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ORIGINAL ARTICLE
Year : 2022  |  Volume : 35  |  Issue : 2  |  Page : 734-740

Prophylactic measure in women with early recurrent pregnancy loss, polycystic ovary syndrome, and hyperhomocysteinemia


1 Department of Obstetrics and Gynecology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Obstetrics and Gynecology, Faculty of Medicine (for Girls), Al Azhar University, Cairo, Egypt

Date of Submission28-Aug-2021
Date of Decision20-Oct-2021
Date of Acceptance24-Oct-2021
Date of Web Publication27-Jul-2022

Correspondence Address:
Samia M Ghonim
Kotour, ElGharbiya
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_147_21

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  Abstract 


Objective
This work aims to evaluate prophylactic measures against early recurrent pregnancy loss (RPL) in women with polycystic ovary syndrome (PCOS) and hyperhomocysteinemia.
Background
PCOS is the most common endocrine disorder in females; hyperhomocysteinemia is frequently associated with PCO. Mild-to-moderate hyperhomocysteinemia increases the risk of RPL through augmentation of hypercoagulable state of pregnancy and thrombosis in maternal and fetal circulation.
Patients and methods
The study was a randomized prospective comparative study. Patients in this study were 60 patients aged between 20 and 35 years with PCOS that was diagnosed according to the Rotterdam criteria if at least two of the following criteria is present: oligoamenorrhea/amenorrhea, clinical or biochemical hyperandrogenism and PCO on ultrasonography, hyperhomocysteinemia, and a history of early recurrent abortion. Patients were randomly classified into three groups by simple randomization (number generation by computer): group 1 included 20 patients with PCOS, hyperhomocysteinemia, and a history of early recurrent abortion, treated with folic acid 5 mg/day and low-dose aspirin (LDA) 81 mg/day until 20 weeks of pregnancy. Group 2 included 20 patients with PCOS, hyperhomocysteinemia, and a history of early recurrent abortion, treated with folic acid 5 mg/day and low-molecular weight heparin (LMWH) 40 mg/day until 20 weeks of pregnancy and group 3 included 20 patients with PCOS, hyperhomocysteinemia, and a history of early recurrent abortion treated with LDA 81 mg/day, LMWH 40 mg/day, and folic acid 5 mg/day until 20 weeks of pregnancy.
Results
RPL is common in women with PCOS and hyperhomocysteinemia. It was found that combined treatment with folic acid' aspirin, and LMWH in women with PCO and hyperhomocysteinemia improved successful pregnancy rates.
Conclusion
Administration of folic acid and LMWH or folic acid, LMWH, and LDA decreases the rate of early RPL in women with PCO and hyperhomocysteinemia better than folic acid and LDA alone.

Keywords: aspirin, folic acid, heparin, hyperhomocysteinemia, pregnancy


How to cite this article:
Gad MS, Ghonim SM, Shahin AE. Prophylactic measure in women with early recurrent pregnancy loss, polycystic ovary syndrome, and hyperhomocysteinemia. Menoufia Med J 2022;35:734-40

How to cite this URL:
Gad MS, Ghonim SM, Shahin AE. Prophylactic measure in women with early recurrent pregnancy loss, polycystic ovary syndrome, and hyperhomocysteinemia. Menoufia Med J [serial online] 2022 [cited 2024 Mar 29];35:734-40. Available from: http://www.mmj.eg.net/text.asp?2022/35/2/734/352121




  Introduction Top


Polycystic ovary syndrome (PCOS) is the most common endocrine disturbance affecting women and comprises a heterogeneous collection of signs and symptoms that gather together to form a spectrum of disorders with mild presentation in some women and severe disturbance of reproductive, endocrine, and metabolic function in others[1].

Of the many etiologies, PCOS is a common endocrine disorder responsible for recurrent pregnancy loss (RPL). Patients with PCOS experience a 30–50% increased rate of early miscarriages[2].

RPL is found in 1–5% of couples desiring pregnancy. The exact mechanisms that may cause RPL in PCOS patients are obscure. Several etiologies have been proposed, related to the pathophysiology, endocrinology, and metabolic disturbances in PCOS. Among these are obesity, insulin resistance (IR) or hyperinsulinemia, thrombophilia-associated disorders, elevated luteinizing hormone, and hyperandrogenism[3].

Elevated plasma homocysteine levels are associated with an increased risk of atherosclerosis and thrombosis, as well as a variety of other pathologies such as birth defects, osteoporosis, diabetes, and renal disease. The prognostic ability of plasma homocysteine level as a hazard factor for atherothrombotic disorders raised the appealing hypothesis that reduction of homocysteine levels by vitamin supplementation might result in a commensurate reduction and risk of atherothrombotic events[4].

Hyperhomocysteinemia could be due to low dietary folate intake or owing to defects in genes involved in folate metabolism such as methylenetetrahydrofolate reductase located in the short arm of chromosome 1 (1p36.3). This enzyme catalyzes the conversion of 5, 10-methylene tetrahydrofolate into 5-methyltetrahydrofolate, which provides the single carbon for homocysteine in methionine synthesis[5].

Hyperhomocysteinemia is a common finding in women with PCOS and was found to be associated with both RPL and PCOS[6].

It was shown that combined treatment with aspirin and low-molecular weight heparin (LMWH) in women with hyperhomocysteinemia improved successful pregnancy rates[7].

This work aimed to evaluate prophylactic measures against early RPL in women with PCOS and hyperhomocysteinemia by the administration of folic acid 5 mg/day, low-dose aspirin (LDA) 81 mg/day, LMWH 40 mg/day as a single agent or in combination before 20 weeks of gestation.


  Patients and methods Top


The study was a randomized, prospective comparative study. After approval of the Local Ethics Committee and with written informed consent, the present study was carried out in Shebin El Kom University Hospital and Basin Central Hospital on 60 patients aged between 20 and 35 years with PCOS that was diagnosed according to the Rotterdam criteria if at least two of the following criteria will be present: (oligomenorrhea/amenorrhea, clinical or biochemical hyperandrogenism and PCO on ultrasonography, hyperhomocysteinemia, and a history of early recurrent abortion. The sample size and the number of the study groups were categorized after the recommendations of the Biostatistics Department, Faculty of Medicine, Menoufia University. The sample size was calculated using the following formula:

The formula used was[8],[9]:



The input items to the sample size equation are as follows:

  1. Null hypothesis (there is no difference between the studied interventions).
  2. The proportion between subgroups of the study is 1: 1: 1 (p).
  3. Attrition rate assumed 0%=0 participants.
  4. p1 = proportion of abortion in the study group = 5%.
  5. p2 = proportion of abortion in the control group = 42.5%.
  6. Smallest harmful ratio = 1.10.
  7. Smallest beneficial ratio = 2.00.
  8. 95% confidence interval (CI) 1.46–2.07.
  9. Between-subject SD of count in unexposed, B or control group = 5.
  10. Prevalence of exposure, or proportion in A/experimental group (%)=14.
  11. Type I error (alpha error)=0.5.
  12. Type II error (beta error)=25.
  13. Total number of participants needed = 60.
  14. Maximum number of subgroups = 3.


Exclusion criteria: women with any systemic disease, women who had other causes of RPL, including chromosomal, uterine abnormalities, antiphospholipid syndrome, inflammatory, autoimmune, or any other condition affecting homeostasis that rolled out by either physical examination or patient history and patients with prolactinoma, congenital adrenal hyperplasia, Cushing syndrome, thyroid disorders' virilizing ovarian or adrenal tumors that was rolled out by measurement of serum prolactin level' 17 hydroxyprogesterone' cortisol level' thyroid-stimulating hormone' testosterone, and anticardiolipin. Patients were randomly classified into three groups by simple randomization (number generation by computer): group 1 included 20 patients with PCOS, hyperhomocysteinemia and a history of early recurrent abortion, treated with folic acid 5 mg/day and LDA 81 mg/day until 20 weeks of pregnancy, group 2 included 20 patients with PCOS, hyperhomocysteinemia, and a history of early recurrent abortion, treated with folic acid 5 mg/day and LMWH 40 mg/day until 20 weeks of pregnancy and group 3 included 20 patients with PCOS, hyperhomocysteinemia, and a history of early recurrent abortion treated with LDA 81 mg/day, LMWH 40 mg/day, and folic acid 5 mg/day until 20 weeks of pregnancy. Patients were selected from the outpatient clinics of Obstetrics and Gynecology at the Faculty of Medicine, Menofia University and Basin Central Hospital for 1 year starting from January 2020 to the end of December 2020.

Written informed consent was obtained from all study participants before taking any data or doing any investigations with a full explanation of the aim, risks, and benefits of this research. It was approved by the Local Ethics Research Committee in Menofia Faculty of Medicine and consent was obtained from patients who participated in this study before sample collection.

All patients included in this study were subjected to full history taking: personal history, present history, husband history, past history including medical diseases, abdominal surgeries, and drug therapy or allergy, menstrual history, general and local clinical examination, ultrasound, and measurement of serum homocysteine by enzyme-linked immunosorbent assay, follicular-stimulating hormone, luteinizing hormone, testosterone–prolactin level, thyroid-stimulating hormone and cortisol levels, 17 hydroxyprogesterone, anticardiolipin level using Vidas and Cobas E 411. Finally, folic acid 5 mg/day, LDA 81 mg/day, and LMWH 40 mg/day were used to evaluate the effect in prophylaxis against early RPL in women with PCOS and hyperhomocysteinemia, and follow-up was done by ANC every 2 weeks. We used transabdominal and transvaginal probe of z6 at the Obstetrics and Gynaecology Department of Basin Central Hospital and chison at Obstetrics and Gynecology clinics of Menoufia University Hospitals.

Statistical analysis

Data were analyzed using IBM SPSS software package, version 20 (IBM Corp., Armonk, New York, USA). Qualitative data were described using numbers and percentages. The Kolmogorov–Smirnov test was used to verify the normality of distribution. Quantitative data were described using range (minimum and maximum), mean, and SD. A χ2 test was used to compare the three groups according to categorical variables. The significance of the obtained results (P value) was judged at the 0.05% level.


  Results Top


In this study, there were no statistically significant differences between the three studied groups regarding maternal age, gravidity' parity' previous abortion, and gestational age (P>0.05) [Table 1],[Table 2],[Table 3].
Table 1: Comparison between the three studied groups according to age

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Table 2: Comparison between the three studied groups according to obstetrics data

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Table 3: Comparison between the three studied groups according to gestational age

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In this study, the mean serum homocysteine was 20.36 ± 3.48 in group 1, range 15.20–26.0 and 20.31 ± 3.34 in group 2, range 15.40–25.80 and 20.23 ± 2.82 in group 3, range 15.70–25.0, with no significant difference between the studied three groups (P = 0.992) [Table 4].
Table 4: Comparison between the three studied groups according to serum homocysteine

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In group 1, 10 (50%) cases had an abortion and 10 cases completed 20 weeks of pregnancy after treatment with LDA 81 mg/day + folic acid 5 mg/day. In group 2: four (20%) cases had an abortion and 16 (80%) cases completed 20 weeks of pregnancy after treatment with LMWH 40 mg/day + folic acid 5 mg/day. In group 3, three (15%) cases had an abortion and 17 (85%) cases completed 20 weeks of pregnancy after treatment with LDA 81 mg/day + LMWH 40 mg/day + folic acid 5 mg/day, with significant differences between group 1 and group 2 (P > 0.05), and between group 1 and group 3 (P > 0.05) but with no significant differences between group 2 and group 3 (P < 0.05) [Table 5].
Table 5: Comparison between the three studied groups according to pregnancy loss after treatment

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  Discussion Top


RPL is defined as the loss of two or more consecutive miscarriages before 20 weeks of gestation. The exact prevalence of RPL is difficult to estimate, but most studies report that RPL affects 1–2% of women in their reproductive age[10].

The prevalence of PCO morphology among women with RPL is thought to be as high as 40%, although there are reports about higher prevalence. Using a combination of clinical findings and ultrasound or biochemical features[11].

Recent evidence suggests another metabolic component, hyperhomocysteinemia, to be a frequent associate in those with PCOS. Moreover, mild-to-moderate hyperhomocysteinemia has been suggested as a possible threat to women with habitual abortions or placental abruption[12].

Hyperhomocysteinemia is a common finding in women with PCOS and was found to be associated with both RPL and PCOS. It was shown that combined treatment with aspirin and LMWH in women with hyperhomocysteinemia improved successful pregnancy rates[7].

The management of recurrent miscarriages is an unsolved problem; up to 50% of cases of recurrent losses will not have a clearly defined etiology. The investigations and management of recurrent miscarriages are one of the most debated topics. LDA is an antiplatelet agent that irreversibly inhibits platelet cyclooxygenase and thereby decreases the production of thromboxane A2, a potent vasoconstrictor. Aspirin has been widely used in attempts to treat pregnant women with recurrent miscarriage associated with antiphospholipid antibodies, an acquired thrombophilic defect, and other autoimmune conditions[13].

This study was designed to evaluate prophylactic measures against early RPL in women with PCOS and hyperhomocysteinemia by the administration of folic acid 5 mg/day, LDA 81 mg/day, and LMWH 40 mg/day as a single agent or in combination.

Maternal age and previous miscarriages increase the risk of subsequent miscarriages. In this study, the mean age of group 1 cases was 27.35 ± 3.01, 26.20 ± 3.78 in group 2, and 26.90 ± 3.51 in group 3; it ranged from 21.0 to 34.0 years in the studied cases, with no significant difference between the three studied groups (P = 0.374).

In this study, in group 1 two (10%) cases were gravida 3, nine (45%) were gravida 4, and nine (45%) were gravida 5 and 6; in group 2: three (15%) cases were gravida 3, 10 (50%) were gravida 4, and seven (35%) were gravida 5 and 6; and in group 3: four (20%) cases were gravida 3, eight (40%) were gravida 4, and eight (40%) were gravida 5 and 6, with no significant difference between the three studied groups (P = 0.912).

In this study, in group 1: five (25%) cases were nullipara, 12 (60%) cases were primipara, and three (15%) were multipara; in group 2: eight (40%) cases were nullipara, eight (40%) cases were primipara, and four (20%) were multipara; and in group 3: eight (40%) cases were nullipara, nine (45%) cases were primipara, and three (15%) were multipara, with no significant difference between the three studied groups (P = 0.758).

In this study, in group 1, 10 (50%) cases had abortions twice and 10 (50%) cases had more than or equal to three abortions, the same was in group 2, while 11 (55%) cases in group 3 had abortions twice and nine (45%) cases had more than or equal to three abortions, with no significant difference between the three studied groups (P = 0.935).

In this study, the mean serum homocysteine was 20.36 ± 3.48 in group 1, range 15.20–26.0; 20.31 ± 3.34 in group 2, range 15.40–25.80; and 20.23 ± 2.82 in group 3, range 15.70–25.0, with no significant difference between the three studied groups (P = 0.992). This was in agreement with the Chakraborty et al.[14] study that was conducted to assess the link between elevated levels of homocysteine in PCOS-associated women with RPL in Kolkata, India, which was conducted on 126 PCOS women in whom the fasting levels of homocysteine (mmol/l) was significantly higher (P = 0.0001) in women with PCOS (13.14-65.04 vs. non-PCOS: 8.39-62.22) having a previous history of RPL. The rate of miscarriage in hyperhomocysteinemic cases was significantly higher (P = 0.008) than that of the corresponding normohomocysteinemia segments and a significant correlation was noted between homocysteine levels and a history of prior miscarriage (<2) in women with PCOS (r = 0.343, P = 0.05). This suggests that hyperhomocysteinemia may set the ground behind the risk of RPL irrespective of IR/non-IR patients[14].

In the Mahmoud et al.[15] study that included 120 pregnant women with PCO and history of RPL divided into three groups, the homocysteine level was high in the three groups, the mean serum homocysteine level was 20.28 ± 2.09, 20.08 ± 3.20, and 19.43 ± 2.82 in the three groups respectively, range 15–20, with no significant difference between the three studied groups (P = 0.353), and this was in agreement with this study results.

In Allam et al.[4] study that was carried out on 80 pregnant women in their reproductive period; they were assorted into two groups: group 1 included 40 adult females having a history of repeated pregnancy loss (RPL) with PCOS. Group 2 included 40 adult females having a history of RPL and non-PCOS, serum homocysteine levels ranged between 15–25 and 5–12 Umol/l with a mean of 20.28 ± 2.09 and 8.99 ± 1.76 for group 1 and group 2, respectively. Homocysteine was significantly higher in women with RPL and PCO than in women without PCO but have RPL (P = 0.001).

The Priyanka et al.[16] study that included 142 women with PCOS and 65 healthy non-PCOS controls showed that serum homocysteine levels were significantly higher in PCOS women than controls, and this coincides with this study results.

In agreement with this study, in the Rohin et al.[17] study included 20 PCOS patients with early RPL, the plasma homocysteine levels were 19.10 ± 1.01 in the RPL group and 15.41 ± 1.24 in the control group (P = 0.0001). Paired comparisons revealed that a statistically significant difference was observed in plasma homocysteine levels of women with PCOS having RPL and the control group comprised PCOS women with uneventful pregnancies.

Pratip and Goswami[18] in their study on RPL in PCOS in Kolkata had established an increased incidence of miscarriage in women with hyperhomocysteinemia and IR; however, the cutoff level used for hyperhomocysteinemia was 12 μmol/l.

In this study, in group 1: 10 (50%) cases had an abortion and 10 cases completed 20 weeks of pregnancy after treatment with LDA 81 mg/day + folic acid 5 mg/day. In group 2, four (20%) cases had an abortion and 16 (80%) cases completed 20 weeks of pregnancy after treatment with LMWH 40 mg/day + folic acid 5 mg/day. In group 3, three (15%) cases had an abortion and 17 (85%) cases completed 20 weeks of pregnancy after treatment with LDA 81 mg/day + LMWH 40 mg/day + folic acid 5 mg/day, with significant differences between group 1 and group 2 (P > 0.05) and between group 1 and group 3 (P > 0.05) but no significant differences between group 2 and group 3 (P < 0.05) and this was in agreement with the Chakraborty et al.[14] study, which was a prospective observational study conducted at the Institute of Reproductive Medicine' Kolkata' India. A total of 967 women with a history of two or more consecutive first-trimester abortions were screened and 336 were selected for the study. The selected patients were initially divided based on the presence or absence of PCOS, while subsequent stratification was based on hyperhomocysteinemia, IR, and/or obesity. The overall rate of pregnancy salvage following aspirin therapy was 43.15%, which was mostly represented by normohomocysteinemic women, while the salvage rate was lower in the hyperhomocysteinemia populations irrespective of the presence or absence of PCOS, IR, or obesity. By contrast, aspirin-LMWH-combined therapy could rescue 66.84% of pregnancies in aspirin-failed cases. Logistic regression analyses showed that hyperhomocysteinemia remained a significant factor in predicting salvage rates in the PCOS, IR, and obese subpopulations controlled for other confounding factors. Concerning pregnancy salvage, combined anticoagulant therapy with aspirin and LMWH conferred added benefits to those with hyperhomocysteinemia phenotype. This study also coincided with the Mahmoud et al.[15] study, which is a randomized prospective comparative study that was conducted on 120 patients with the use of clexane or clexane with LDA, which is found to be better than LDA alone (P = 0.006' P = 0.001) to prevent early RPL in patients with PCOS and hyperhomocysteinemia. This study results also agreed with Gris et al.[19]. A total of 160 patients with heterozygous factor V Leiden mutation, prothrombin G20210A mutation, or protein S deficiency were given 5 mg folic acid daily before conception, to be continued during pregnancy, and LDA 100 mg daily or LMWH enoxaparin 40 mg was taken from the 8th week onward. Twenty-three of the 80 patients treated with LDA and 69 of the 80 patients treated with enoxaparin had a healthy live birth [odds ratio (OR), 15.5; 95% CI, 7–34; P < 0.0001]. Enoxaparin was superior to LDA in the maintenance of pregnancy.

This study results also agreed with the Brenner et al.[20] study, which evaluated the efficacy and safety of LMWH enoxaparin in 50 women (mean age, 26 ± 3 years) with RPL (>or = 3 losses in first, >or = 2 losses in the second, and >or = 1 loss in the third trimester), who were found to harbor thrombophilia. Sixty-one subsequent pregnancies were treated with the LMWH enoxaparin throughout gestation until 4 weeks after delivery. Dosage was 40 mg/day in women with solitary defect and 80 mg/day in combined defects. Forty-six (75%) out of 61 gestations treated by enoxaparin resulted in live birth compared with only 38/193 (20%) of the untreated pregnancies in these 50 women before a diagnosis of thrombophilia (P < 0.00001). Enoxaparin is safe and effective in the prevention of pregnancy loss in women with inherited and acquired thrombophilia.

This study also agrees with the Allam et al.[4] study, which a randomized blind comparative study that was carried out on 80 pregnant women in their reproductive period, their age ranged from 20 to 35 years diagnosed as PCO with hyperhomocysteinemia and have a history of RPL. Folic acid was given in an oral daily dose of 5 mg/day to women of group 1 and in a dose of 0.5 mg/day for women of group 2. We found that the effect of folic acid 5 mg/day was significant, while the effect of folic acid 0.5 mg was nonsignificant against the occurrence of early RPL (P < 0.05).

In contrast to this study' Kaandorp et al.[21] report that neither aspirin alone nor combined with LMWH improved the live birth rate as compared with placebo among women with RPL. Live-birth rates were 54.5% in the combination therapy group, 50.8% in the aspirin-only group, and 57.0% in the placebo group.

In contrast to this study, Batta[13] study found that among women with recurrent early miscarriages, there was no significant difference in the live-birth rate between those who took aspirin (251/367; 68.4%) compared with those who did not take aspirin (278/438; 63.5%; OR, 1.24; 95% CI, 0.93–1.67]. This relationship was independent of the number of previous early miscarriages. In contrast, women with a previous late miscarriage who took aspirin had a significantly higher live birth rate (122/189; 64.6%) compared with those who did not take aspirin (30/61; 49.2%: OR, 1.88; 95% CI, 1.04–3.37).


  Conclusion Top


Administration of folic acid and LMWH or folic acid, LMWH and LDA decreases the rate of early RPL in women with PCO and hyperhomocysteinemia better than folic acid and LDA alone.

Recommendations

The study recommends the use of folic acid and LMWH or folic acid, LMWH and LDA as a prophylactic measure of early RPL in women with PCO and hyperhomocysteinemia. Further studies should include more number of women with an early RPL to confirm the results of this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Escobar-Morreale H. Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment. Nat Rev Endocrinol 2018; 14:270.  Back to cited text no. 1
    
2.
Rosati R. Plasma homocysteine levels in polycystic ovarian syndrome with early recurrent pregnancy loss: a case-control study. J Clin Biomed Sci 2015; 5:114–117.  Back to cited text no. 2
    
3.
Sugiura-Ogasawara M. Recurrent pregnancy loss and obesity. Best Pract Res Clin Obstet Gynaecol 2015; 29:489–497.  Back to cited text no. 3
    
4.
Allam IA, Dawood AS, El-Hawary TM, ELGharib MN. The effect of folic acid in women with recurrent pregnancy loss, polycystic ovary syndrome and hyperhomocysteinemia. MOJ Women's Health 2018; 7:109–112.  Back to cited text no. 4
    
5.
Wu X, Lanjun Z, Hui Z, Dajian H. Association between the MTHFR C677T polymorphism and recurrent pregnancy loss: a meta-analysis. Genet Test Mol Biomarkers 2012; 16:806–811.  Back to cited text no. 5
    
6.
Kazerooni T, Ghaffarpasand F, Asadi N, Dehkhoda Z, Dehghankhalili M, Kazerooni Y. Correlation between thrombophilia and recurrent pregnancy loss in patients with polycystic ovary syndrome: a comparative study. J Chin Med Assoc 2013; 76:282–288.  Back to cited text no. 6
    
7.
Philippe M, Rosalie C, Emmanuelle L, Segolene L, Carole A, Henri C, et al. Comparison of two preventive treatments for patients with recurrent miscarriages carrying a C677T methylenetetrahydrofolate reductase mutation: 5-year experience. J Int Med Res 2017; 45:1720–1730.  Back to cited text no. 7
    
8.
Faul F, Erdfelder E, Buchner A, Lang AG. Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses. Behav Res Methods 2009; 41:1149–1160.  Back to cited text no. 8
    
9.
Smith PG, Day NE. Matching and confounding in the design and analysis of epidemiological case-control studies. Bithell JF, Coppi R, editors. Perspectives in medical statistics. London: Academic Press; 1987. pp. 39–64.  Back to cited text no. 9
    
10.
ESHRE Guideline Group on RPL, Bender Atik R, Christiansen OB, Elson J, Kolte AM, Lewis S, Goddijn M. ESHRE guideline: recurrent pregnancy loss. Human Reprod Open 2018; 2018:hoy004.  Back to cited text no. 10
    
11.
Cocksedge K, Saravelos S, Metwally M. How common is polycystic ovary syndrome in recurrent miscarriage? Reprod Biomed Online 2009; 19:572–576.  Back to cited text no. 11
    
12.
Pacchiarotti A, Mohamed M, Micara G, Linari A, Tranquilli D. The possible role of hyperhomocysteinemia on IVF outcome. J Assist Reprod Genet 2007; 24:459–462.  Back to cited text no. 12
    
13.
Batta A. Aspirin can prevent miscarriages. Int J Curr Res Med Sci 2017; 3:15–20.  Back to cited text no. 13
    
14.
Chakraborty P, Goswami SK, Rajani S, Sharma S, Kabir S. Recurrent pregnancy loss in polycystic ovary syndrome: role of hyperhomocysteinemia and insulin resistance. PLoS ONE 2013; 8:644–646.  Back to cited text no. 14
    
15.
Mahmoud F, Mahdia A, Tarek M, EL-Hawary A, Shahnaz H, EL-Shorbagy A, et al. Prophylactic measures in early recurrent pregnancy loss in women with polycystic ovary syndrome and hyperhomocysteinemia. Med J Cairo Univ 2019; 87:195–199.  Back to cited text no. 15
    
16.
Priyanka M, Vijayabhaskar M, Sharma S., Praveen K. Status of homocysteine in polycystic ovary syndrome (PCOS). J Clin Diagn Res 2014; 8:31–33.  Back to cited text no. 16
    
17.
Rohin M, Frsha N, Prathyusha A, Bhavana N, Nusrath F. Plasma homocysteine levels in polycystic ovarian syndrome with early recurrent pregnancy loss: a case-control study. J Clin Biomed Sci 2015; 5:114–117.  Back to cited text no. 17
    
18.
Pratip C, Goswami S. Recurrent pregnancy loss in polycystic ovary syndrome: role of hyperhomocysteinemia and insulin resistance. PLoS One 2013; 8:5.  Back to cited text no. 18
    
19.
Gris J, Mercier E, Quéré I, Lavigne-Lissalde G, Cotchery-Nouvellon E, Hoffert M, et al. Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder. Blood 2004; 103:3695–3699.  Back to cited text no. 19
    
20.
Brenner B, Hoffman R, Blumenfeld Z, Weiner Z, Younis JS. The gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin. Thromb Haemost 2000; 83:693–697.  Back to cited text no. 20
    
21.
Kaandorp S, Goddijn M, Post JAM, Hutten BA, Verhoeve H. Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. N Engl J Med 2010; 362:1586–1596.  Back to cited text no. 21
    



 
 
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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