Comparison of the Effect of Micronized Progesterone (Utrogestan) and Hydroxyprogesterone Caproate (Proloton) on Maternal and Fetal Blood Circulation in Women at Risk of Preterm Labor

² Trauma Nursing Research Center, Kashan University of Medical Sciences, Kashan, Iran

³ Department of Epidemiology, Kashan University of Medical Sciences, Kashan, Iran

⁴ Obstetrician and Gynecologist, Kashan, Iran

*Corresponding author: Masoumeh Abedzadeh-Kalahroudi, Trauma Nursing Research Center, Kashan University of Medical Sciences, Kashan, Iran. Email: abedzadeh@kaums.ac.ir

EXTENDED ABSTRACT

Background

Preterm birth, defined as birth before 37 completed weeks of gestation, remains a major cause of neonatal mortality and morbidity. It is reported in approximately 7-12% of pregnancies in developed countries and may be more frequent where access to neonatal intensive care is limited [1, 2]. In Iran, the incidence of preterm birth increased from 8.9% to 12.1% between 2005 and 2019 [3]. Several pharmacologic approaches are used to prevent or delay preterm delivery, and progestogens have become an important option in women at increased risk [4, 5]. Proposed mechanisms of progesterone include anti-inflammatory activity, inhibition of myometrial gap-junction formation, effects on cervical ripening, modulation of potassium channels, inhibition of oxytocin and prostaglandin pathways, and vasodilatory effects on the uterine circulation [6-10]. Natural progesterone can be administered orally or vaginally, whereas hydroxyprogesterone caproate is administered by injection [11]. Uncertainty persists regarding the optimal preparation, route, dose, and timing of progesterone therapy [12, 13]. Micronized progesterone (Utrogestan) was developed to improve oral absorption and has been used during pregnancy, while 17-alpha-hydroxyprogesterone caproate (Proloton) is an injectable preparation requiring intermittent intramuscular administration [15-18]. Previous Doppler studies have reported both vasodilatory effects and little or no change in maternal or fetal circulation after progesterone therapy [8, 9, 19-24]. Therefore, this randomized trial compared oral micronized progesterone with intramuscular hydroxyprogesterone caproate in women at risk of preterm labor, focusing on Doppler indices of the uterine, umbilical, and fetal middle cerebral arteries.

Methods

This randomized, single-blind clinical trial included 80 pregnant women at risk of preterm labor who were referred to Shabihkhani and Shahid Beheshti hospitals in Kashan during Iranian calendar year 1400. The sample size was 40 women per group. Risk of preterm labor was defined by a history of preterm birth, a second-trimester cervical length below 25 mm, or regular uterine contractions requiring hospitalization. Eligible women had a singleton pregnancy at 20-34 weeks of gestation confirmed by last menstrual period and ultrasonography, cervical length below 25 mm on transvaginal ultrasonography, intact membranes, a history of preterm delivery or regular uterine contractions, cervical dilatation of at least 2 cm, and no hypertension. Exclusion criteria were failure to return for follow-up Doppler ultrasonography, incorrect medication use, known fetal anomaly or fetal death, treatment with tocolytics, progesterone hypersensitivity, or an indication for immediate delivery such as fetal distress or severe bleeding. After written informed consent, uterine, umbilical, and fetal middle cerebral artery Doppler ultrasonography was performed by a perinatologist blinded to treatment allocation. Randomization used computer-generated block allocation with block sizes of four and six and sequential opaque envelopes. Women assigned to Utrogestan received oral micronized progesterone 200 mg twice daily for 48 hours; those assigned to Proloton received 500 mg hydroxyprogesterone caproate intramuscularly. Doppler ultrasonography was repeated one week later by an examiner unaware of the intervention. Examinations were performed with a Medison 200 ultrasound system and a 2-5 MHz abdominal transducer. Pulsatility index (PI), resistance index (RI), peak systolic velocity (PSV), and systolic-to-diastolic ratio (S/D) were measured in the uterine, umbilical, and fetal middle cerebral arteries. Data were analyzed using SPSS version 16. Within-group comparisons used the Wilcoxon signed-rank test; between-group comparisons used Fisher's exact test, independent-samples t test, or Mann-Whitney test as appropriate. ANCOVA was used to adjust for baseline differences in Doppler indices, and linear regression evaluated predictors of post-treatment values. Statistical significance was defined as P<0.05. The study was approved by the Kashan University of Medical Sciences ethics committee (IR.KAUMS.MEDNT.REC.1398.096; grant 98146), and the trial was registered as IRCT20200201046324N1.

Results

The two treatment groups were comparable at baseline with respect to maternal age, body mass index, gestational age, gravidity, history of preterm delivery, cervical length, and initial cervical dilatation. Mean maternal age was 31.53±3.64 years in the Utrogestan group and 29.20±7.57 years in the Proloton group (P=0.84). Mean gestational age was 26.60±4.73 and 27.57±4.70 weeks, respectively (P=0.40). Previous preterm birth was reported in 8 women (20%) receiving Utrogestan and 10 (25%) receiving Proloton (P=0.79), while cervical dilatation of at least 2 cm was present in 14 (35%) and 20 (50%), respectively (P=0.25).

Table 1. Demographic and reproductive characteristics of patients in the two study groups.

Within-group Doppler analysis showed that uterine artery RI, PI, and S/D decreased significantly after Proloton, with P=0.030, P<0.001, and P=0.019, respectively. In the Utrogestan group, uterine artery RI and S/D decreased significantly (P<0.001 and P=0.002), whereas the change in PI was not significant (P=0.085). Umbilical artery S/D decreased from 3.58±0.80 to 3.50±0.77 after Proloton (P=0.021), while the reduction from 3.70±1.36 to 3.60±1.14 after Utrogestan was not significant (P=0.090). For the fetal middle cerebral artery, Utrogestan was associated with a significant change in S/D from 5.78±1.03 to 6.11±0.81 (P<0.001); other within-group changes in this artery were not statistically significant.

Before treatment, several Doppler indices differed between groups, including umbilical artery RI and fetal middle cerebral artery RI, S/D, and PSV. After treatment, unadjusted between-group comparisons continued to show differences in umbilical artery RI (P=0.037), fetal middle cerebral artery RI (P<0.001), PI (P=0.036), and PSV (P=0.002), while the difference in fetal middle cerebral artery S/D was borderline (P=0.054). Because baseline values of some Doppler indices differed between groups, ANCOVA was used to control for these potential confounders. After adjustment, only fetal middle cerebral artery S/D and PSV remained significantly different between the two treatment groups (P<0.05). The article concluded that the two progesterone preparations had generally similar effects on uterine and umbilical circulation, whereas Proloton produced the more favorable effect on fetal cerebral circulation.

Table 3. Comparison of Doppler indices of the uterine, umbilical, and fetal middle cerebral arteries before and after drug administration between the two groups.

Linear regression further showed that post-treatment Doppler values were influenced not only by treatment assignment but also by maternal age, gestational age, previous preterm birth, BMI, and the corresponding pre-intervention PI, RI, PSV, or S/D values. No adverse effects were reported with either Utrogestan or Proloton during the study.

Conclusion

Oral micronized progesterone and intramuscular hydroxyprogesterone caproate produced broadly similar effects on uterine and umbilical blood flow in women at risk of preterm labor. After adjustment for baseline Doppler differences, the principal between-group differences involved fetal middle cerebral artery S/D and PSV, favoring Proloton. On the basis of the study findings, either preparation may be selected according to patient preference and available facilities, while Proloton may provide a greater effect on fetal cerebral circulation.

Keywords: Hydroxyprogesterone Caproate, Maternal and Fetal Blood Circulation, Micronized Progesterone, Preterm Labor

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