics. For women in whom labor was not stopped, despite treatment with tocolytics, data were documented and collected. At the end of the study, the age of the pregnancy at the time of birth and the preterm labor incidence rates were compared between both groups.

Inclusion criteria for this study included: singleton pregnancy with an accurate age of pregnancy (pregnancy was confirmed with sonography before the 12th week and based on LMP. If LMP was not available, age of pregnancy would be determined by two sonography studies, two weeks apart); history of preterm labor before the 37th week; history of premature birth; history of premature birth in sister; acquired and/or congenital uterine abnormalities (unicorn uterus, double corn uterus, septated uterus, arcuate uterus and double uterus); and age of more than 18 and less than 45 years.

The exclusion criteria included: diseases in the mother that required therapy such as high blood pressure, cancer, seizure, thromboembolic disease or asthma under beta adrenergic treatment; age of less than 18 and more than 45 years; intrauterine growth retardation; vaginal bleeding; PROM; cervical dilation more than 2 cm; major known embryonic abnormalities; progesterone sensitivity; non-following the patient; twin or multiple pregnancy; contraindications for tocolysis such as fetal distress, chorioamnionitis, preeclampsia or unstable hemodynamics; uterine contractions; diabetes; history of cerclage; and cervical shortness

4. Results

In this double-blinded clinical trial of 100 pregnant women admitted to the Besat high-risk clinic, 50 women were assigned to the intervention group and 50 women to the placebo group. The average and standard deviation of age in the intervention group was 25.4 ± 2.58 with a confidence interval of 24.6 - 26.1. In the placebo group, the average and standard deviation of age was 27.4 ± 2.21 with a confidence interval of 26.6 - 27.8 (Table 1).

Table 1. Average (SD) of age in the two Groups
AgeNumberMean (SD)Confidence interval
Drug5025.4 (2.58)24.4 - 26.1
Placebo5027.4 (2.21)26.6 - 27.8

Regarding gravidity, the distribution in the intervention group was: 16 women (32%) were in gravida 1, 22 (44%) in gravida 2, 11 (22%) in gravida 3 and 1 (2%) in gravida 4. In the placebo group, 8 women (16%) were in gravida 1, 27 (54%) in gravida 2, 14 (28%) in gravida 3 and 1 (2%) in gravida 4. Using statistical tests, Chi-Square and P values were obtained, and it was shown that there was no significant difference between the two groups. Regarding parity, the distribution of para was: of the 35 women in the intervention group, 25 (71.4%) were in para 1 and 10 (28.6%) were in para 2, while of the 42 women in the placebo group 27 (64.2%) were in para 1, 14 (33.3%) in para 2 and 1 (2.5%) was in para 3. According to the calculated P value and using the Chi-Square test, there was no significant difference between the two groups. Regarding the frequency distribution of previous preterm labor, in the intervention group 20 women (42%) had a history of previous preterm labor and 30 women (58%) had no history of preterm labor. In the placebo, group 20 women (40%) had and 30 (60%) women did not have a previous preterm labor. The chi-square test and P value showed that there was no significant difference between the two groups. In regards to the frequency distribution of a previous premature birth in the intervention group, four women (8%) had a history of previous premature birth, and 46 women (92%) had no history of premature birth. In the placebo group, three women (6%) had and 47 (94%) women did not have a previous premature birth. The Chi-Square test and P value showed that there was no significant difference between the two groups. In the frequency distribution of previous premature birth in a sister, in the intervention group three women (6%) had a history of previous premature birth in a sister, and 47 women (94%) had no history of premature birth in a sister, while in the placebo group three women (6%) had and 47 (94%) women did not have history of premature birth in a sister. The chi-square test and P value indicated that there was no significant difference between the two groups. Regarding the frequency distribution of a history of acquired uterine abnormalities, in the intervention group 13 women (26%) had a history of acquired uterine abnormalities and 37 women (74%) had no history of acquired uterine abnormalities. In the placebo group 14 women (28%) had and 36 (72%) women did not have a history of acquired uterine abnormalities. Using the chi-square test and the P value, it was shown that there was no significant difference between the two groups. In the frequency distribution of previous congenital uterine abnormalities, in the intervention group seven women (14%) had a history of congenital uterine abnormalities, and 43 women (86%) had no history of congenital uterine abnormalities, while in the placebo group, six women (12%) had and 44 (88%) women did not have a history of congenital uterine abnormalities. The chi-square test and obtained P value showed that there was no significant difference between the two groups (Table 2).

Table 2. Detailed Information for the two Groups
DrugaPlaceboaChi-SquareP Value
Gravida2.990.39
116 (32)8 (16)
222 (44)27 (54)
311 (22)14 (28)
41 (2)1 (2)
Para1.120.57
125 (71.4)27 (64.2)
210 (28.6)14 (33.3)
31 (2.5)
Previous preterm labor01
Has20 (42)20 (40)
Doesn’t have30 (58)30 (60)
Previous premature birth0.150.69
Has4 (8)3 (6)
Doesn’t have46 (92)47 (94)
Previous premature birth in sister01
Has3 (6)3 (6)
Doesn’t have47 (94)47 (94)
History of acquired uterine abnormality0.110.82
Has13 (26)14 (28)
Doesn’t have37 (74)36 (72)
History of congenital uterine abnormality0.110.73
Has7 (14)6 (12)

aValues are expresses as No. (%).

Comparing the effect of 17α-hydroxyprogesterone caproate on preventing preterm labor in pregnant women between 18 - 45 years old in the intervention group, 11 women (22%) had preterm labor before the 37th week and 39 women (78%) had preterm labor after the 37th week, meanwhile, in the placebo group these figures were 29 (58%) and 21 (42%), respectively. These differences show the preventive effect of 17α-hydroxyprogesterone caproate on prevention of preterm labor (Table 3).

Table 3. Comparing the Effect of 17α-Hydroxyprogesterone Caproate on Prevention of Preterm Labor in Pregnant Women Aged 18 - 45 Years old
Preterm LaborDrugPlaceboTDegree of Freedom (df)OR (Confidence Interval)
Before 37th week11 (22)29 (58)-3.9110.69 (0.58 - 0.83)
After 37th week39 (78)21 (42)-3.9110.69 (0.58 - 0.83)

Comparing the effect of 17α-hydroxyprogesterone caproate on prevention of preterm labor in pregnant women aged 18 - 45 years old, using logistic regression analysis, it was shown that there was a significant difference between the intervention and placebo groups, and 17α-hydroxyprogesterone caproate was effective in women with a history of congenital uterine malformation, history of preterm labor and age group (Table 4).

Table 4. Comparing the Effect of 17α-Hydroxyprogesterone Caproate on Prevention of Preterm Labor in Pregnant Women Aged 18 - 45 Years old Based on Different Groups
VariableORConfidence IntervalP Value
Drug-Placebo0.19(0.07 - 0.47)0.0001
History of congenital uterine abnormality2.31(0.64 - 8.3)0.20
History of acquired uterine abnormality0.39(0.29 - 2.08)0.62
History of preterm labor0.66(0.27 - 1.62)0.37
History of premature birth0.33(0.24 - 7.11)0.74
History of preterm labor in sister1.65(0.27 - 9.87)0.55
History of preterm labor in mother1.01(0.19 - 5.37)0.98
Age group (less than 25 and more than 25 years)0.65(0.19 - 2.19)0.49

5. Discussion

Results from our study showed that no significant difference was observed between the two groups in regards to gravidity, parity, history of preterm labor, history of premature birth, history of premature birth in sister or history of acquired and congenital uterine abnormalities. Comparing the effect of 17α-Hydroxyprogesterone caproate on preventing preterm labor in pregnant women between 18 - 45 years old, in the intervention group 11 women (22%) had preterm labor before the 37th week and 39 women (78%) had preterm labor after the 37th week. Meanwhile, in the placebo group these figures are 29 (58%) and 21 (42%), respectively. These differences show the preventive effect of 17α-Hydroxyprogesterone caproate on prevention of preterm labor.

Comparing the effect of 17α-Hydroxyprogesterone caproate on the prevention of preterm labor in pregnant women aged 18 - 45 years old using logistic regression analysis, it was shown that there is a significant difference between the intervention and placebo groups, and 17α-hydroxyprogesterone caproate was effective in women with a history of congenital uterine malformation, history of preterm labor and age group.

A study in 2003 by Meis et al. was published in the New England journal of medicine. This double-blinded clinical trial was carried out on 503 Scottish pregnant women with a proved history of preterm labor. In this study, 310 women with a history of preterm labor were given weekly injections of 17α-hydroxyprogesterone caproate from the 16th week until the 36th week. Results showed that treatment with progesterone decreased the rate of preterm labor before the 37th week. This result is consistent with our findings (P = 0.02) (15).

In a study by Pessel et al. in 2013 at the Boston College, in the U.S., 237 pregnant women with similar cervical length were assessed. In this study, 184 women were given 17α-hydroxyprogesterone caproate from the 16th week until the 37th week. The age of the pregnancy and history of previous preterm labor were similar in both groups. It was proven in this study that cervical shortness among women with a history of preterm labor occurs similarly, regardless of receiving or not receiving 17α-hydroxyprogesterone caproate (P = 0.67) (16).

In another large study by Fonseca et al. in 2007, 413 pregnant women who had cervical shortness based on sonography (15 mm or less) were characterized during routine prenatal care. These women were randomized into two groups. One group was treated with a 200 mg progesterone vaginal suppository, and the other was given a placebo. Treatment with progesterone caused significant reduction of spontaneous labor before the 34th week (P < 0.05) (17).

Progesterone is a natural hormone that is secreted by the corpus luteum and the placenta at the beginning of pregnancy and its vital role in maintaining pregnancy has been proven. Researchers have used this hormone for preventing preterm labor in late pregnancy. In a study by Fontenot and Fantasia in 2012 in Brazil, it was shown that vaginal progesterone given from the 16th week to the 34th week is effective in preventing preterm labor in women with history of preterm labor (18).

In a study by O’Brien et al. in 2007, 659 pregnant women with history of preterm labor were randomized into two groups. One group was treated with a progesterone vaginal suppository (90 mg) from the 16th until the 32nd week and the other with a placebo. It was shown that there was no significant difference between the two groups regarding preterm labor rates, and preventive therapy with vaginal progesterone did not decrease preterm labor recurrence before the 32nd week in women with history of preterm labor (19).

Oven et al. studied 302 pregnant women in Columbia in 2009 who had been referred from 16 pregnancy control in America and had a history of preterm labor and cervical shortness (cervical length of less than 25 mm). They were randomized into two groups: one cerclage group and the other group without intervention. In this study, 190 pregnant women with cervical shortness and cerclage before the 24th week were compared with the other group without cerclage. This comparison showed that in the group with cerclage before the 4th week, the rate of preterm labor before the 35th week was significantly lower (35% vs. 65%). This study also showed that in pregnant women with history of preterm labor it is possible to prevent recurrent preterm labor (P < 0.05) (1).

Results from the present study showed that 17α-hydroxyprogesterone caproate had a preventive effect on preterm labor. However, further studies with larger sample size are required to assess the role of 17α-hydroxyprogesterone caproate in preventing preterm labor.

Acknowledgements

Footnote

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