Conceivability_What I Learned Exploring the Frontiers of Fertility
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Yet pairing awareness of how our environment affects us with a greater understanding of the time frame in which our eggs are maturing and forming their genetic material opens the door to exciting new possibilities. Armed with this knowledge, women can actually improve their chances of developing healthy eggs in as little as two to three months.
Key vitamins such as folate (a B vitamin, or folic acid, its synthetic supplement), B6, B12, and Coenzyme Q10 (CoQ10), for example, have all been shown to play important roles in the development of healthy eggs, the smooth operation of the ovulatory process, and the quality of embryos.18 Folate, widely recognized for its impact in preventing birth defects, also plays an important function in making new copies of DNA when a cell divides, rendering it essential at every stage of fertility, from egg to fetal development.19 Multiple studies from a range of countries demonstrate the significance of adequate levels of folate and vitamins B6 and B12 on the development of healthy eggs;20 a Dutch group found that women with twice as much folate as their peers were three times as likely to conceive in a given cycle, and that women with higher levels of vitamin B12 produced better-quality embryos.21
Similarly, researchers in Italy have found high levels of CoQ10, a molecule found in just about every cell in the body and critical to preserving egg quality and fertility, in ovarian follicles containing high-quality eggs and in eggs that became high-quality embryos.22 CoQ10 is believed to improve egg quality by helping eggs to produce more energy, which is critically important to an egg’s ability to successfully complete the process of meiosis. As women age, the mitochondria in their eggs becomes less efficient at producing the energy needed to mature and fertilize, perhaps the single most determinative factor in egg and embryo quality.23 CoQ10, importantly, improves mitochondrial function and protects mitochondria from damage,24 enabling an egg to have a far greater chance of growing and dividing successfully.
Simply taking a prenatal vitamin including these important B vitamins and CoQ10 during the months before conception can substantially increase the odds of conception and decrease the odds of miscarriage. Women like Sharon and Stacy are great believers. After five years of unsuccessful fertility treatments following her first baby, Sharon turned to multivitamins and acupuncture and conceived naturally, giving birth to a beautiful, healthy boy. Stacy likewise conceived after giving up on IVF following multiple failed attempts, turning instead toward a more natural approach—multivitamins, acupuncture, and eliminating toxins like BPA. She now has a gorgeous, healthy girl.
Bisphenol A, or BPA, found in a great many plastics, such as water bottles and food containers as well as paper receipts, is a fertility disaster. Numerous studies illuminate the devastating effects of BPA on fertility,25 not to mention the hundreds of studies over the last fifteen years that point to the toxic effects of BPA on diabetes, heart disease, liver failure, and obesity. Women with high levels of BPA have lower estrogen levels (estrogen is needed to stimulate ovarian follicles to grow), fewer eggs, a lower fertilization rate for those eggs, and fewer fertilized embryos implanting in the uterus—all factors that create enormous challenges to a woman trying to conceive.26 A group of researchers at the Harvard T. H. Chan School of Public Health found that the impact of BPA on getting pregnant was so significant that the quartile of women with the highest BPA exposure had only half as much chance of an embryo implanting as the quartile with the lowest BPA exposure.27 Crucially, BPA also impedes normal cell division during meiosis, leading to severe chromosomal abnormalities, and has been shown to interfere with stimulation protocols and egg development in women undergoing IVF.28
Not surprisingly, given the impact of BPA on egg quality, studies in the United States29 and Japan30 also indicate that BPA raises the risk of miscarriage. In one study, where pregnant women with fertility challenges (either trouble getting pregnant, a history of miscarriage, or both) were separated into four groups based on the level of BPA in their blood serum, it was found that the women with the highest levels of BPA had an 80 percent greater likelihood of miscarriage than those with the lowest levels. Even tiny amounts of BPA distort hormonal systems and damage eggs, decreasing the chances of conception and increasing rates of miscarriage.
Frighteningly, the impact of BPA may be multigenerational. Because fetal exposure may damage all the immature egg cells in a developing female, “the implications for human fertility are profound.”31 Not only is a daughter of a woman exposed to BPA at risk, but if the daughter’s eggs are all affected, her future children may be at risk too. Unfortunately, because the potential disturbances occur in utero, any impact on the offspring will not become evident until the children reach maturity, making a clear connection between cause and effect a daunting task.
But importantly, the effects of BPA on the body are temporary. Eliminating or minimizing exposure to BPA will swiftly lower the amount of BPA in the system. Given the impact of BPA during the all-important time of meiosis, it can be extremely beneficial to limit exposure during the months before trying to conceive. Simple things like throwing out plastic containers (yes, including bottled water!), avoiding hot food packaged in plastic, washing hands after handling receipts, and choosing shampoos and cosmetics that are BPA free, particularly in the weeks and months before ovulation, can increase the odds of a healthy baby.
In her book, It Starts with the Egg, Rebecca Fett describes her journey from her diagnosis of diminished ovarian reserve to the mother of a healthy baby. Not yet thirty years old when she was diagnosed and told she faced very low odds of producing healthy eggs, Rebecca followed a comprehensive, scientific “self-help” approach, taking daily supplements, eliminating plastics and other toxins, and altering her diet. In only a few months, she increased the number of eggs developing in her ovaries from just a handful to over twenty, nineteen of which eventually fertilized and grew to the blastocyst stage—rendering a record for her prestigious fertility clinic. She and her husband opted to transfer only one blastocyst, resulting in the birth of her beautiful, healthy son.
Similarly, my friend Susan, who had experienced multiple IVF failures with very low egg counts when attempting to conceive her second child in her late thirties, pursued a program of vitamins and eliminating toxins, together with acupuncture and traditional Chinese medicine, improving her egg quality so radically that she conceived naturally.
Low Dosage or “Mini” and Natural-Cycle IVF
“Far too little proper research is being done to improve IVF. We are very complacent,” said IVF pioneer Lord Winston in 2008, noting the disappointing lack of improvement in IVF success rates over several decades. Observing that even the lackluster success rate of around 30 percent was possible only because doctors were “picking the right patients to treat,” Lord Winston concluded: “I can see in five to ten years time at most, new therapies to produce eggs which are much more likely to be viable and the embryos quality depends on the quality of the egg.”32
Nearly nine years later, many experts agree with Lord Winston, and there is mounting evidence that conventional IVF stimulation may not be the best way forward—at least not in all cases. “We have created an enormously wasteful system,” Dr. Bart Fauser, chair of the department of reproductive medicine and gynecology at University Medical Center Utrecht, declared at an international conference of expert scientists and doctors.33 “Not all eggs are created equal,” the widely cited Dutch specialist continued, explaining that eggs come from very different follicles and very different stages of development. In response to the idea that the more eggs you start out with, the more good ones you will get: “It is not that simple,” he concluded. “Embryo quality is very complex.”
An IVF cycle has many variables contributing to its eventual success or failure. While the generation of eggs is clearly key, it is not the only ingredient needed for a winning recipe. The egg must develop into a healthy embryo and then implant. The ovarian stimulation protocols used in IVF do not only have implications for the quality of the eggs, but also for the endometr
ium, or endometrial lining, which lines the uterus, and which typically thickens throughout the menstrual cycle in preparation for receiving a fertilized egg. In addition to the higher rates of chromosomal abnormalities seen in the embryos of stimulated cycles, as many as half of all embryos transferred do not implant, suggesting that it is not only the quality of the embryo that is important to conception but also a uterine lining ready to provide a hospitable environment.
I experienced the problems of a thinning endometrium firsthand, as my uterine lining dwindled in successive IVF cycles, to the point that it reached a mere four to five millimeters in my last few attempts in London, far short of the minimum eight to ten millimeters hoped for by my doctors. When they added Viagra to my drug cocktail, my lining increased slightly to six millimeters, still short of the goal. But I was simply told that, among my many challenges, I had a thin lining. I had no idea that my repeat high-dosage IVF cycles might be causing or contributing to the thin lining.
Due to the falloff in numbers at every stage of the process, it takes nearly twenty oocytes (immature egg cells) to generate one live birth using conventional IVF. Yet interestingly, two studies found limits to the optimal number of eggs retrieved. The first showed that retrievals of more than ten eggs produced lower-quality eggs and lower fertility rates than retrievals of ten or fewer eggs. The latter study showed a similar fall in pregnancy rates when more than thirteen eggs were retrieved in a given cycle.34
“The US is much more aggressive than Europe in obtaining eggs,” Dr. Jacques Cohen declared.35 Educated in Holland, Dr. Cohen, a renowned embryologist who began his career at Bourn Hall Clinic, the world’s first IVF clinic, is director of the ART Institute of Washington as well as director and cofounder of Reprogenetics. Sometimes this aggressive approach is better, he explained, but not always. Acknowledging the potential impact on embryo quality, aneuploidy, and the endometrium, experts in much of the world are moving toward using the lowest effective dosages in treating their patients. For example, highlighting the lack of evidence that higher dosages of stimulation help people have children, Dr. Zion Ben-Rafael, one of Israel’s leading fertility experts and founder and chairman of the World Congress on Controversies in Obstetrics, Gynecology & Infertility, emphasized that the use of any dosage higher than 300 to 350 IUs of gonadotropins should be questioned, urging his colleagues to in fact lower the doses if a patient is responding well. Those like Dr. Oxana, Dr. Ben-Rafael, Dr. Fauser, and a host of others, believe we can get better results in IVF with fewer drugs, less intervention, and yes, fewer eggs.
Low dosage or “mini” IVF aims to do exactly that. Focusing, as the New Hope Fertility Center in New York City aptly states, on “quality over quantity,” low-dosage IVF seeks to stimulate a far smaller number of eggs with ideally less disruption to the system. As Dr. Oxana first told me in Moscow, it takes only one good egg to make a baby, and that egg is more likely to be obtained with fewer external threats to its natural development. Although mini IVF protocols vary, ranging from clinics that use only Clomid or letrozole for stimulation to those that use Clomid in combination with several days of low-dose (150 IU) gonadotropin injections to those, like mine, that included over a week of low-dose injections, the goal is generally to produce in the range of three to five eggs, a higher proportion of which is expected to be normal.
Mini IVF offers certain advantages for patients, not the least of which is financial. Lower dosages of hormones over fewer days results in fewer side effects, quicker cycles, and lower costs, without reducing pregnancy rates per embryo transfer. The promise of an easier cycle is no small thing: when I tried the lower dose IVF, I was certain that it wasn’t working because I didn’t feel a thing. No tension headaches. No bloating. No irritability (my polite way of saying I was a crazy person about to snap at any moment). And its success rates are impressive. Dutch researchers found higher ongoing pregnancy rates per embryo transfer with mild stimulation.36 A Spanish study found significant increases in rates of fertilization and chromosomally normal blastocysts in reduced-dose IVF cycles.37 A Russian team similarly found higher numbers of chromosomal abnormalities among eggs subject to conventional controlled ovarian stimulation than those without.38
In use in other countries for more than a decade, it is finally starting to catch on in the United States, albeit at very few clinics, due to the distinct benefits it offers: a higher proportion of chromosomally normal embryos than that of conventional IVF, fewer mosaics, lower risk of ovarian hyperstimulation, reduced impact on the uterine lining (important for implantation), and lower risk of multiples.39 In perhaps the first randomized controlled study in the United States, Dr. Zhang and his team at New Hope Fertility Center assigned 564 women to either a mini IVF group, which underwent single embryo transfers, or a conventional IVF group, which experienced double embryo transfers. The cumulative live birth rate was 49 percent for the mini IVF group compared to 63 percent for the conventional group, but the mini IVF group had no cases of ovarian hyperstimulation compared with sixteen cases, or 5.7 percent, of moderate to severe hyperstimulation in the conventional group. Additionally, the mini IVF group experienced a multiple pregnancy rate of only 6.4 percent, as compared to 32 percent for the conventional group, at a far lower cost per cycle.40 While costs vary between clinics, mini IVF in the United States typically costs approximately $5,000 to $7,500 per cycle, which can be two to four times less than the cost of conventional IVF. So while the success rate per cycle (although not per embryo) may be lower, some women, particularly those with polycystic ovaries who are at higher risk of ovarian hyperstimulation, or those with low ovarian reserve, may prefer the less expensive, less invasive protocol that can be repeated in back-to-back cycles.
Going one step—or perhaps a leap—further than mini IVF is the practice of natural cycle IVF. Natural cycle IVF, pioneered in Japan more than twenty years ago, involves removing an egg in an unstimulated cycle. No Clomid, no hormone shots. In the vast majority of these cycles, one egg is obtained through the egg retrieval—a “one shot” situation I imagine would be stressful for a good deal of women and couples. But I was amazed to discover how well those solo embryos could do. The live birth rate per embryo for women under thirty-five was 26.6 percent using natural IVF, as compared to 20.6 percent using mini IVF and 4.3 percent using conventional (high-dose) stimulation protocols. That’s nearly four times higher than conventional IVF! The overall success rates, not surprisingly, were lower among older women, but the correlations remained the same; for women aged thirty-eight to forty, for example, the natural stimulation group had live birth rates of 13.6 percent per embryo compared to 10.6 percent and 3.1 percent for the mini and conventional IVF groups, respectively.41
These statistics do not address the fact that it may take many cycles to achieve success with natural IVF, and that in stimulated IVF there is a bigger pool of embryos from which to choose. But the implication seems clear: an egg obtained without the typical high-dose gonadotropins is more likely to be viable than one obtained through conventional ovarian stimulation, and has a greater chance of becoming a live baby.
Critics of both low-dose and natural IVF argue that these methods are not for everyone, contending that many women will end up with no embryos to transfer and insisting that higher numbers of eggs are needed to find the viable ones.
But the point is: there are options. And it is important to ask about them and to assess what makes the most sense in each individual case. Identify specific problems. Understand that there are different paths.
For certain categories of women, such as those with polycystic ovaries, like me, who have a tendency to produce high numbers of eggs and are at risk of ovarian hyperstimulation syndrome, or who—also like me—experience irregular or absent ovulation, or those with endometriosis or a low ovarian reserve, low-dose IVF seems to make a lot of sense. It is certainly worth discussing with a specialist. Others may require higher levels of stimulation. If there is one thing I have learned through my own experien
ce, as well as my encounters with numerous others, it is that no one size fits all in confronting infertility.
Improving Egg Quality through Hormones: The Pregmama Story
“What if we could use hormones to actually make eggs healthier inside the woman? Improve egg quality and possibly eliminate the need for IVF in some cases?” Dr. Lori Bernstein’s enthusiasm came through on the phone, and I was excited too. A medical way to cure aging eggs?
Dr. Bernstein’s interest is both personal and professional. A doctor of biology educated at Johns Hopkins University and Harvard College, Dr. Bernstein and her husband easily conceived six times but miscarried each time. Her seventh pregnancy happily was a charm, and she gave birth to their healthy, beloved baby daughter. But when they tried to conceive a sibling for their daughter, she was back on the treadmill of losses. After nine pregnancies, Dr. Bernstein and her husband had one daughter, lots of heartache, and also lots of data. They had tested the remains from many of her miscarriages, and each one had chromosomal abnormalities. Driven by an intellectual desire to understand the root causes of egg aneuploidy as well as an emotional desire to help others have babies, she decided to switch her professional focus from cancer research to reproductive endocrinology and egg biology.
“We have to overcome the dogma,” Dr. Bernstein told me when we first spoke. She is now the founder and chief scientific officer of Pregmama, LLC as well as an adjunct professor at the University of Maryland School of Medicine and at Texas A&M University College of Veterinary Medicine & Biomedical Sciences. “The ‘eggs can’t be cured’ dogma . . . the ‘inherent aging problem with eggs’ dogma,” she explains.