This headline is a bit misleading in that a similar technique was used in the 1990’s before it was decided that we need to proceed more cautiously in mixing DNA. Currently, the technique described is not available for couples treated in the USA and is only approved for use in treating specific genetic conditions. However, this is an exciting breakthrough that may prove to be useful in areas of reproductive medicine. https://www.newscientist.com/article/2107219-exclusive-worlds-first-baby-born-with-new-3-parent-technique/
One of the most challenging problems to diagnose and treat for couples trying to conceive is the problem of recurrent early pregnancy loss (REPL). As fertility specialists, we spend a tremendous amount of time and energy making sure that we control all of the variables that might improve the chances that a pregnancy gets a healthy start. New evidence shows that women can—and should—make some simple changes in their lifestyle to also improve their chances for a successful outcome.
A study presented at the 2015 meeting of the American Society for Reproductive Medicine recently highlighted the potential impact of a chemical called phthalates on the pregnancies of women going through IVF. This was part of a study called the EARTH study; an investigation on how environmental and lifestyle can impact reproductive health. They measured phthalate levels in the urine of about 250 women going through fertility treatment and then followed these levels in nearly 300 pregnancies. What they found was that women going through fertility treatment that had higher levels of this chemical in their body had a much higher chance of miscarrying then the fertility patients with lower levels. In fact, their risk could be as much as three to four times higher—depending upon their level of exposure.
An important aspect of modern research is to pose the question of “why?” In this case, the question would be “why would phthalates increase the risk of miscarriage.” The answer to that question is by interfering with the ability of ovary to support the development of the early pregnancy. Specifically, after an egg is released from the ovary; the cells that remain at the site of the egg’s origin form a hormone producing unit called a corpus luteum (CL). The function of this CL is to help get the pregnancy off to a strong start until the placenta is large enough to take over hormone production. In 2014 a well designed study found that phthalates directly interfere with the ability of the CL to perform this critical role.
A recent multi-centered clinical study found that women pursuing Advanced Reproductive Treatments (ART) like IVF had lower levels of phthalate in their body than infertility patients pursuing other forms of treatment. The believed explanation for this finding was that patients undergoing IVF may pursue healthier lifestyle choices. For instance, it is estimated that at least 90% of the phthalates in our bodies are due to dietary intake. By reducing processed foods and decreasing consumption of animal fats, phthalate levels fall rapidly. In fact, our bodies are able to eliminate phthalates after only 6 to 12 hours. So it is only through the continued exposure that these chemicals persist in the bloodstream. So by making better choices, patients may be able to reduce their risk of miscarriage by 75%.
Here are some easy steps that you can take to begin reducing your phthalate level today:
- Only use nail polishes that are phthalate free—most add a phthalate called DBP to reduce chipping
- Don’t microwave or cook your food in plastic containers or use plastic utensils to eat hot foods—heat leaches this chemical out of the plastics and into food—the easiest pathway into your body
- Avoid plastic bottles—seek out glass or metal instead. When you must use plastic seek out bottles with the #2, #4 and #5 in the recycle triangle
- Avoid perfumes and scented products—phthalates (DEP) are used to prolong fragrances
- Don’t use air fresheners—most contain phthalates
- Avoid vinyl containing products—many products like lawn furniture, rain coats or shower curtains can not only release phthalates that can be inhaled but they can also be absorbed through the skin as well.
Let’s take a few moments to review some of the latest findings in reproductive medicine. This month there is another first in reproductive medicine as well as new evidence that hormone problems may be passed to spouses. Check out the following:
Ovarian Stimulation for IVF does not increase the risk of cancer: The largest review of the data available provides more reassuring news to women undergoing advanced reproductive treatment. Included in their review was the information obtained from nearly 180,000 women that had undergone IVF therapy. They found that there was no increased risk of ovarian cancer, endometrial cancer, cervical cancer or breast cancer. Although a few isolated studies raised concerns in the past; this new information should further reassure patients and egg donors of that ovarian stimulation will not create future health risks.
First successful birth after woman receives her own ovarian tissue frozen during her childhood: In a new report, it has been proven that ovarian tissue from a child can be removed, frozen and replaced later in her life to restore lost fertility. Previously there have been about 3 dozen cases of women freezing ovarian tissue prior to receiving life-saving chemotherapy. However this was the first report a 14 year old having her fertility preserved through removing an ovary prior to the onset puberty and before receiving chemotherapy. Now at age 27—and two years after a piece of her ovary was transplanted back into her body—she conceived and delivered a healthy child naturally. This proof-of-concept should make fertility preservation a more tangible option for children faced with the need for chemotherapy.
Diet and lifestyle impact embryo quality: A research group recently looked at the quality of 2659 embryos produced by 269 patients. They had data on the diet and some of the social habits of the women that were undergoing treatment as well. They found that eating fruit, vegetables and fish was associated with higher embryo quality. By contrast consumption of red meat, smoking and alcohol reduced the chances that an embryo would develop to the blastocyst stage—the last stage before it hatches. They also found that women that consumed red meat have a lower chance for implantation as well. This is only one study so patients shouldn’t feel compelled to make dramatic dietary changes. However, it should encourage women trying to conceive to pay greater attention to their diet and lifestyle.
Fathers at risk of diabetes after their partners experience Gestational Diabetes: As we continue to seek to prevent new cases of diabetes, an emerging risk factor may be having a partner with a history of gestational diabetes. A study from Canada followed nearly 72,000 male partners after the delivery of their child. They found that the risk of developing diabetes was 33% higher following a pregnancy complicated by gestational diabetes vs. normal controls. The authors theorized that this increased risk may be likely due to shared diet/lifestyle as well as ethnocultural risks. If confirmed however it could provide support that counseling the entire family to prevent later risk may be in order.
Sunshine boosts IVF success: Many studies have looked at seasonal variations on pregnancy rates and tried to explain their fluctuations. But a new study from Belgium has taken their analysis a step further. They looked at a group of almost 11,500 women undergoing IVF at the same center between 2007 and 2013. They then analyzed what the weather was like the month prior to their cycle. Although they did not find a clear seasonal pattern; they did find that women exposed to more sunlight the month prior to their IVF cycle had a higher pregnancy rate. This boost in success translated to about a one third higher chance of conceiving. The authors theorized that the boost might be related to higher melatonin and vitamin D production. The strongest correlation was actually with live birth rate.
Men with low-normal testosterone levels have high rate of depressive symptoms: There has been a recent trend to check testosterone levels in men; most likely due to media attention and advertising. This prompted a group of researchers to study whether or not there was a higher rate of depression and/or depressive symptoms in people requesting such testing. They screened 200 men with an average age of 48 (range 20 to 77) with a validated symptom questionnaire. They found 56% screened positive. In fact, the risk that a man experienced depressive symptoms seemed highest for the younger men with low-normal testosterone levels. Follow up studies are needed to determine if testosterone replacement—instead of traditional antidepressants—would relieve these symptoms.
Robert Greene, MD, is a reproductive endocrinologist with Conceptions Reproductive Associates in Denver.
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.
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
Unlike men, it is very difficult to assess a woman’s fertility at any given time. A man simply needs a quick trip to the video closet to collect a sperm specimen for viewing under the microscope; whereas it is only through the process of IVF that it is possible to truly assess the quality of a woman’s eggs. This entails several weeks of medication to prepare for an egg retrieval at which time her eggs are collected, fertilized and then monitored for normal embryo development prior to placing them back in her body to implant and become a pregnancy. There is no comparable test. As a result, recommendations of treatment to improve egg quality have been based upon unproven and often misguided observations.
One of the more popular myths has been to encourage women to consume wheat grass. Although the suggestion is harmless enough, the only basis for its link to “improved fertility” can be traced back to a Kansas farmer from the 1930’s named Charles Schnabel. He claimed that when he fed wheat grass to his ailing chickens that they not only recovered but increased their egg laying potential. Not the best model to making assumptions about human egg quality.
Another folk remedy is the use of royal jelly. This is a special secretion made by honey bees and fed to future generations in order to cultivate the conversion of a drone to a fertile queen bee. Unfortunately, it doesn’t work as well in humans and has been linked to severe allergic reactions, asthma and even in rare situations death. Analysis of this chemical product reveals that it is little more than vitamins and other healthy nutrients. I think the lesson here is that good nutrition is important which is why it is a good idea to start a prenatal vitamin at least 3 months prior to trying to conceive.
A more recent recommendation has been for women with low ovarian reserve to take the pre-hormone supplement DHEA. While there is limited data that it may cause a slight increase in the number of eggs produced— in this clinical trial the average participant went from producing three eggs to four—there was not any demonstration of an improved pregnancy rate. From a practical standpoint, since it required 90 days of the supplement prior to undergoing IVF these patients may have produced even more eggs by going through 2 or 3 cycles of IVF instead. Most importantly, without a measureable improvement in pregnancy rate, it is premature to suggest that this may improve egg quality. There are ongoing studies which may provide insight as to whether there are some women that can benefit from this treatment but at this point the question remains unresolved. In fact, the available research is given a “C” grade indicating “there is unclear scientific evidence for its use.”
A well researched suggestion has been to optimize the energy storage/ utilization of the egg through supplementation with CoEnzyme Q10. This has not been considered a necessary supplement since your body can manufacture this on its own. However, the human egg has the greatest energy demand of any cell in the body; and its needs go up considerably during the process of follicle growth. It was therefore theorized that supplementing with CoQ10 could improve egg quality. Early studies have confirmed this theory.
Finally, it’s worth mentioning that avoiding harmful chemicals is also likely to improve egg quality as well. There is a growing list of toxins referred to as endocrine disrupting chemicals (EDC’s) that have been linked to diminished fertility and reduced egg quality in animals. Many of these same products have been tied to a reduction in male fertility which is easier to track through diminished sperm counts and decreased motility. Until it’s confirmed that EDC’s don’t compromise egg quality as well, I recommend that you take steps to reduce your exposure to chemicals like Bisphenol A (BPA) and phthalates.
In summary, here are some steps you can take and have confidence that you’re doing all that you can to optimize your chance becoming pregnant:
- Avoid well intended but not well researched recommendations
- Begin a prenatal vitamin several months before you want to become pregnant
- Take CoEnzyme Q10 to optimize the quality of your eggs—typical dose is 100 mg taken two or three times each day
Consider modifying your food choices, cooking preparation, personal care products and lifestyle to reduce your exposure to endocrine disrupting chemicals. If you need some specific advice, check out my book PERFECT HORMONE BALANCE FOR FERTILITY which is loaded with useful charts, tables and tips.
A reader of this blog recently requested that I explain why I utilize certain medications for my IVF/fertility patients and caution against the use of others. It all comes down to their effect upon egg quality. Although there is still much to be learned, most fertility specialists agree that what is going on hormonally in a woman’s body will impact the success of her cycle. That’s why I feel that it’s so important to optimize their hormone balance and individualize the protocol to suit each woman’s unique situation. Here’s what we know.
Prior to the month that an egg is going to have its opportunity to ovulate, the DNA within it remains inactive. It has been in this state of rest since birth. Whether or not egg develops in an environment that is balanced more toward estrogen or testosterone is the key factor which will determine whether it will mature normally. Eggs that are “estrogenized” are more likely to mature earlier, fertilize normally and develop into healthy embryos. “Androgenized” eggs are more likely to become atrophic, fertilize abnormally or become a first trimester miscarriage.
Typically, a woman’s fertility begins to drop dramatically about 13 years before she’s going to enter menopause; typically their mid to late thirties. This drop is associated with a shift toward a higher level of testosterone within the ovary and not surprisingly a drop in egg quality. What triggers this hormone shift within the ovary is that as women age they produce a more potent form of the hormone LH as well as develop a tendency to have greater sensitivity to this hormone. Therefore, when designing a protocol for a fertility treatment cycle, I feel it is important that we shift the balance toward a higher level of FSH relative to LH in order create a more favorable setting for egg maturation. Creating such protocols has been among the great accomplishments of my friends and colleagues Drs. Geoffrey Sher and Jeff Fisch when they demonstrated in their landmark paper that pregnancy rates can be substantially improved in women with a history of previous fertility treatment failure. The trick is to stimulate the ovaries with an FSH dominant signal early in their development and then add in a low level of LH late in maturation to optimize the quality of as many eggs as possible. From a practical standpoint, that means being able to control FSH and LH levels independently.
Many centers use simplified preparations of FSH and LH for their ease or lower cost. But I describe this as being similar to mixing your salt and pepper together in the same shaker. It may work in some situations but most patients need varying degrees of adjustment get “more salt” or “less pepper.” What makes this approach even more problematic is that these mixed preparations—called urinary derived gonadotropins—are made from the urine of the least fertile population, women in menopause. In effect, that “makes the pepper even spicier” as these women produce a far more potent form of LH. All too often, this results in a disappointing outcome. It is true that the lower cost, pre-combined products work well enough when given to the most fertile patients. I believe that’s what keeps the market for them alive. In addition to their impact upon egg quality however, I am also concerned about the impurities that they contain.
A recent analysis of both the standard and more highly purified urinary preparations found them to be 95 to 99% free of contamination. These contaminating proteins can not only impact the how a woman’s ovaries respond to them, they can also initiate an allergic reaction. Even more problematic, they carry a very low but real risk of transmitting infection which recently resulted in their use being banned in England and the rest of the United Kingdom.
In summary, the use of the latest technology has made it possible for companies to manufacture untainted FSH and LH in separate preparations so that their dosing can be uniquely adjusted to each patient’s individual needs. Better still, these are BioIdentical products that are exact replicas of the hormones produced by fertile women. Additionally, they are 100% pure and therefore free from the risk of allergic reaction or infection. For all of these reasons, I believe that these products are most suited toward meeting the needs of the patients that I see in my practice.