A clinical comparative study was performed to investigate whether treatment with LMWH versus ALD results in increased live birth rate in women with history of RPL and APS, in Maternity Teaching Hospital, Erbil city, Kurdistan region, North of Iraq from 15th of September 2007 to the 1st of August 2010.
Women considered participants in this trial fulfilled the following criteria: aged 18–42 years at the time of interview; a history of ≥2 unexplained consecutive pregnancy losses before 20 weeks gestation; persistent presence of anticardiolipin antibodies and or Lupus anticoagulant in two occasions 8 weeks apart.
The included Systemic Lupus Erythematosus, known peptic ulcer disease, sensitivity to Aspirin or Heparin depending on patients’ history report, previous venous thromboembolic disease requiring ongoing anticoagulant therapy and failure to consent to participate.
Cases with SLE were excluded from the study because pregnant mothers with SLE should remain under medical care until delivery, they have an extra increased risk for pregnancy complications, usually they are on multiple medications depending on the system involved by the disease (patients require warfarn or cyclophosphamide therapy should not get pregnant), they may be on Non-steroidal antiinflammatory drugs, Anti-malarial drugs, glucocorticoids, or immunosuppressive drugs like methotrexate. SLE may flare up during pregnancy and has its own complications regarding the fetus and newborn babies.
Other causes for RM were regarded as exclusion criteria. Hormonal assay was carried out to exclude polycystic ovarian syndrome and thyroid dysfunction, hysterosalpingogram/Ultrasound was done to exclude anatomical causes for RM, cervical cultures for mycoplasma and urea plasma to exclude bacterial vaginosis infection. To exclude frank diabetes as a risk factor for RM, glucose tolerance test was done for suspicious cases, karyotype analysis for both parents was done for both parents depending on a local laboratory in the city which was available recently in our city, and other cases we depend on the results done abroad by the patients themselves.
Only one case with type 1 diabetes mellitus was not excluded from the study being a case with strictly controlled blood sugar with a high level of anticardiolipin antibody titer in two occasions.
To confirm the diagnosis of APS in the participant, positive serology was defined as at least one of the following tests to be positive in two occasions:
Anticardiolipin antibodies in medium to high titer levels were identified using a standardized enzyme-linked immunosorbent assay (ELISA) IgG >15 IgG phospholipids units (GPL) or IgM >25 IgM phospholipids units (MPL).
Lupus anticoagulant measured by prolonged phospholipid-dependent coagulation (aPTT, Kaolin clotting time, dilute Russell viper venom test, dilute PT), the prolonged coagulation time was failed to be corrected by a mix with platelet poor plasma and the prolongation of coagulation time was also corrected with excess phospholipids .
Anti-β2 glycoprotein 1 IgG and/or IgM isotype in serum or plasma is also regarded as one of the criteria for diagnosis of APS, it was not done in the current trial because the method was not available in our city and to diagnose APS at least one of the clinical criteria and only one of the laboratory criteria should be met.
The sample size consists of 146 ladies presented to the maternity teaching hospital, with RM, clinical and laboratory evaluation done for all the cases; all known causes for RM were excluded except for APS and they were asked to attained the hospital as soon as they miss a period of their menstrual cycle. Both groups were advised to use prenatal folic acid, the LDA group women were given the drug assuming that the pregnancy occurs if she was not using any contraception. The study time was about 3 years and most of patients got pregnant within this period of time except five cases who were referred to a special infertility unit in the maternity teaching hospital. Sixty-one cases were randomly assigned to receive Low Dose Aspirin (LDA) before pregnancy was diagnosed at suspected month and continued throughout pregnancy till 36 weeks gestation, the other group of 80 cases were assigned to receive LMWH (Bemiparin) with the diagnosis of pregnancy. Pregnancy in both groups was confirmed by either two rising quantitative beta human chorionic gonadotropin (βhCG) hormone 48 h apart or by ultrasound confirming fetal heart activity, randomization to the treatment group done using alternative criteria, the 1st case attained the hospital complaining from RM and proved to have APS, was randomized to LDA group, the second case attained the hospital and full filled the inclusion criteria; LMWH was prescribed to her, sometimes two cases of Heparin followed one case of LDA. All the cases received the drug randomly.
All women in the two treatment groups were evaluated every 6 weeks during their pregnancy. The assessment included detailed history, obstetrical and general examination, a specially designed questionnaire to record the obstetrical data at each visit, fetal development and well-being as well as maternal complications. Delivery information was obtained from the obstetrician on call at the time of labor for cases which delivered spontaneously vaginally, and cases which delivered abdominally.
Side effects of both medications were asked for by each woman and recorded in the same questionnaire.
The trial drugs
Bemiparin sodium (Hibor; Laboratories Rovi Pharmaceuticals, a Spanish integrated and specialist company) is a LMWH with a lower mean molecular weight (3,600 D) and a higher anti—FXa/F11a ratio (8:1) than other LMWHs. Bemiparin 2,500 IU anti Xa/0.2 ml solution for injection in pre-filled syringes was provided for each patient in the heparin group; all patients were taught to self inject the medication subcutaneously once daily in the anterior abdominal wall or anterior aspect of upper thigh until 36 weeks of gestation.
ASPIRIN protect 100, BAYAR Company, (active ingredient: Acetyl Salicylic Acid 100 mg coated tablets) was prescribed for the LDA group before pregnancy and continued till 36 weeks gestation.
Side effects of both treatment groups like gastritis, vaginal bleeding, echymosis, and abruption placentae were recorded.
The study was approved by the scientific committee in the Maternity teaching hospital and the patients gave their written informed consent after full explanation of the aims of the study and confidentiality was approved.
Statistical analysis was conducted using the Statistical Package for Social Sciences (SPSS version 18). Data were described using mean, standard deviation for contentious variables and proportions for categorical variables. Independent t test was used to analyze the difference between 2 meanvalues. Levene’s test was used for equality of variance. Chi-square test was used to analyze the difference between proportions. A P < 0.05 was considered statistically significant.