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.

Uterine stem cells deficiency linked to Recurrent Pregnancy Loss (RPL).

Stem cells have the potential to treat a myriad of diseases and have acted as a powerful tool to treat many life threatening diseases. Researchers have opened up a new avenue in stem cell therapy by tying stem cell deficiency in endometrium to recurrent pregnancy loss.

According to a recent paper published in February issue of Stem cells by Lucas E S et al researchers postulated that stem cell deficiency in the endometrial tissue and accelerated stromal aging is responsible for RPL by limiting the endometrial capacity to decidualize. Most miscarriages are sporadic and are due to chromosomal aberration in the conceptus, but RPL is a distinct entity.  In about 50% of RPL, the etiology is not defined. It is estimated that roughly 5% of women suffer from 2 clinical miscarriage and 1% ending up with 3 or more losses. While many factors seems to play role in RPL, the underlying endometrial pathology is not yet explored.

It is indicated that RPL is associated with impaired differentiation of endometrial stromal cells (HESCs) into specialized decidual cells. The differentiation termed as decidualization, predicts the end of implantation window and confers endometrium the ability to recognize, respond to and eliminate implanting compromised embryos, theory of natural selection. The theory suggests that it is the response of the decidualized endometrium to embryonic signals, which decides the future implantation and development of the  embryo or its rapid demise through menstruation-like shedding. Current evidence suggests that it is the abnormal decidualization which causes the loss of selectivity leading to implantation without further progress leading to pregnancy loss. So, the endometrium acts as a ‘biosensor’ detecting the embryo derived signal and deciding the fate of the embryo.

It is already known that decidualization of the endometrium in not dependent on embryo. It happens in post ovulatory phase of every cycle due to increase in progesterone levels and cAMP. It is because of cyclic activation of mesenchymal stem cells which differentiate into stromal cells in regenerating endometrium.

The authors hypothesized that defect in cyclic regeneration of endometrium in RPL patients is impacted due to defect in DNA methylation status of human endometrial stromal cells (HESCs).

A total of 183 endometrial biopsies were taken from patients with  normal women and those with RPL, except 8 random samples, all other were timed between 6 and 10 days after the preovulatory luteinizing hormone surge.  HESCs were isolated from the samples and cultured in laboratory. They were further tested for epigenetic markers for recurrent pregnancy loss.

It was seen that endometrial lining in patients with RPL showed loss of plasticity, with included increased senescence, deficiency and limited capacity to differentiate. Epigentic signature was lacking in women who experienced RPL as compared to their normal counterparts.

The endometrium also had decreased number of stem cells that had limited capacity to renew the endometrium, resulting in aging. Aging cells mount an inflammatory response that is enough for implantation but not for development and sustaining the embryo.

In an interview with medscape  Dr. Brosens said “"We also found that the greater the number of miscarriages a woman had experienced...the more depleted the lining was."

"Cultured cells from women who had had three or more consecutive miscarriages showed that aging cells in the lining of the womb don't have the ability to prepare adequately for pregnancy," Dr. Brosens notes.

He futher explained hat medicine usually regards recurrent miscarriage as being associated with an underlying disease, and normal practice is to investigate clotting abnormalities, hormonal imbalances, or immune responses. In the United States, patients are referred to specialist care after two consecutive losses; patients are referred after three losses in the United Kingdom. "It is often stated that a cause for recurrent miscarriage can be found in 50% of patients. However, for every woman with an apparent known 'cause' of miscarriage, there will be 50 to 100 women who have the same disorder but do not experience miscarriage. So current tests completely lack specificity."

With sporadic miscarriages, the majorities are caused by chromosomal abnormalities in the fetus, but with recurrent miscarriages, the majority involves normal fetuses. The more miscarriages a woman has, the greater the likelihood pregnancy loss involves a fetus with normal chromosomes. "Also, as the number of miscarriages increases, there is a higher chance of recurrent miscarriage," Dr. Brosens added.

According to Dr. Brosens, the real challenge lies in translating these findings into something clinically meaningful. He believes that this could further lead to development of some sort of screening tests, eventually ending up with some sort of treatment for women at risk. "The abnormalities we have identified all precede pregnancy, so it is possible to test the uterine lining for these markers and help predict if a patient is at risk of recurrent miscarriages."

He also pointed that stem cells in the uterine lining were highly dynamic and active pool, that are undergoing  cyclic shedding and regeneration, so intermittently the defects in the uterine lining could undergo self-repair, changing from an unsupportive environment to a supportive one. This explains why many women have a successful pregnancy even after recurrent miscarriages.

The authors concluded that “These findings open up new avenues to screen women prior to pregnancy for the risk of miscarriage and point to the potential of cell-based therapies in the prevention of RPL.”

References:

Lucas, E. S., Dyer, N. P., Murakami, K., Hou Lee, Y., Chan, Y.-W., Grimaldi, G., Muter, J., Brighton, P. J., Moore, J. D., Patel, G., Chan, J. K.Y., Takeda, S., Lam, E. W.-F., Quenby, S., Ott, S. and Brosens, J. J. (2016), Loss of Endometrial Plasticity in Recurrent Pregnancy Loss. STEM CELLS, 34: 346–356. doi: 10.1002/stem.2222

http://www.ncbi.nlm.nih.gov/pubmed/22835448

http://www.ncbi.nlm.nih.gov/pubmed/1975862

http://www.ncbi.nlm.nih.gov/pubmed/20847090

Large randomized trial does not support the use of progesterone in recurrent miscarriage.

Recurrent miscarriage affects about 1% of all women of child bearing age.

50% of all early pregnancy loss are due to chromosomal aberration, most common being aneuploidy.  

Progestogens play an important role in implantation, cytokine balance, natural killer cell activity, arachidonic acid release and myometrial contractility. It is secreted by corpus luteum till 7-8 weeks, when the function is taken over by developing placenta. Lack of progesterone support in the luteal phase increases the chances of early pregnancy loss; hence progesterone is often used specially in women with history of recurrent pregnancy loss!

Results of a recent large RCT published in the November issue of  New England Journal of Medicine concluded that Progesterone Doesn't Improve Outcomes After Recurrent Miscarriages.

This large multicenter, double-blind, placebo-controlled, randomized trial recruited 1568 women aged 18-39 years with a history of three or more consecutive or nonconsecutive first-trimester pregnancy losses. Women with anatomical, medical or hematological causes that explain the reason behind miscarriages were excluded from the study.

The study group (n=404) were assigned to receive 400mg of vaginal micronized progesterone , while the control group ( n=432) received a similar looking placebo as soon as the pregnancy were confirmed till 12 weeks of naturally conceived pregnancy.

The live birth rate in progesterone group was 65.8% vs. 63.3% in placebo group. The rate of ectopic pregnancy, congenital anomalies, miscarriage and still birth rates were also comparable in both the groups.  

A Cochrane review in 2013 based on smaller number of trials and subject reported lower rate of miscarriage with progesterone support. This large RCT lead us to a different conclusion.

Management of women with RPL is a challenge in itself, as these women are very anxious and apprehensive and ask for some form of ‘therapy’ to avert a loss again. Over the years many other modalities like heparin, aspirin and acupuncture have been evaluated with mixed results.

There are many unanswered question in therapy of RPL, including the definition of RPL, the evaluation and the timing of starting treatment. Progesterone is an important part of regimen offered, being having endometrial supportive and immune-modulating effects.

Different studies have come up with different results; the study also differed in patient population, mode and type of progesterone and the initiation of treatment since pregnancy confirmation.

Whatever the results and conclusions of different trials may be, the psychological and placebo effect of the progesterone cannot be overlooked for patients who have a high level of anxiety and are afraid of another loss.

References:

http://www.ncbi.nlm.nih.gov/pubmed/26677905

http://www.medscape.com/medline/abstract/22503277

http://www.nejm.org/doi/full/10.1056/NEJMoa1504927

http://www.ncbi.nlm.nih.gov/pubmed/24173668