The obstetric outcome following treatment in a cohort of patients with antiphospholipid antibody syndrome in a tertiary care centerV Dadhwal, AK Sharma, D Deka, B Gupta, S Mittal
Department of Obstetrics & Gynaecology, All India Institute of Medical Sciences, New Delhi, India
Background: Antiphospholipid antibody syndrome (APAS) is regarded as the most frequently acquired risk factor for thrombophilia. The obstetric manifestations of APAS include early or late pregnancy losses and complications like preeclampsia and fetal growth restriction. Its timely diagnosis and treatment can improve maternal and neonatal outcome. Aims: To study the pregnancy outcome of patients with APAS treated with heparin and aspirin. Settings and Design: This was a retrospective study of pregnancy outcome in 42 consecutive women with APAS, treated with heparin and aspirin. Materials and Methods: The case records of 42 diagnosed cases of APAS with pregnancy, over a 3-year period, were studied. The pregnancy outcome in this group was compared before and after treatment with heparin and low-dose aspirin in terms of abortions, intrauterine deaths and live birth rate. The outcome of the present pregnancy in terms of fetal and maternal complications was analyzed. Results: The mean age and average parity of women with APAS were 30.1±4.1 years and 3.2±1.2, respectively. Among the treated patients of APAS, 13 (30.9%) had preeclampsia and 9 (21.4%) had intrauterine growth restriction (IUGR). There were 2 (4.7%) intrauterine deaths, 4 (9.5%) missed abortions and 3 (7.1%) abruptio placentae. Women with APAS had a live birth rate of 4.6% before treatment and 85.7% in the index pregnancy after treatment. Conclusion: Treatment of pregnant women with APAS results in marked improvement in the live birth rate (4.6-85.7%). However, complications like preeclampsia and IUGR occur even after treatment, requiring strict monitoring and timely delivery.
Keywords: Antiphospholipid antibody syndrome, aspirin, heparin, pregnancy outcome
Thrombophilia is the tendency to thrombosis. The contact between placenta and maternal circulation is crucial for the success of pregnancy. Pro-thrombotic changes and thrombosis may interfere with these processes, leading to adverse pregnancy outcomes at any gestational age. Thrombophilias can either be inherited or acquired. Antiphospholipid antibodies (APA) are regarded as the most frequently acquired risk factor for thrombophilia and as a treatable cause for pregnancy loss.  The antiphospholipid antibody syndrome (APAS) is a disorder of recurrent vascular thrombosis, pregnancy loss and thrombocytopenia, associated with persistently raised levels of APA. The APA are phospholipids (part of a cell's membrane) recognized by the body as foreign and antibodies are produced against them. Of these, clinically significant are lupus anticoagulant, anticardiolipin antibodies and anti-β2 glycoprotein-I (anti-β2 GP-I) antibody.
There is a paucity of Indian data on the pregnancy outcome in treated patients with APAS. This study presents a retrospective analysis of pregnancy outcome in a cohort of Indian women with APAS following treatment, in a single unit in a tertiary care center.
This was a historical cohort study. Case records of the patients diagnosed with APAS in the preconceptional period and who were booked in our antenatal clinic from 2007 to 2009 were retrieved and analyzed. The diagnosis was made according to the Sapporo criteria or revised criteria given by Miyakis et al, in 2006 (depending on when the diagnosis of APS was made).  The patients were screened for APAS if there was a history of two or more consecutive abortions, three nonconsecutive abortions, placental abruption or severe early onset preeclampsia, severe unexplained intrauterine growth restriction (IUGR) and death of a normally formed fetus after 10 weeks. In cases of recurrent pregnancy losses (RPLs), the other known causes like chromosome abnormalities, thyroid dysfunction, overt diabetes, uterine anomalies and syphilis were ruled out. After counseling and informed consent, 20 ml of blood was drawn for thrombophilia studies. All the samples were tested in duplicate and the tests repeated after 12 weeks. In patients diagnosed as APS before 2007, the test was repeated at 6 weeks, from the same laboratory. Anticardiolipin antibodies (aCL) were measured by enzyme-linked immunosorbent assay (ELISA) (AESKULISA cardiolipin,- AESKU Diagnostics, Wendelsheim Germany)
Both IgG and IgM were assayed. The lupus anticoagulant (LAC) was measured using kaolin clotting time (Sigma Diagnostics, St. Louis, MO USA). Anti-β2 GP-I was measured by an enzyme immunoassay for the quantitative determination of IgG or IgM antibodies to β2 GP-I in human serum or plasma (GA generic assays GmbH, Dahlewitz/Berlin Germany).
The patients with APAS were started on low-dose aspirin (75 mg/day) preconceptionally and it was continued until 36 weeks. In the index pregnancy, low-molecular weight heparin/unfractionated heparin (LMWH/UFH) was started after confirmation of fetal heart activity. The patients on LMWH were switched over to UFH at 36 completed weeks of pregnancy. The UFH or LMWH was stopped the night before labor induction or cesarean delivery. If elective delivery was planned for patients on adjusted dose anticoagulation, it was stopped 24 hours before induction or cesarean section. Heparin was started again 6-12 hours after delivery and continued for 6 weeks. The group of patients treated with LMWH received enoxaparin (40 mg s.c.) daily while those receiving UFH were given 5000 U s.c. twice daily. Out of three patients with thrombosis, two had history of venous thrombosis and one had history of arterial thrombosis. Patients with history of venous thrombosis received adjusted dose anticoagulation. All antenatal investigations were done, and calcium, iron and folic acid supplementation were given as in routine antenatal cases. In patients on heparin, the platelet levels were checked weekly for 4 weeks and then monthly till term. Ultrasound for growth parameters and liquor was done every 2-3 weeks from 28 weeks onward with doppler in cases with IUGR and hypertension. Fetal surveillance was monitored with nonstress test and biophysical profile starting at 28-30 weeks on individualized basis. Strict maternal monitoring was done for development of hypertension and other disease-related or therapy-related complications. Delivery was conducted as per the discretion of the treating physician in individual cases. The outcome of the index pregnancy in terms of antenatal and intranatal complications, fetal outcome and the complications of therapy was recorded. The overall live birth rate and the early or late pregnancy loss rate were compared to the same group prior to treatment. Intrauterine growth restriction was defined as birth weight below 10th centile for the gestational age. Preeclampsia was defined as development of hypertension (BP≥140/90) on two occasions, 6 hours apart, with proteinuria (>300 mg protein/24 hours urine) after 20 weeks of pregnancy. Severe preeclampsia was defined as persistent BP of >160/110 associated with symptoms of impending eclampsia like headache, epigastric pain, blurring of vision or features of HELLP syndrome or deranged kidney function tests, oliguria or intrauterine growth restriction.
The mean age and average parity of the pregnant patients with APAS were 30.1±4.1 years and 3.2±1.2, respectively. The main indication for screening women for APAS was RPL. Out of 42 patients, 20 (47.6%) were screened for RPL at less than 12 weeks, 6 (14.2%) for RPL at more than 12 weeks, 1 (2.3%) had RPL and thrombosis and two patients had RPL with rheumatoid arthritis. Four patients of systemic lupus erythematosus who presented to gynecological OPD with RPL were screened positive for APAS. A history of thrombosis was the criteria for screening in two patients, while a history of severe preeclampsia and unexplained IUGR was the reason for screening in 3 (7.1%) women.
Out of the 42 cases with APAS, 35 (83.3%) were primary APAS and the rest seven were associated with other connective tissue disorders. Of these, four females had systemic lupus erythematosus (SLE), two females had rheumatoid arthritis and one had idiopathic thrombocytopenic purpura (ITP).
The majority (78.6%) of the patients with APAS belonged to category II (single positive) (LAC/aCL/anti-β2 GP), while the rest (21.4%) belonged to category 1 (double/triple positive). The details with respect to antiphosphpolipid antibody positivity are provided in [Table 1].
For treatment, aspirin plus UFH was given to 26 patients (61.9%) and aspirin plus low-LMWH to 13 patients (30.9%). A combination of LMWH and intravenous immunoglobulin (IVIg) was given to a patient with APAS with prior loss, despite treatment with LMWH. However, in spite of the treatment and strict monitoring, this patient developed renal complications in terms of deranged kidney function tests, significant proteinuria and decreased urine output for which the pregnancy had to be terminated at 24 weeks. Another patient with ITP was on prednisolone throughout pregnancy and required IVIg when the platelet counts fell at a later gestation.
The outcome of the index pregnancy and a comparison with the previous pregnancy outcomes are summarized in [Table 2] and [Table 3], respectively. The majority of patients delivered before 37 weeks, of which 10 (25.6%) delivered before 34 weeks, while 18 (48.7%) delivered between 34 and 37 weeks. Out of 21 (50%) total inductions, there were 11 (26.1%) preterm inductions (5 for preeclampsia, 4 for IUGR and 2 for poor biophysical profile). Twelve patients delivered by a cesarean section (30.8%) and the rest had a normal vaginal delivery. The average birth weight was 2.31±0.68 kg. Out of the nine patients antenatally diagnosed with IUGR, three had absent end diastolic flow and one had reversed end diastolic flow. All the four babies postnatally required NICU admission and monitoring till appropriate weight gain. Four neonates developed hyperbilirubinemia requiring phototherapy, while one of the nine babies with IUGR developed hypoglycemia. Two of the emergency cesarean sections were done for thick meconium stained liquor. However, both the babies were vigorous at birth. One of the neonates delivered by elective cesarean developed transient tachypnea of new born, requiring NICU admission for 24 hours.
In one of the cases, aspirin and UFH had to be stopped due to a large retroplacental clot which later resulted in an intrauterine death at 24 weeks. This could have been a complication of the therapy or the disease process per se. One patient on treatment with heparin developed mild transaminitis. However, we did not encounter any case of heparin induced thrombocytopenia.
The present standard of care for women with APAS and RPL is treatment with heparin and aspirin. This approach is not supported by unquestionable data due to studies with small sample size, weak study design or was not uniform in diagnosis of APAS and inclusion criteria. The Cochrane data base review concluded that treatment with UFH and aspirin may reduce pregnancy loss by 54%. 
In the present study, the live birth rate in the index pregnancy was 85.7% on treatment, and in the previous untreated pregnancies, it was 4.6%. This compares favorably with the other reports of a successful pregnancy outcome of 75-80% live birth rate with treatment.  Heparin has been observed to attenuate apoptosis and facilitate trophoblast invasion; therefore, its role in the treatment of thrombophilias may be more than just being an anticoagulant.  In a review of eight studies using low-dose aspirin plus heparin, live birth rates varying from 71 to 84% have been reported.  LMWH has been found to be as effective as UFH. The recent HepASA Trial  (a randomized control trial) concluded that LMWH/ASA did not confer incremental benefit compared to ASA alone in women with RPL, including women with APAS. But the study has its drawbacks. The study recruited 88 women with RPL, of whom only 42 had APAS. The study did not complete the recruitment and the results are an interim analysis.
The reported prevalence of primary APS is around 53%  and that of secondary APS is 47%. In our observation, 83.3% had primary APAS. This can be explained by the predominant clustering of women with RPL in the gynecologic OPD. However, the distinction between primary and secondary has been removed in the modified criteria for APAS. 
Pregnancy outcomes in APAS have been correlated to the presence of multiple antibodies as compared to one single antibody with poor outcomes occurring more frequently in category I than in category II primary APS patients.  In our study, we did not find a difference in outcome on this basis. However, the number of patients in category I (n=9) is too small to prove or refute an association.
It was reported by Nodler et al.  that in women with APAS having recurrent miscarriage as the predominant symptom, preeclampsia and IUGR occurred in 11.36 and 6.82%, respectively (odds ratios being 2.77 and 4.33, respectively). In another study by Bats, out of 33 pregnancies with APS diagnosed after an intrauterine death treated with aspirin and LMWH; there were six cases of IUGR and one was associated with preeclampsia. Eight patients delivered preterm.  In our study also, despite treatment, 7% developed severe preeclampsia and 10% had severe IUGR. A corollary of the above findings may support the hypothesis that by treating women who have suffered early pregnancy loss in the first trimester with aspirin and heparin, the late pregnancy complications may increase. It may be possible that aspirin and heparin do not eradicate the underlying pathology but merely reduce the severity or alter disease expression. 
The high rate of cesarean section (30.8%) can be explained by the high risk population involved, with RPL being the most common presentation. A low threshold for cesarean section was the norm rather than an exception.
Similarly, an increased incidence of preterm deliveries can be attributed to both the disease process and iatrogenic factors because of preterm inductions (26.1%).
Treatment with corticosteroids and aspirin to suppress autoantibodies is not recommended because of unacceptable side effects. , The use of steroids in women with APS in our study was limited to one patient with thrombocytopenia.
Intravenous immunoglobulins have not shown to improve the obstetrical outcome in patients of APAS, as found in a recent systematic review.  We did not find any benefit with its use in a patient refractory to aspirin and heparin.
The strength of the study lies in the fact that this presents the data in the Indian context. The awareness of this entity as a treatable cause of bad obstetric history can help in the management of a number of hitherto unexplained cases of RPL. The limitation of the study is a small sample size which precludes meaningful statistical calculations regarding fetal outcomes in various subgroups like primary and secondary APAS or categories I and II. The present study consolidates the current evidence of successful pregnancy outcome following treatment in patients with APAS, especially in the Indian scenario where the awareness of this clinical entity is still limited. The continued occurrence of late pregnancy complications like preeclampsia, IUGR and prematurity despite treatment further emphasizes the need for strict monitoring of the disease and therapy-related complications throughout pregnancy. Also, the management of cases of APAS who continue to have poor obstetric outcome despite treatment with heparin and aspirin still remains a challenge. The role of newer modalities like IVIG and plasmapharesis needs to be defined by targeted trials on these refractory patients.
[Table 1], [Table 2], [Table 3]