Despite the overwhelming success of In Vitro Fertilization (IVF) in helping couples to conceive in the past 25 years, there remains a group of women for whom there is no obvious explanation for repeated IVF failures. This has led to hundreds of theories, most debated and subsequently discarded, to explain these inexplicable, yet relatively uncommon embryo implantation failures.

One popular theory that lingers is that the implantation process is facilitated in part by the maternal immune system, acting at the contact point of the uterine lining and the normal embryo. While there is little doubt that many biological processes are likely at work here, the exact mechanisms of embryo implantation remain poorly understood. More basic research is underway to further understanding of this complex process.

Taking off on this theory that some abnormality in the immune system is responsible for implantation failures, some IVF practitioners will run a battery of tests for antibodies to phospholipid molecules on their IVF patients. These phospholipids are everywhere on cell surfaces. At high levels, such as with some auto-immune diseases, the presence of antibodies to phospholipids can lead to clotting disorders and sometimes repeated, mostly second trimester pregnancy losses. Much more controversial is the question of whether or not anti-phospholipid antibodies play any direct role in inhibiting embryo implantation. Approximately 9% of normal fertile women can be found to have anti-phospholipid antibodies in their blood.

A well designed study from 1997 by Denis and colleagues found that in a large number of patients undergoing IVF, the presence or absence of these anti-phospholipid antibodies prior to treatment had no effect on IVF outcome. This is why the majority of reproductive endocrinology and infertility specialists, including Pacific Fertility Center, do not run anti-phospholipid antibody tests on their infertility patients. But some IVF practitioners routinely run these tests and, based on the presence of any positive titers of antibodies, will prescribe a regimen of twice daily injections of heparin and a tablet of children’s aspirin daily. Heparin is a blood thinner and is known to inhibit the binding of anti-phospholipid antibodies to phospholipids on cell membranes.

Prior studies examining heparin use have resulted in conflicting findings, some studies showing amazing benefits and others finding none at all. Most of the prior studies had design limitations that made it difficult to form firm conclusions. This conflict, coupled with the inherent potential risks of heparin use, have limited the use of this controversial therapy to a very small number of centers.

A new study, recently published in the August issue of Fertility and Sterility (an official professional journal) may finally put the debate to rest. The study was designed as a randomized, double-blind, placebo-controlled trial of heparin and aspirin for women with prior in vitro fertilization failure, and with positive signs of anti-phospholipid antibodies or anti-nuclear antibodies. This study protocol is considered the “gold standard” design for a clinical trial and when performed as designed, the results are very hard to dispute.

Basically, some of the women, all of whom had had at least 10 embryos transferred over several prior IVF cycles and who had no known explanation for the implantation failure, were randomly assigned to receive either heparin and aspirin or a placebo (blank) during their IVF or frozen embryo transfer cycle. Neither the researchers nor the patients were aware whether or not the patient was receiving the active drug until the study was completed, to eliminate any potential study biases.

For the women receiving heparin and aspirin, a total of 296 embryos were transferred. This resulted in 20 cases with positive fetal heartbeats on early ultrasound (7%). For the placebo group, 259 total embryos were transferred and there were 22 positive fetal heartbeats (8%). Keep in mind that these patients had been through several prior IVF attempts so their overall chances for success would be low to start with. The live birth rate for the heparin and aspirin group was 6% and was 7% for the placebo group. There was no statistical difference in these numbers.

The bottom line on this study is that even with positive anti-phospholipid antibody tests, women with repeated IVF failures were no more likely to conceive if they received a treatment regimen with heparin and aspirin or with nothing at all. This study provides Class A medical evidence that recommendations to use heparin for infertility must be viewed very cautiously, as heparin’s effect on certain patients can be even detrimental to their overall health. For more information regarding the use of low-dose aspirin while attempting conception, please see our Sept. ’03 issue of Fertility Flash.

A new study, just published in the British Medical Journal has received quite a bit of press attention. This study, conducted at Kaiser Permanente in Northern California, suggests there may be a relationship between the use of aspirin and aspirin- like medications (called non-steroidal anti-inflammatory drugs, or NSAIDs) and first trimester miscarriage. We at PFC took a closer look at the study and determined that it has severe shortcomings.

NSAIDs, including aspirin, ibuprofen, naproxen and others, have not as yet been strictly forbidden during pregnancy, although most doctors, PFC physicians included, recommend acetominophen (Tylenol) if needed for headaches and other minor ailments during pregnancy.

Research has long established the impact of aspirin on women trying to get pregnant. At low doses (e.g. 81 mg), aspirin has markedly different effects on such things as platelet function as compared to higher doses (325-1000 mg). At low doses, some studies have suggested that aspirin may improve uterine blood flow and enhance embryo implantation. At higher doses, NSAIDs may inhibit prostaglandins, substances important for ovulation and implantation. This is the basis upon which we, at PFC, have designed our medication treatment protocol. We suggest patients not take drugs such as ibuprofen and naproxen during treatment, yet we do recommend patients undergoing infertility treatment take a daily baby aspirin.

This recent study surveyed 1055 women immediately after their pregnancy was diagnosed, and the women were followed up to 20 weeks of pregnancy. Only 53 women reported using NSAIDs around the time of conception or during pregnancy (5% of those surveyed). Of these, 15 (25%) miscarried. Of the 980 women who reportedly did not use NSAIDs, 149 (15%) miscarried. The 95% confidence interval was 1.0-3.2. When the 95% confidence interval is less than 1.0, the results are not considered statistically significant. Therefore, these results just barely achieved statistical significance. If the study had been able to find more women who had used NSAIDs, it might be more conclusive.

With so few women reporting NSAID use, and with results barely in the statistically significant range, more questions than answers are raised. It is disappointing that the authors did not include the average age of the mothers in their data presentation. Miscarriage is strongly associated with maternal age, as more embryos are genetically abnormal and will likely miscarry, as the mother is older at conception. Is there a possibility that the average age of the women using NSAIDs was greater, by chance or not? The study did not specify the maternal ages or how the data was adjusted to eliminate this potential important bias.

However cautiously we must review these results, PFC will continue to recommend a daily dose of baby aspirin to our patients undergoing infertility treatment. At such a low dose, baby aspirin improves uterine blood flow and this study does not warrant alarm. The primary conclusion from this Kaiser study strongly suggests that further research is needed.