Aspirin in combination with heparin results in more live births in Repeated Pregnancy Loss: a systemic review and meta-analysis

Aspirin in combination with heparin ups the odds of live births 2.5 times as compared to aspirin alone among women with antiphospholipid syndrome (APS) who had experienced repeated pregnancy loss says the result of a systematic review and meta-analysis.

The prevalence of APS in women with RPL varies according to studies, from as low as 6% to as high as 42%, but it is generally accepted to be 5%–20%.

The results were presented at the International Society on Thrombosis and Haemostasis (ISTH)2017 Conference.

Researchers at Leiden University Medical Center in the Netherlands conducted a systematic literature search for randomized controlled trials that compared low dose aspirin (LDA), low-molecular-weight heparin (LMWH)or unfractionated heparin (UFH), or both on the effect of live birth in women with APS and recurrent pregnancy loss.

The study is an update of earlier Cochrane Database Systematic Review by Empson andcolleagues from 2005.

The investigators identified 939 research studies, full text review resulted in 9 studies, of which only 5 were included in the final analysis. Combined data resulted in a total of 398 women. Studies were excluded if they did not meet the diagnostic criteria   for APS.

The study results showed that:

LDA alone did not have much potential benefits in increasing the live birth rates as compared to a placebo.

Heparin of any kind resulted in live birth rate 2.5 times that of LDA alone (odds ratio [OR] 2.51; 95% CI 1.48–4.25, P<0.001).

When unfractionated heparin (UFH) was combined with LDA the likelihood of live birth rates increased to 3.75 times as compared to LDA alone in an analysis of pooled data from three studies. (odds ratio [OR] 3.75; 95% CI 2.04–6.90, P<0.001).

However, when LMWH was paired with LDA in two studies, there was no significant difference in odds of having a live birth.

This systematic review and meta-analysis findings were limited by sample size, lack of adverse effects reporting of heparin and aspirin in the original studies, dose disparities. Mauritia Marijnen from Academic Medical Center, Amsterdam, the Netherlands stressed on urgent need of rigorous randomized controlled trials, particularly on the use of LMWH.

Unfractionated heparin (UFH) is an older drug with side effects, but in this meta-analysis it appeared to be more effective in increasing the odds of live birth rates. It maybe because of some other confounders which were not analyzed in this study, which makes it all the more important to carry out future studies with LMWH.

The authors concluded, “Heparin plus aspirin compared with aspirin improves live birth in women with APS and recurrent pregnancy loss. This effect is driven by studies that investigated UFH and not LMWH.”

All the abstract presented at the conference can be accessed here.

Primary source: Marijnen MC, Scheres LJJ, Middeldorp S, et al. Aspirin, heparin or both to improve live birth in women with antiphospholipid syndrome and recurrent pregnancy loss. ISTH 2017; July 11, 2017; Berlin, Germany. Abstract ASY 22.3.

Guidelines revised for preventing thromboembolism in pregnancy.

Obstetric Venous thromboembolism (VTE) is a leading cause for maternal morbidity and mortality. Venous thromboembolism encompasses deep vein thrombosis(DVT) and pulmonary embolism (PE) complicates 0.5 to 3.0 per 1,000 pregnancies.[1] PE is the seventh leading cause of maternal mortality and contributes to 9% of maternal deaths.[2]

Maternal deaths due to VTE are preventable by forming and implementing comprehensive guidelines for prophylaxis of thromboembolism. But, presently sufficient clinical trial data remains unavailable to formulate VTE prophylaxis guidelines in pregnancy.

In US only women who are at high risk for VTE receive pharmacologic prophylaxis, thereby increasing the rate of obstetric VTE in the last decade.

On the contrary, RCOG guidelines in U.K recommend screening and assessment of antepartum and postpartum women for at risk for VTE. Due to regular assessment many women receive pharmacologic thromboprophylaxis, bringing down the rates of VTE since the release of the guidelines.

Observational data support risk-factor-based prophylaxis in bringing down the incidence of VTE, hence the National Partnership for Maternal Safety under the guidance of the Council on Patient Safety in Women's Health Care developed safety bundle. Safety bundle supports routine risk evaluation for obstetric patients with pharmacological and mechanical thromboprophylaxis when needed. [3] It outlines simple practices that can be implemented in every maternal units, adapting according to the healthcare resources available in each community.

The article was published in October issue of Obstetrics and Gynecology journal.[4] The bundle is grouped into 4 domains: Readiness, Recognition, Response, and Reporting and Systems Learning. 

Readiness: Every Unit should use standard VTE risk assessment tool during prenatal outpatient visits, antepartum admissions to hospital, post labor and post cesarean stay in hospitals and 6 weeks postpartum.

Recognition and Response: Once the risk assessment is done, physicians should use patients Caprini[5] or Padua score[6] to identify those patients who will need thromboprophylaxis according to clinical situation and risk score. The thromboprophylaxis guidelines are as advocated by ACOG, American College of Chest Physicians and RCOG.

• Antepartum outpatient prophylaxis: women with a history of multiple VTE or thrombophilia episodes low-molecular-weight (LMW) heparin or unfractionated heparin (UFH) is recommended.
• Antepartum Inpatients for more than 3 days: Women who are not at risk for bleeding or imminent childbirth, prophylaxis with daily LMW heparin or twice-daily UFH is advocated.
• Women with a history of VTE who are undergoing a trial of vaginal birth are given intrapartum mechanical thromboprophylaxis using pneumatic compression devices while in bed. After the delivery, LMW heparin or UFH can be for those at high risk for VTE based on RCOG criteria or a Padua score of 4 or greater.
• Those women undergoing an operative delivery are prescribed mechanical thromboprophylaxis using pneumatic compression. Once the surgery is over, they can also be given LMW heparin or UFH, based on RCOG criteria or modified Caprini scores.
• RCOG criteria also advocates that all women who are undergoing operative delivery may be routinely prescribed LMW heparin or UFH due to complications with mechanical prophylaxis.
• Women with repeated history of VTE, high-risk thrombophilia, or VTE with acquired thrombophilia can be put on extended 6-week treatment-dose of LMW heparin or UFH postpartum.

Reporting and Systems Learning: All centers should meticulously keep records of patients receiving prophylaxis for VTE, adverse reactions and complications.  Routine audits should be performed to check whether physicians are evaluating, assessing the risk factors for VTE and planning the treatment accordingly.

However, in an accompanying editorial Baha M. Sibai, MD, from the University of Texas Medical School at Houston, and Dwight J. Rouse, MD, MSPH, associate editor for Obstetrics & Gynecology, have expressed concern that the widespread use pharmacological prophylaxis may do more harm than good. 

The authors are specially concerned with 3 days’ prophylaxis for antepartum hospitalized patients and women at high risk for VTE and have undergone vaginal birth.

They were especially worried about following the RCOG criteria of pharmacological prophylaxis after cesarean delivery, which would apply to more than half of the C.S. patients in the US. 

According to the editorial analysis” approximately 1 million women would require pharmacologic prophylaxis to prevent even one maternal death from cesarean delivery–associated pulmonary embolism."

Nevertheless, they advocate the use of mechanical prophylaxis in all obstetrics units’ post-cesarean and building a database of huge obstetric patients in whom the mechanical method was used. In the future, this large data base created can be used to assess the pros and cons of using pharmacological prophylaxis in obstetrics patients.

---

[1] Snow V, Qaseem A, Barry P, et al., for the American College of Physicians, American Academy of Family Physicians Panel on Deep Venous Thrombosis/Pulmonary Embolism. Management of venous thrombo-embolism: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2007;146(3):204–210....

[2] The Confidential Enquiry into Maternal and Child Health (CEMACH). Saving mothers’ lives: reviewing maternal deaths to make motherhood safer — 2003–2005: the seventh report on confidential enquiries into maternal deaths in the United Kingdom. London: CEMACH, 2007

[3] http://www.safehealthcareforeverywoman.org/secure/vte-prevention-patient-safety-bundle.php

[4] http://journals.lww.com/greenjournal/Citation/2016/10000/National_Partnership_for_Maternal_Safety_.3.aspx

[5] http://www.wikidoc.org/index.php/Caprini_risk_assessment_model

[6] http://www.mdcalc.com/padua-prediction-score-for-risk-of-vte/