Use of Oral Progestogen in Women With Threatened Miscarriage in the First Trimester

A Randomized Double-blind Controlled Trial

Diana Man Ka Chan; Ka Wang Cheung; Jennifer Ka Yee Ko; Sofie Shuk Fei Yung; Shui Fan Lai; Mei Ting Lam; Dorothy Yuet Tao Ng; Vivian Chi Yan Lee; Raymond Hang Wun Li; Ernest Hung Yu Ng

Disclosures

Hum Reprod. 2021;36(3):587-595. 

In This Article

Materials and Methods

This randomized double-blind controlled study was conducted in three public hospitals in Hong Kong: Queen Mary Hospital (QMH), Kwong Wah Hospital (KWH) and Pamela Youde Nethersole Eastern Hospital (PYNEH). Ethics approval was obtained from the Institutional Review Board of each hospital (Reference numbers: UW13-292 [QMH]; KW/EX-16-045(97-04) [KWH]; HKEC-2016-056 [PYNEH]). Written informed consent was obtained from women at the time of recruitment. The study was registered at ClinicalTrials.gov (registration number: NCT02128685). The protocol of the study was previously published (Chan et al., 2016).

Women presenting with vaginal bleeding during the first trimester in Early Pregnancy Assessment Clinics were approached and recruited if they satisfied the selection criteria. Threatened miscarriage was defined as vaginal bleeding, with or without abdominal pain, in a pregnant woman with pelvic ultrasound confirming an intrauterine gestational sac(s) or foetus(es) with positive foetal heart pulsations (Cunningham, 2001).

Inclusion Criteria

The inclusion criteria for the study were:

  • age of women from 18 to 40 years at the time of recruitment;

  • between 5 and 12 completed weeks' gestation;

  • presence of intrauterine gestational sac(s) only if a urine pregnancy test was first positive within the past 2 weeks or presence of intrauterine foetus(es) with positive foetal heart pulsations or presence of intrauterine foetus(es) with crown-rump length of <7 mm and no foetal pulsation on pelvic scanning; and

  • absence of fever (temperature ≥38.5°C).

Exclusion Criteria

The exclusion criteria for the study were:

  • history of recurrent miscarriage defined as three or more consecutive spontaneous miscarriages;

  • history of known parental chromosomal abnormalities;

  • heavy vaginal bleeding or severe abdominal pain requiring surgical intervention;

  • absence of cardiac pulsation in a foetal pole with crown-rump length of ≥7 mm on transvaginal scanning;

  • use of hCG or progestogen for threatened miscarriage prior to recruitment; or

  • women with current or suspected breast or genital cancers, hepatic disease or tumours.

Women underwent history taking including age, race, last menstrual period, severity of bleeding (mild, moderate and severe, self-reported), presence of abdominal pain, medical history, obstetric and gynaecological history. After physical examination and speculum examination to exclude a local cause of vaginal bleeding and confirm the cervix was closed, transvaginal scanning was performed to assess the presence of an intrauterine sac with or without foetal pole and pulsation. Any abnormal adnexal mass was also noted during scanning. Blood was then taken to measure serum hCG and progesterone levels.

Randomization and Intervention

Consecutive women were then randomly assigned into one of the two groups: the progestogen and control groups by computer-generated randomization in a 1:1 ratio in blocks of 10. Each randomization result was put into a sealed opaque envelope. One sequential envelope was opened by the research assistant if a woman agreed to join the study. Both the clinicians and women were blinded from the group assignment. An unblinding procedure was considered if there were adverse drug reactions after treatment, as deemed necessary by the clinician in charge.

Women in the progestogen group received dydrogesterone (Duphaston®, Abbott, Chicago, IL, USA) 40 mg orally, followed by 10 mg orally three times a day (in accordance with the prescription instruction), and a placebo with the same external appearance was used in the control group accordingly. Concomitant use of any other hormonal medications or tocolytic agents was not allowed. Women were followed up with weekly pelvic ultrasound and blood tests until 12 weeks of gestation were completed, or 1 week after the bleeding stopped, whichever was later. Drugs were packaged in small bottles at a fixed number of tablets. The number of remaining tablets inside the bottle would be checked during follow-up and compliances would be recorded. Any adverse effects from drugs were also recorded during follow-up.

Treatment was also stopped if the vaginal bleeding became severe and required surgical intervention, or a diagnosis of silent miscarriage was confirmed upon a follow-up scan (i.e. the gestational sac or foetal pole failed to grow after 1 week, or there was no cardiac activity in a foetal pole with crown-rump length of ≥7 mm). If the woman had a spontaneous miscarriage, the tissue mass passed or obtained after medical or surgical evacuation was sent for histology and karyotyping by quantitative fluorescence PCR (QF-PCR) or the array comparative genomic hybridization method. QF-PCR, which was a simple and cheap method, would first be used to exclude common aneuploidy of chromosomes 13, 18, 21 and XY. The array comparative genomic hybridization method was employed in those with negative QF-PCR results to confirm or exclude aneuploidy.

Women received a standard antenatal check-up and follow-up routinely in the antenatal clinic until delivery. Written consent regarding retrieval of pregnancy and delivery data was sought from the women at the time of study entry. The obstetric outcomes were traced.

Statistical Analysis

Nominal data were described by frequencies and percentages, whereas continuous data were expressed as mean ± SD or median (25–75th percentile) for normally distributed or skewed data, respectively. Chi-square test and Fisher's exact test were used for categorical variables. T-test was used to compare the continuous variables between two groups. The analysis was performed with the intention-to-treat (ITT) and per protocol (PP) analyses. Differences were considered as statistically significant if the P-value was <0.05. All statistical analyses were performed using the IBM SPSS Statistics Version 25(IBM, Armonk, NY, USA).

The primary outcome was miscarriage before 20 weeks of gestation (Zegers-Hochschild et al., 2009). Subgroup analysis for the primary outcome was performed with regard to age of women ≥35 years, positive foetal pulsations, drug compliance >80% and abnormal karyotypes in the abortus.

Based on the two previous studies (El-Zibdeh and Yousef, 2009; Pandian, 2009), with the pooled miscarriage rate in the progestogen group and control group being 27/182 (14.8%) versus 42/155 (27.1%), respectively, a sample size of 171 women per group was needed to demonstrate such a difference with power of 80% and type I error of 0.05. To allow for some drop-out, we aimed to recruit 400 women in total with 200 women in each group.

The secondary outcomes were the live birth rate, gestational weight at delivery, Apgar score and obstetric complications including antepartum haemorrhage, placenta praevia, pregnancy-induced hypertension, pre-eclampsia, preterm labour, low birthweight at term and congenital abnormality. The definitions of the obstetric complications were as follows:

  • antepartum haemorrhage: any vaginal bleeding during pregnancy from the 24 weeks' gestation to term;

  • placenta previa: placenta inserting partially or wholly in the lower uterine segment, diagnosed by antenatal ultrasound at the second and third trimesters;

  • pregnancy-induced hypertension: development of new-onset hypertension (blood pressure persistently 140/90 mmHg or higher on two occasions at least 4 h apart) during pregnancy after 20 weeks' gestation, labour or the puerperium in a previously normotensive non-proteinuric woman;

  • pre-eclampsia: development of new-onset hypertension and proteinuria (total protein excretion of ≥300 mg per 24 h, estimated by spot urine protein to creatinine ratio or 24-h urine collection) during pregnancy after 20 weeks' gestation, labour or the puerperium in a previously normotensive non-proteinuric woman;

  • preterm labour: any premature spontaneous delivery from 24 to 36 weeks' gestation;

  • low birthweight at term: baby born with birthweight <2500 g at or after 37 weeks' gestation; and

  • intrauterine death: foetal death in utero after 24 weeks' gestation.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....