Finding at least one high quality egg is the most important factor in achieving a successful pregnancy. In previous blog posts, I have outlined various strategies to achieve that goal. But what about women whose ovaries do not respond well to standard ovarian stimulation protocols? For them treatment can sometimes seem frustrating or even futile. New data supports that “ovarian priming” may help women with diminished ovarian reserve (DOR) achieve that goal even if they have a history of poor response to IVF treatment.

The common theme of Advanced Reproductive Treatments (ART) is to produce a group of mature healthy eggs in order to create at least one or more healthy embryos. In 2011 a large consensus  meeting agreed upon the definition of a ‘poor response’ to ovarian stimulation and described it as three or fewer oocytes recovered with a conventional IVF protocol. Pregnancies do occur when even one egg is recovered. However, success rates are markedly lower in patients with DOR. The goal of creating this definition was to encourage research on how we can better serve women with this biological challenge.

The most common reason for DOR is a simple depletion in the number of eggs secondary to aging. However new information now suggests that the quality of the remaining eggs is also impacting their ability to respond to the hormonal signals and thus limiting the ability of the ovaries to produce multiple follicles. The goal of preparing or “priming” the potential population of eggs prior to IVF is to optimize the ability of the ovaries to respond prior to starting the hormonal stimulation. Several strategies for priming have been used for the last several years with much debate about which (if any) is best. The FOLLPRIM study  was designed to compare them in patients with an established history of DOR.

The FOLLPRIM study was a randomized prospective study intended to minimize the risk of bias based upon protocol selection. Patients that had failed an IVF attempt were randomly assigned to one of three priming protocols prior to their next IVF attempt. They were either given estradiol (to simulate the cycle of young fertile women), an oral contraceptive (to synchronize follicle development) or testosterone (which serves as a precursor to estradiol as well as to help promote the earlier stages of egg development). The patients then repeated their IVF cycle with a comparison of number of eggs recovered after priming compared to their initial response without priming. The results were very encouraging.

They found that all three strategies increased the number of mature eggs that were recovered through IVF compared to the unprimed cycle. In fact, they averaged two to three more eggs per patient. Although it was uncertain which priming protocol had the highest pregnancy rate, the data suggested that the testosterone priming might be the best. Further research will be needed to determine if this is true. In fact, another technique (not tested in this study) to boost testosterone levels is to give women the supplement DHEA for one to three months prior to IVF. Many centers have adopted this strategy as well.

What’s most important about this research is that women with DOR are being given choices rather than simply discouraged or re-directed to egg donors. Ovarian priming prior to IVF is one option that should be considered. Combined with other tools like anti-oxidants and CoQ10, more women are overcoming this biological challenge of DOR and having healthy babies.

[r1]Link to http://humrep.oxfordjournals.org/content/26/7/1616.full.pdf+html

[r2]Link to http://www.pubfacts.com/detail/25955224/Antral-follicle-priming-FOLLPRIM-prior-to-ICSI-in-previously-diagnosed-low-responders-A-randomized-c

Recently I was interviewed for a piece on the EndocrineWeb. Here is a link for anyone interested: http://www.endocrineweb.com/infertility-insulin-resistance-5-tips-your-odds-getting-pregnant?page=1

One of the most difficult subjects to discuss—especially for those treating or experiencing infertility—is miscarriage. Yet not talking about it often leads to unnecessary guilt, exacerbated shame and all too often to treatments of questionable value. So let’s review some of the most recent findings about this challenging topic in order to foster better communication and improved outcomes.

Miscarriage occurs in at least one out of every five pregnancies. Most of these miscarriages—estimated to be 60% to 80% depending on the woman’s age—are due to a genetic abnormality in the developing fetus. Yet a recent national survey  demonstrated that both men and women in the USA believe that miscarriage is rare; occurring in fewer than 6% of pregnancies. Even worse, the same respondents felt that lifting heavy objects and stressful events were among the most common causes of pregnancy loss. Maybe this false sense of responsibility explains why feelings of guilt and shame are so frequently reported by patients following a miscarriage. So let’s set the record straight by reviewing what the science has taught us.

For a successful pregnancy to occur there are three critical factors. First, there must be a healthy, genetically competent embryo. Then the embryo must arrive into the woman’s uterus during the hormonally synchronized window of time to support implantation. Finally the blood flow to the implantation site and woman’s immunologic functions must foster the growth of the pregnancy along with providing continued hormonal support. So let’s consider what interventions we can take to assist women with recurrent pregnancy loss (REPL)—defined as at least two pregnancy losses—to improve their chance of delivering a healthy baby.

In general, REPL is fairly uncommon and occurs in less than 5% of women. However, it is becomes increasingly more frequent after the age of 35 due to the increased likelihood of producing genetically abnormal embryos associated with aging. Comprehensive chromosomal screening (CCS) involves performing a biopsy on developing embryos created through IVF. These biopsies can then be tested for missing or extra copies of all 24 (including X & Y) chromosomes in each embryo—the most common cause of miscarriage. Several studies have demonstrated that doing so can reduce the risk of miscarriage substantially. In fact, one recent study  performed on women with REPL demonstrated that selecting and transferring only genetically competent embryos reduced the subsequent miscarriage rate to around 7%; making it three to five times less common than women that did not undergo this important test. So taking steps to insure that a pregnancy is started with an apparently healthy embryo is an effective strategy but some argue that it is too costly. Given that about half of the women with REPL are never given a diagnosis explaining why their pregnancy loss occurred; the insight gained from CCS might be considered invaluable. In fact, the lack of this diagnostic information likely fuels many of the other—often unnecessary—treatments offered to prevent subsequent miscarriage.

It has long been theorized that decreased blood flow and inflammation were major contributors to pregnancy failure and that low dose aspirin would help correct these problems. Unfortunately a randomized study  involving over 1200 women with REPL demonstrated that using low-dose aspirin (started before conception) was no better than placebo in reducing the risk of subsequent miscarriage. Given that low-dose aspirin is inexpensive; many may continue to use it anyway on the outside chance that it may help some individuals with REPL even though it is clearly not a major preventative measure for most women. However, other more expensive and risky treatments are often suggested as well.

Since immunologic problems have long been theorized to contribute to recurrent pregnancy loss, treatment with intravenous immunoglobulin (IVIG) has been proposed for nearly two decades to modulate the immune response. In truth this expensive and potentially hazardous treatment has failed to show benefit in multiple studies. Nonetheless, it has recently been put to the test yet again. This time the study was a larger prospective, randomized trial  where both the patients and their providers were blinded as to whether they were receiving the actual treatment or a placebo. The group studied included 82 patients that had each experienced four or more miscarriages in previous attempts at conception. Unfortunately, the live birth rate was no different between the treatment group and the placebo group. This is yet another study demonstrating that immunologic therapy is not likely to help most REPL patients.

Another strategy to reduce inflammation and improve blood flow as well as boosting health in general is to look at the patient’s diet and lifestyle. Obesity is associated with an increase in miscarriage risk as well as a higher risk of nearly every pregnancy related complication. Recently the Nurse’s Health Study II —a prospective monitoring of over 17,000 women that had conceived over 25,000 pregnancies provided some helpful insight. They found that pre-pregnancy weight gain and obesity were associated with a higher risk of miscarriage. So helping overweight or obese women with REPL to lose weight prior to pregnancy may be one of the best ways to help them have a baby as well as a healthier life.

Sharing the latest research on miscarriage is critical. Not only can it reassure and empower women but also help them avoid further heartache. It can also help prevent them from making emotionally based decisions to pursue treatments that may even cause further harm as well as financial hardship.

[r1]Link to http://journals.lww.com/greenjournal/Pages/currenttoc.aspx

[r2]Link to http://www.fertstert.org/article/S0015-0282(15)00134-X/abstract

[r3]Link to http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)60157-4/abstract

[r4]Link to http://onlinelibrary.wiley.com/doi/10.1111/1471-0528.13192/abstract

[r5]Link to http://journals.lww.com/greenjournal/Abstract/2014/10000/Prepregnancy_and_Early_Adulthood_Body_Mass_Index.3.aspx

Fertility treatment in the USA has always been different from most of the rest of the world. Although the first IVF pregnancy was conceived in England; the first IVF pregnancy involving ovarian stimulation  to produce more eggs occurred in Norfolk, VA in 1981. Thus began the modern trend of producing multiple embryos in order to boost the chance for a pregnancy. We’ve achieved that goal. As I wrote about several months back fertility treatments have become both safer and more successful. Yet pregnancy following IVF still has higher risks than naturally conceived pregnancies. New data now supports that lowering the number of embryos transferred per cycle may be the key to both higher pregnancy rates and lower risks. Here’s what we now know.

Multiple pregnancies—twins in particular—remain fairly common after IVF. In 2013, (the most recent year that we have outcome data available for ) most embryo transfers involved two embryos or dual embryo transfer (DET). Not surprisingly, the incidence of twins or higher order multiples nearly reached 30% of those that became pregnant. By comparison the natural incidence of twins is about 2%. One of the major factors that appear to drive this continued trend for twins over singletons is that most patients don’t have enough information available to them to make a fully informed decision of one vs. two embryos.  In fact as one recent editorial stated “it is not the fear of multiples that drives decisions about the number of embryos to transfer…but rather the fear of not conceiving at all .”

Many of the most successful programs have been urging their patients to consider single embryo transfer based upon their clinic-specific success rates. Some have even demonstrated that imposing a mandatory policy of single embryo transfer (SET) is well supported by patients in these settings . But now we have new data suggesting that patients at the typical center should also be considering SET.

A just published study  using the national database for IVF centers’ information gathered from 2006 to 2012 has provided new insights into live birth rates (LBR) from elective SET vs. DET. They demonstrated that LBR is as good as or better with two SET cycles than with one DET cycle. In fact, in some patients the LBR was up to 20% higher with an incidence of twins of around 1 to 3% (due to a single embryo splitting and forming identical twins). Other studies have also demonstrated that when two or more embryos are transferred, the excess embryos have a negative effect on the one remaining. This impact may manifest as a low birth weight, a higher risk of preterm labor or an elevated risk of miscarriage. It can even contribute as adverse neurologic effects on the embryo that survives to term; resulting in a child with cognitive or developmental impairment. The studies’ authors concluded that “success for modern IVF should be defined as a singleton pregnancy that results in a healthy singleton infant who is born at term.”

The greatest challenge toward achieving that goal remains the cost and availability of fertility services. Currently, only about a quarter of the states require insurance companies provide any coverage for fertility treatments. However, databases  demonstrate that in states where IVF is covered by insurance; fewer embryos are transferred per cycle and lower multiple gestations occur. This actually lowers the cost to insurance companies since there is universal coverage mandated for pregnancies and singleton pregnancies cost less. Therefore, the burden for the cost of multiple pregnancies tends to fall back upon the insurance companies that often opposed providing the fertility treatment as a covered benefit. Hopefully, as this information becomes more widely available we will see more patients choosing SET as the best outcome; instead of simply making a choice based upon personal financial pressures  which are becoming more a by-product of where they live .

[r1]Link to first IVF  http://www.fertstert.org/article/S0015-0282(07)02985-8/fulltext

[r2]Link to https://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?ClinicPKID=0

[r3]http://www.ajog.org/article/S0002-9378(15)00248-3/abstract

[r4]http://www.fertstert.org/article/S0015-0282(11)02256-4/fulltext

[r5]http://www.ajog.org/article/S0002-9378(15)00127-1/abstract

[r6] http://www.asrm.org/insurance.aspx

[r7]http://www.fertstert.org/article/S0015-0282(10)00983-0/abstract

[r8]http://familybuilding.resolve.org/fertility-scorecard

An important aspect of “lifestyle medicine” is helping our patients take control of the factors of their daily routine that may tip them towards a higher pregnancy rate. Toward that end, one of important determining factors of egg quality has to do with whether not the egg has been damaged prior to fertilization. So let’s consider what causes egg damage and what we can do to prevent it.

Each egg that you have has been waiting since you were an infant for the opportunity to grow and develop. During the years that the eggs remain dormant, they are very susceptible to adverse conditions. For instance, small charged particles called free radicals can damage the proteins, membranes and the DNA within the eggs. These free radicals are formed normally as a result of physiologic processes like digestion and ovulation. However, there are lifestyle situations like tobacco use or over-eating that can promote free radical formation.  Additionally, conditions like endometriosis are believed to impair fertility at least partially due to the increase in the production of free radicals. A recent review  detailed how eggs that have been damaged by free radicals have a lower capacity to produce a successful pregnancy.

Your body makes chemicals called antioxidants whose purpose is to be there to capture and neutralize free radicals when they are formed. Since free radicals only exist for an instant, it is important that these antioxidants are always around. Unfortunately, most of us don’t make enough of these little protectors. That’s why foods that contain antioxidants are believed to be so healthful. Not only can they provide us with these chemicals that we need but they can do so when they would be most useful—during digestion. There is evidence that berries of the Acai—a palm tree grown primarily in northern Brazil—may be able to tip the delicate balance in your favor and therefore protect your ovaries from damage.

Studies suggest that Acai berries may contain more antioxidants than blueberries, raspberries or any other potent natural antioxidants. Additionally, the juice contains healthy omega-3 fatty acids suggesting that this may be another means by which it may provide health benefits. To date, one on-going study suggested that women that had failed IVF due to poor egg quality; had an improved outcome after taking an Acai supplement prior to their next attempt. The two to three months prior to an egg’s release represent the time when it is most susceptible to harm. Therefore if you have a low ovarian reserve and/or a history of poor egg quality; you should consider taking an Acai Supplement. A convenient dosing schedule is 1000 mg taken twice each day. There are various supplements available or you can try consuming Acai products two to three times each day as part of a healthy diet. I find the Sambazon products (http://www.sambazon.com/products ) to be diverse and very appealing because they are organic and sustainably harvested.

[r1]Link to http://www.fertstert.org/article/S0015-0282(14)02371-1/fulltext

Earlier this year, a comprehensive review  of advanced fertility treatments demonstrated that the risk of serious complications as a result of advanced reproductive techniques (ART) was relatively low.  Still, there is always an effort to try to reduce any adverse outcomes even further. One of the rare but more serious complications associated with successful IVF treatments is the risk of developing an ectopic pregnancy; a situation that results when the embryo migrates from where it had been placed within the patient’s uterus to another site, most commonly the fallopian tube. The frequency of ectopic pregnancy in patients that conceive through IVF is between 2% and 5%. Ironically, this is higher than the 2% to 3% incidence seen with naturally conceived pregnancies. New insights suggest what may be contributing to the elevated risk associated with ART and what steps that we can take to prevent it from happening

In order to better understand why IVF has a higher risk of ectopic pregnancy, let’s consider what we now know about implantation. The process whereby an embryo successfully establishes contact with the uterine lining is actually a coordinated event that depends upon the timing of several important factors. One major factor is development. The embryo must be develop to the blastocyst stage—where it appears as a fluid filled ball with a clump of cells concentrated at one location. It then must break out of its protective coating in a process called hatching. Another important factor is the hormonal milieu. The uterine lining must be hormonally prepared for the initial contact with the hatched blastocyst; there is typically a limited time period of about 36 hours during which the conditions are ideal for attachment (the first step towards implantation) to occur. A recent analysis   compared several variables associated with different embryo transfer strategies.

For their study, they reviewed over 3,300 embryo transfers. They compared the developmental stage of the embryos as well as whether the embryo transfers were done during the same cycle as the egg retrieval (Fresh) or whether they had been cryopreserved and transferred later (Frozen). The difference between a Fresh transfer and a Frozen transfer is two-fold. Not all embryos develop at precisely the same rate. So with Fresh transfers, some embryos are more developed than others. In fact, they separated their analysis based upon whether it was 3, 5 or 6 days after the egg retrieval. In a natural cycle, an embryo typically enters the uterus 5 or 6 days after it is released from the ovaries. With Frozen embryos, they are actually preserved when they have reached a specific stage of development chosen by the IVF center. As a result most frozen embryos are at the morula stage (day 3) of development or the blastocyst stage where they are ready to hatch. Some embryos reach this preimplantation stage on the 5th day of development and others take until the 6th. If they do not make it by day 6 it is considered an unhealthy embryo. The other distinction is that Fresh transfers tend to be associated with higher than normal hormone levels as a result of the ovaries producing multiple mature eggs instead of just one or two. By contrast, the goal of a Frozen transfer is to create a hormonally balanced environment within the uterus that more closely represents what happens in a natural physiologic conception.

In order to try to differentiate both of these factors, this study compared Day 3-Fresh and Day 5-Fresh to Day 3-Frozen, Day 5-Frozen and Day 6-Frozen, The finding in this analysis was that risk of ectopic pregnancy was lowest for Day 5-Frozen embryo transfers. In fact, the calculated risk for those patients was far less than 1% suggesting that the ideal transfer strategy is to split the ART cycle to optimize the healthy pregnancy rate while minimizing the risk of ectopic pregnancy. A previous study  also found that embryos that were judged to be of poorer quality—based upon their appearance under the microscope—also pose an elevated risk of ectopic pregnancy making the embryo grade a potential third factor to consider. There have also been two other studies  that have also found that frozen embryo transfers (FET) have lower ectopic pregnancy rates than fresh embryo transfers.

Since many centers now have advanced freezing techniques to safely preserve embryos it makes sense for more patients to separate the process of ART into two parts; the first month to create the embryos and the second month to transfer them. Although this split cycle strategy lengthens the time from start to pregnancy, there is compelling evidence that for many patients it will improve their chance of having the highest pregnancy rate with the fewest possible complications and the lowest possible risk.

Link to http://jama.jamanetwork.com/article.aspx?articleid=2088842#Discussion

Link to http://www.fertstert.org/article/S0015-0282(14)02379-6/abstract

Link to http://journals.lww.com/greenjournal/Fulltext/2006/03000/Ectopic_Pregnancy_Risk_With_Assisted_Reproductive.11.aspx

Link to http://www.fertstert.org/article/S0015-0282(12)01889-4/abstract and http://www.fertstert.org/article/S0015-0282(11)00267-6/abstract

There are few topics as emotionally driven as food choices. For most of us, our dietary choices are guided mostly by our taste preferences, familiarity (think comfort foods) and convenience. In fact, much of what passes as nutritional science in the popular media is incorrect or overstated. As a result there are often widely held misconceptions and untruths about what is a “healthy food.” A classic example is soy based food products. About 4 years ago, I wrote a column  to debunk the popular (and inaccurate) belief that some of the hormone-like chemicals—called phytoestrogens—in these healthy beans could interfere with fertility. The latest research goes one step further suggesting that these foods actually boost the pregnancy rates in women undergoing advanced reproductive techniques (ART).

It’s been well established that adding soy based foods can lead to small changes in the hormone balance  of people that eat them. But for too long, people that wanted to promote unhealthy dietary choices successfully created concerns among fertility patients. Then two clinical studies came along that demonstrated women taking soy supplements during either ovulation induction  treatment or IVF cycles  had higher pregnancy rates. The problem with these studies however was that the supplements that were used boosted the level of phytoestrogens to levels that are over 10 times higher than people eating a traditional Asian diet. New research has provided more practical insights into the health benefits achieved by simply switching to easily obtained soy based foods.

This latest study  was very practical because they looked at the dietary choices in a group of 315 women that ultimately completed 520 ART cycles in 2013. Better still, they followed them prospectively to minimize the risk of obtaining biased results. They then looked at various results from their IVF cycles. They found that the eggs from women that were eating foods that contained soy had a higher fertilization rate. More specifically, they found that the clinical pregnancy rate was 11% and live birth rate was 13% when they compared women that were eating soy to age-matched women that were not. In fact, women that were consuming the most amount of soy had a nearly 80% higher chance of success. Bottom line was that soy containing foods seem to be very beneficial to women undergoing fertility treatment without making huge dietary changes.

An important step towards validating any finding is to then try to establish a theory of how the intervention may have resulted in the finding. The previous studies on soy supplements and IVF outcome suggested that the isoflavones—these are the estrogen-like chemicals in soybeans—resulted in a healthier uterine lining and thereby improved the ability of embryos to implant. They based this assumption on the fact that the ultrasound imaging of the lining appeared different. This recent study did not find any such changes. Instead, they hypothesized that the benefit are demonstrated by the fertilization rate of the eggs from the women eating soy vs. those that weren’t The fact that it was higher in the soy group suggests that eating soy may improve egg quality. Regardless of the mechanism, all of the research agrees that dietary soy is associated with higher pregnancy rate and greater chance at a live birth.

Maybe the most important aspect of clinical research is guiding and motivating patients on how and when to implement changes. Given the large number of products that now contain soy as well as the various “meat substitutes” (ie, veggie patties, soy milk, soy yogurt, soy butter) it makes sense to encourage women going through IVF to try to make some conscious changes to select these products or to eat soybeans. Another potential advantage of reducing meat, chicken and fish consumption is that plant based proteins contain far less of the unhealthy aspects of our modern diet like; hormone disrupting chemicals, pesticides and antibiotics. The end result is not only a higher chance of conceiving but also having a healthier pregnancy and giving your child the very best start possible.

[r1]Link to https://thegreeneguide.wordpress.com/?s=soy

[r2]Link to http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=906924&fulltextType=RA&fileId=S0007114500001872

[r3]Link to http://www.rbmojournal.com/article/S1472-6483(10)60465-8/abstract

[r4]Link to http://www.fertstert.org/article/S0015-0282(04)02356-8/abstract

[r5]Link to http://www.fertstert.org/article/S0015-0282(14)02529-1/abstract

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