TIMING OF INITIATION OF LOW-MOLECULAR-WEIGHT HEPARIN (LMWH) AND ASPIRIN ADMINISTRATION ON THE PREGNANCY OUTCOMES IN WOMEN WITH ANTIPHOSPHOLIPID SYNDROME (APS) AND RECURRENT ABORTION

INTRODUCTION

Recurrent pregnancy loss (RPL) is characterized as two or more unsuccessful pregnancies in a row, causing emotional burden to women and their families. Approximately 5% of women lose two or more pregnancies in a row, and 1% of women lose three or more pregnancies in a row. Further examination is indicated after two consecutive clinical pregnancy failures; however, a clearly characterized cause is not established in 50% of RPL patients. RPL is caused by a combination of genetic, chromosomal, immunological, endocrinologic, anatomical, and structural factors.¹

Obstetrical antiphospholipid syndrome (APS) is an autoimmune illness that impairs pregnancy and leads to repeated abortions, intrauterine growth restriction

(IUGR), stillbirth, or extreme preeclampsia with or without artery and/or venous clotting. Antiphospholipid antibodies were discovered in 1%–5% of the population as usual variations, but their incidence soared to 15% in women who had repeated abortions and 40percent in women having systemic lupus erythematosus (SLE).²

Thrombosis in the vascular beds, whether arterial, venous, or placental, was long assumed to be the cause of APS, leading in placental inadequacy, ³ but this concept was called into question in obstetrical APS, especially in the lack of clinical findings of vascular thrombosis or infarction in the placental tissues of certain instances, allowing obstetrical APS to be classified as an autoimmune disease. ⁴

Endothelial cells are activated when APS auto-antibodies attach to negatively charged macromolecules in cell membranes, like phospholipids. Defective placentation or complement activation may set off a chain of events, each of which creates pro-inflammatory molecules that injure the developing of the placenta or the baby. ⁴

In women with APS, the efficacy of anticoagulation therapy with LMWH and/or aspirin is still debated. a protective effect of aspirin in those at increased incidence of heart disease or intrauterine growth ⁽⁵⁾. Furthermore, for women with either main or secondary APS, therapy with LMWH in addition to aspirin was recommended. ^6-8

At the cellular level, LMWH is thought to reduce trophoblast apoptosis and increase the synthesis of proteases participating in trophoblast invasion of the maternal endometrium.^{9, 10}

In vitro investigations have demonstrated that LMWH affects angiogenesis in the placental villi and has an impact on soluble vascular endothelial growth factor dysregulation^11. Heparin also has an inhibitory impact on complement activation, which may minimize the incidence of pregnancy problems. ¹². LMWH, on the other hand, may have a negative impact by boosting soluble FMS-like tyrosine-kinase-1 , which is linked to HD ¹³. Aspirin is believed to enhance trophoblastic invasion of the uterine spiral arteries by inhibiting thrombocyte aggregation and/or acting as an anti-inflammatory. This might help the placenta form and operate more effectively. ¹

Several studies have looked at the effects of aspirin and/or LMWH on pregnancy end results; for example, one study found that the prenatal and maternal results of the total cohort revealed that anticoagulant treatment subgroups had greater maternal and perinatal problems than those who did not. ^14.

Another recent research showed that the early initiation group (aspirin and LMWH) had a considerably greater incidence of continued pregnancy than the later initiation group. However, the rates of pregnancy loss, premature labor before 34 weeks of pregnancy, and IUGR were identical in both groups, as was the live birth rate.²

Numerous studies indicated that pre-conception enoxaparin treatment resulted in a considerable enhancement in the clinical gestation rate and a decrease in the frequency of repeated miscarriage as compared to individuals received placebo at the preconception phase.^{15, 16}

Because the effects of aspirin and LMWH, as well as the time of beginning, are debatable, we conducted our research.

The purpose of this research was to see how varied timings for starting low-molecular-weight heparin (LMWH) and aspirin therapy affected pregnancy end results in women with antiphospholipid syndrome (APS) and recurrent abortion.

PATIENTS AND METHODS

Study type: randomized clinical trial study

Study site: the participants was collected from outpatient clinic of gynecological and obstetric department of Sayed Galal and Etay Elbarod hospitals

Study population:

The participants was collected from outpatient clinic till fulfill sample size as they seek to be pregnant in next months, according to following criteria.

Inclusion criteria:

A history of 3 successive early abortions (before the 10th week of pregnancy), and/or one morphologically normal fetus fatality from an unknown cause at or beyond the 10th week of pregnancy, and/or one preterm born of a morphologically normal neonate before 34 weeks of gestation due to serious preeclampsia, eclampsia, or placental inadequacies;

Anticardiolipin antibodies (immunoglobulin m and/or immunoglobulin g) in high or medium titer (>40 mL/L or >99 %) in plasma or serum on ≥two separate occasions at a minimum of 12 weeks apart, and/or lupus anticoagulant in plasma on≥ two separate occasions at a minimum of 12 weeks apart. The occurrence of lupus anticoagulant was determined using the dilute Russell viper venom time and the titer of anticardiolipin antibodies was assessed using a conventional ELISA.

Exclusion criteria:

Under the age of 20 or  above the age of 38.

Body weight in the first trimester of pregnancy: 50 kg or >90 kg

SLE

Thromboembolic diseases that are active

Previous thromboembolic disease history

Coexisting Hereditary thrombophilia

Pregnancy loss due to genetic or hormonal factors

Uterine aberration or malformation, as uterine septum, bicornuate uterus, or unicornuate uterus that might cause improper placentation, early gestation loss, or premature delivery.

Uterine myoma, which might cause complications during pregnancy.

Cervical insufficiency.

A medical problem that has an impact on the pregnancy's outcome

Known LMWH or aspirin allergic or contraindication.

All eligible individuals were split into two groups at random. They asked to be notified once a positive pregnancy test was confirmed.

Study Procedures

Taking all participants demographic data, medical history and gynecological and obstetric history

A quantitative measurement of serum beta component of human chorionic gonadotropin was used to confirm biochemical gestation.

All participating women in the investigation was divided into two groups;

Group I (50 cases): Early LMWH initiation group; aspirin (81 mg/day) and LMWH (enoxaparin; Clexane®; Sanofi-Aventis, Paris, France) were administered subcutaneously at a dosage of 40 mg/day until the end of the first trimester. The aspirin and LMWH was started before being pregnant by 2 to 3 months.

Group II (50 cases): later LMWH initiation group (start aspirin and LMWH in same doses in group A, but started once pregnancy test be positive).

Two weeks after a positive pregnancy test, all participants had a transvaginal sonography (TVS) scan to confirm clinical intrauterine embryo, which was known as the availability of at least one intrauterine gestational sac with fetal pole and cardiac function on a TVS scan at 6–7 weeks of pregnancy.

Every 2–3 weeks, all women got regular prenatal care and supplements, as well as follow-up. Women were asked at each follow-up appointment to ascertain whether they had had vaginal bleeding or any other adverse events.

At each follow-up appointment, ultrasonography was used to verify fetus viability and evaluate fetus development and well-being.

To establish compliance with LMWH for each individual, the numbers of ampoules really used was divided by the total number of ampoules that should have been used.

Follow up visits was continued till the last of 1st trimester after stabilization of heart pulsation.

Statistical analysis:

The information was gathered and input into a computer. The Statistical Package for Social Sciences (SPSS/version 22) software was employed to conduct statistical analysis. To compare two groups, the mathematical mean, standard deviation, and chai square test were employed for classified parameters, while the t-test was utilized for numerical data. The relevance threshold was set at> 0.05.

RESULTS

The basic demographic and clinical data showed that the mean age of group I was 26.2±2.56 years, and in group II was 27.12±2.36 years, the BMI in group I was 28.22±2.27 and in group II was 27.22±2.56, In terms of age and BMI, there was no substantial distinction between the tested groups. Regarding maternal history, parity in group I ranged from 0-7 with mean value 3.18±2.057 and in group II ranged from 0-7 with median value 1.96±1.85. There was statistical substantial distinction between the two studied groups regarding parity (p < 0.05) while there was no statistical substantial distinction regarding gravidity and nulliparous (p > 0.05).

The comparison between the two groups regarding miscarriages, showed that the previous 1st trimester miscarriages in group I ranged from 2-4 with median value 3.46±0.613 and in group II ranged from 2-7 with mean value 4.52±1.40. There was statistical substantial distinction between the two groups according to Previous 1st trimester miscarriages (p < 0.05) while there was no statistical substantial distinction regarding women with previous second trimester miscarriages, preterm labor and previous fetal loss (p > 0.05)

Table (1) shows that gestational age at start of treatment in group I ranged from 4-6 with mean value 4.9±0.814 and in group II ranged from 5-7 with mean value 5.92±0.85. There was statistical substantial distinction between the two studied groups according gestational age at start of treatment (p < 0.05). Also, this table shows that there was no statistical substantial distinction between the two investigated groups regarding bleeding (p > 0.05). Also it was found that there was no substantial distinction between the two studied groups regarding pregnancy (p > 0.05).

Table (1) shows also that there was no statistical substantial distinction between the two investigated groups regarding miscarriage (p > 0.05). There was a statistical substantial distinction between the two groups according fetal loss while live birth show insignificants difference (p > 0.05).

Table 1: Comparing the two investigated groups in accordance of gestational age at start of therapy (weeks) and incidence of bleeding, pregnancy and miscarriage and final outcome.

Table 2: Comparing the two investigated groups in basis of gestational age at delivery and incidence of complication.

Table 3: Comparing the two investigated groups in basis of neonatal data.

Table (3) shows that the birth weight in the two groups showed insignificant difference between the two groups. Only one case had congenital malformation in group II.  Neonatal RDs in group I was 4 (12.5%) while in group II was 9(32.1%) respectively.  Admission to NICU in group I was 5 cases (15.6%) while in group II was 15 (53.6%), there was a substantial increase in NICU in group II more than group I.  Mechanical ventilation in group I was none while in group II was 10 cases (35.7%), there was a highly substantial increase in mechanical ventilation neonate in group II more than group I. Early neonatal death in group I was none while in group II was 5 (17.9%), there was a substantial increase in early death neonatal in group II more than group I.