Is Hydroxychloroquine having arole for Prevention of Unexplained Recurrent Miscarriage?

INTRODUCTION

Recurrent miscarriage (RM) impacts 1%–2% of fertile couples and is characterized by 3 or more consecutive miscarriages during the 1st trimester of gestation. In around half of the cases, standard examinations uncover no obvious reason.¹

There is currently no therapy whose effectiveness has been clearly demonstrated, even in the context of well-known risk variables for RM.²

In about 10%–15% of conceptions, a sporadic abortion is clinically observed. Usually, fetal growth ceases before the age of ten weeks. Aside from the discovery of a fatal chromosomal defect in pregnancy products.³

In 1955, HCQ, a quinacrine-derived molecule, was first employed as an antimalarial drug. Soon after, HCQ was widely applied as an anti-inflammatory as well as immunomodulatory drug at dosages ranging from 200–400 mg/day for the therapy of autoimmune illnesses like systemic erythaematosus lupus (SLE) and rheumatoid arthritis (RA). Prior to the routine usage of LMWH, HCQ was briefly utilized as a thromboembolic prophylactic drug following total hip replacement in certain centers in the 1970s at a higher dosage (600–1200 mg/day).⁴

HCQ is a molecule with a long track record of safety in pregnant women. HCQ's pharmacological characteristics (antithrombotic, vascular protecting, immunomodulatory, enhanced glucose tolerance, lipid reducing, and anti-infective, for example).³

PATIENTS AND METHODS

Study design

This is a prospective, double-blind, randomized, 1:1 placebo-controlled trial on 300 patients (containing 2 parallel groups [HCQ 400 mg or placebo]). The minimization approach would be used at randomization to balance the two groups and two primary predictors of miscarriage recurrence: mother age (≤37) and number of prior miscarriages (≥ 3), with an upper limit of 8 months for giving hydroxychloroquine, if not get pregnant, we stop giving hydroxychloroquine.

Place of the study

Sayed Galal University Hospital.

Period of the study

2 years at Sayed Galal University Hospital from January 2020 to December 2021.

Population

The study participants are made up of women who are trying to conceive and have suffered at least 3 consecutive losses during the first trimester of their pregnancy (normal parental karyotypes and no abnormalities in the uterine cavity that could explain the miscarriages). All obstetricians as well as internal medicine practitioners operating in the catchment region of every participating center were notified about the hydroxychloroquine trial via medical meetings, emails, and letters. All of them are urged to refer possibly eligible women to the study's screening unit. Every center ensures patient recruitment by utilizing existing settings like specialist RM consults and other OBS/GYN patient treatment units.  Additionally, as part of this recruitment technique, posters are placed in consultation waiting rooms to reach out to additional patients.

Intervention

The medical examiner evaluates the inclusion and exclusion criteria of nearly 1,000 eligible women during the inclusion visit. 300 women only were finally concluded and divided into 2 groups by randomization system (envelops) and listed by serial numders and telephone numbers on computer data

Group A: 150 women were given Hydroxycloroquine 400mg daily and up to 8 months.

Group B: 150 women were given placebo.

All women informed to communicate with us by telephone number for follow up or if get pregnant within 8 months. Follow up persisted till the end of pregnancy by their serial number.

Inclusion criteria

Females between the ages of 18 and 37 years old.

Women who are trying to conceive a child.

Women who have had at least 3 prior consecutive losses of unclear aetiology in the 1st trimester of gestation, described as

Parental karyotypes that are normal.

There are no uterine cavity abnormalities that could explain the RM (hysterography, hysteroscopy, or ultrasound scan).

No prior thrombotic or obstetrical incident described in APS, with the exception of RM in the first trimester if APL antibodies are persistently positive according to Myakis' biological criteria.

Women who gave written consent.

Exclusion criteria

An ongoing pregnancy.

Since the previous miscarriage, a normal pregnancy (living and viable delivery) has occurred.

A uterine cavity anomaly, which could explain RM during the first trimester.

APS defined as both

Persistently positive APL antibodies: titers of lupus anticoagulant and/or APL (anticardiolipin or anti-beta2 GPI, IgG or IgM) greater than the 99th percentile or greater than 40 with a 12-week interval between two positive findings (persistent antibodies).

A particular clinical setting of APS based on the Myakis criteria (thrombotic or obstetrical, excluding RM in the 1st trimester of gestation).

Recognized uncommon lactose metabolic disorder (excipient) or known HCQ contraindications (hypersensitivity to chloroquine or HCQ, retinopathy, G6PD deficient, severe intermittent porphyria, chronic hepatic or renal failure, widespread cutaneous psoriasis not managed by local therapy, significant chronic digestive or hematological illness).

A history of epilepsy or psychotic diseases in the past.

Impossible to follow-up.

​Sampling ​​Method:​​​​​​ Convenient sample.

Sample​​ Size:​​​​​​ 300 women with unexplained recurrent miscarriage.

This number of cases was adopted by using Medcalc 19 program by setting alpha error of 5%, 95% confidence level and 80% power sample.

Sample size justification:

The sample size for this study was calculated from the prevalence of the live birth rate in cases taking HCQ (67%), according to a prior study by Sciascia et al., 2016. Equations are described in Plantone and Koudriavtseva (2018).

The sample size is computed according to the following formula:

Z = 1.96 (The critical value that separates the Z distribution's central 95% from the tail's 5%).

P: prevalence of live birth rate in cases taking HCQ, according to prior study of Sciascia et al., 2016. (=67%)

E: The desired margin of error(alpha error =0.05)

n= 0.67 x 0.33x 1536.64 = 339.75

Sample size before correction is 340cases.

Correction of sample size

Correction of this size for finite population by the following formula:

Sample size for finite population = n / [1 + {(n − 1)/Pop}]

Where,

n:calculated sample size for infinte population (=340)

Pop: finite population, considering it nearly 2600 cases according to registered data of average yearly flow of the outpatient clinic.

Sample size = 340 / 1+ {339/2600}

= 340/1.13

= 300.88

Statistical Analysis

The Statistical Package for Social Sciences (SPSS) version 21 was used to sort and analyze the data.

 Numbers and percentages were used to describe qualitative data in this research.

To present quantitative data, the mean, standard deviation (SD), and range have been used.

Categorical variables were analyzed and compared using the Chi-square test.

Multivariate analysis (Binary Logistic regression) was employed for multiple risk factor analysis.

The significant level has been set at P<0.05.

RESULTS

This study is a randomized, placebo-controlled, double-blind study. It included 300 women who were trying to get pregnant and had suffered at least three miscarriages in the first trimester.

The patients in the study have been split into two groups:

Group I: 150 patients who received hydroxychloroquine.

Group II: 150 controls who received placebo only did not receive hydroxychloroquine.

Table 1: shows that the average age of the study participants was 20.09±5.20 years.

Table 2: shows the obstetric history of the study patients. Regarding gravidity, 28.0% of the patients were gravida five, 17.3% were gravida six, and 18.7% were gravida seven. Regarding parity, 45.3% were para one, and 36.0% were para zero. As for number of miscarriages, 32.0%, 26.7%, and 21.3% had four, three, and five miscarriages, respectively.

Table 3: shows that 24.7% of the patients had positive APS antibodies and 100% didn’t have anatomical insult that may explain the recurrent miscarriages.

Table 4: shows that 21.3% of the control patients were on clexane therapy during the study.

Table 5: shows that 30.0% of all study patients completed their pregnancy while 70.0% did not complete it.

Comparison of the cases and controls:

Table 6: demonstrates that the average age was 30.64±4.47 years for cases and 27.51±5.39 years for controls. At a p value of 0.001, the difference between them was statistically significant.

Table 7: shows that both study groups had equal percentages regarding gravidity and parity. At a p value of 0.985, the association between the number of miscarriages was statistically insignificant.

Fig. 1: Number of miscarriages among study groups

Table 8: shows that 28.0% of cases and 21.3% of controls had APS antibodies, and the association between them was statistically insignificant at p values of 0.180.

Regarding outcome, 18.0% of cases completed their pregnancy while 82.0% did not complete it. For controls, 20.0% of them completed their pregnancy while 80.0% did not complete it. The association between them was not statistically significant at p values of 0.659.

Fig. 2: APS antibodies among study groups

Fig. 3: Percentages of pregnancy completion among study groups