Fertility

A large body of scientific research supports the safety and effectiveness of intrauterine devices and other forms of long-acting, reversible contraception (LARC) for adolescents, and physicians should offer these birth control methods to young women in their care. That’s the message behind a series of review articles published this week in a special supplemental issue of the Journal of Adolescent Health.

Stanford ob/gyn expert Paula Hillard, MD, who edited the supplement, explained to me that doctors are missing a great opportunity to prevent unwanted pregnancies by not offering young women the LARC birth control methods, which include IUDs and hormonal implants. Not only are the LARC methods very safe, the rate of unintended pregnancy with typical use of these techniques is 20 times lower than for alternate methods such as the Pill or a hormone patch.

But a design flaw in one specific IUD used in the 1970s - the Dalkon Shield - increased women’s risk for pelvic infections and gave all IUDs a bad rap. Use of IUDs among adult American women has been low ever since; it’s even lower in teens.

“Long after it was proven that the Dalkon Shield was particularly bad and newer IUDs were much safer, women were just scared,” Hillard said. “Not only did women stop asking for for them, many doctors also stopped using IUDs.”

The new review articles that Hillard edited are targeted at physicians but contain some interesting tidbits for general readers as well. The article titled “Myths and Misperceptions about Long Acting Reversible Contraception (LARC)” provides scientific evidence to refute several common myths, concluding, for instance, that IUDs don’t cause abortions or infertility, don’t increase women’s rates of ectopic pregnancy above the rates seen in the general population, and can be used by women and teens who have never had children.

And, as Hillard put it for me during our conversation, “These birth control methods are very safe and as effective as sterilization but completely reversible. They work better than anything else, and they’re so easy to use.”

Previously: Will more women begin opting for an IUD?, Promoting the use of IUDs in the developing world, and Study shows women may overestimate the effectiveness of common contraceptives
Photo, by ATIS547, shows a public sculpture on the campus of the University of California, Santa Cruz that is affectionately known as the “Flying IUD”

Updated 12-6-12: In the video above, Shawn Chavez, PhD, first author of the study, describes the work and its significance.

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12-4-12: Couples who turn to in vitro fertilization, or IVF, are desperate to have a family. But, despite many advances, the odds of a successful pregnancy from each round of costly, emotionally demanding embryo transfer are only about 30 percent. The problem stems from the fact that many human embryos are faulty from the earliest stages and will never develop successfully.

Stanford researchers Renee Reijo Pera, PhD, and Barry Behr, PhD, have been working to find out why - and to develop ways to increase the odds of a successful pregnancy through IVF. They report findings from some of their work in today’s Nature Communications, which I describe in a release:

The research suggests that fragmentation — a common but not well-understood occurrence in the early stages of human development in which some of the cells in an embryo appear to break down into smaller particles — is often associated with a lethal loss or gain of genetic material in an embryo’s cells. Coupling a dynamic analysis of fragmentation with an analysis of the timing of the major steps of embryonic development can significantly increase the chances of selecting an embryo with the correct number of chromosomes, the researchers found.

…

“It is amazing to me that 70 to 80 percent of all human embryos have the wrong number of chromosomes,” said [Reijo Pera], professor of obstetrics and gynecology. “But less than 1 percent of all mouse embryos are similarly affected. We’re trying to figure out what causes all these abnormalities.”

Reijo Pera and Behr started a company called Auxogyn to investigate ways to bring these findings into the clinic. The company, which is now privately held, is currently conducting clinical trials of an earlier version of the technique. Reijo Pera and Behr hold stock in the company.

Continue Reading »

Bioengineer Stephen Quake, PhD, has been in the news a lot lately. Earlier this month, his lab reported the first non-invasive whole-genome sequencing of a fetus using only the mother’s blood. Now he’s broken new ground again by sequencing the whole genomes of single sperm cells. The research is published today in Cell. As I explain in our release:

The entire genomes of 91 human sperm from one man have been sequenced by Stanford University researchers. The results provide a fascinating glimpse into naturally occurring genetic variation in one individual, and are the first to report the whole-genome sequence of a human gamete — the only cells that become a child and through which parents pass on physical traits.

Quake and his colleagues, including Barry Behr, PhD, HCLD, the director of Stanford’s In Vitro Fertilization Laboratory, were able to identify places in each sperm genome where sections of chromosomes had been swapped in a natural process called recombination. The exact locations and number of times the swaps occur vary in each cell. When the process goes well, it’s an important way to add genetic variation and ensure that a child is a blend of DNA from all four grandparents. When it goes awry, it can lead to infertility or genetic problems in the fetus.

More from the release:

The Stanford study showed that the previous, population-based estimates were, for the most part, surprisingly accurate: on average, the sperm in the sample had each undergone about 23 recombinations, or mixing events. However, individual sperm varied greatly in the degree of genetic mixing and in the number and severity of spontaneously arising genetic mutations. Two sperm were missing entire chromosomes. The study has long-ranging implication for infertility doctors and researchers.

“For the first time, we were able to generate an individual recombination map and mutation rate for each of several sperm from one person,” said [Behr]. “Now we can look at a particular individual, make some calls about what they would likely contribute genetically to an embryo and perhaps even diagnose or detect potential problems.”

Previously: New techniques to diagnose disease in a fetus

Polycystic ovarian syndrome (PCOS) affects as many as 5 million women in the United States and can occur in girls as young as 11 years old, according to the most recent data from the federal Office on Women’s Health.

Women with PCOS produce excessive amounts of the hormone androgen, which inhibits ovulation and can cause fluid-filled sacs to develop on the ovaries. The conditions is the most common cause of female infertility. For women with PCOS who are undergoing infertility treatment, physicians may administer the hormone progestin in a single course before drug treatment begins.

But new research from the National Institutes of Health (NIH) shows using progestin in infertility treatment for women diagnosed with PCOS may decrease the odds of becoming pregnant. In the study, researchers analyzed data from a 2007 study and compared the effectiveness of ovulation induction combined with advance progestin treatment to that of ovulation induction alone. According to an NIH release:

The researchers found…that women who skipped the progestin treatment before receiving fertility drugs were four times more likely to conceive than were women given progestin. Ultimately, 20 percent of the women who did not receive progestin gave birth, compared with about 5 percent of the women who received progestin.

Interested to know more about the implication of the findings on fertility research and treatments, I contacted Lynn Westphal, MD, associate professor of obstetrics and gynecology at Stanford. She commented on the study, saying:

These are very interesting findings that need to be confirmed with a prospective study. If confirmed, these results will change how we manage our PCOS patients, and perhaps other infertile women, needing ovulation induction.

Previously: Patients turning to acupuncture to boost fertility, New York Times shows how Stanford researchers solved the “egg maturation puzzle” and Stanford researchers help awaken sleeping egg-producing cells

Will in vitro fertilization gradually morph from a blessing for infertile couples to a preferred pathway to parenthood?

In January, I wrote about a talk given by Stanford law professor Hank Greely, JD. In that talk, Greely noted science’s steady advances in the genetic analysis of living embryos; the production of gametes (egg and sperm cells) from other easily accessed cell types; the matching of genetic variations to not only disease predispositions but also behavioral and physiognomic traits; and gene therapy, which could in theory modify those characteristics in gametes. Greely followed up with a stark prediction: Within the next 50 years or so, the majority of babies in developed countries will be spawned in IVF clinics.

As I wrote then, quite apart from some cautionary arguments regarding the ethics of such interventions, there were some strictly scientific grounds for skepticism. This report of a recent meta-analysis of IVF’s effects, which concludes that babies conceived this way are at increased risk of having birth defects, reinforces those concerns:

Zhibin Hu at Nanjing Medical University and colleagues collected the results of 46 studies that compared the number of birth defects among children conceived using an IVF technique to children conceived normally. For more than 124,000 children born through IVF or using [an associated technique] in which a single sperm is injected directly into the egg, the risk of having a birth defect was 37 percent higher than that of the other children, they found.

This is by no means proof that IVF is, in itself, a dangerous procedure. It may merely be that the people who tend to use IVF are already more likely to have children with birth defects.

Still, the could be another flashing yellow light for birthing technocracy. The medical trade-offs of IVF and related technologies are such, and likely to remain such for a long time, that people without fertility problems per se will likely opt to go the old-fashioned route rather than high-tech option. A prominent exception: people who are carriers for a single-gene disorder they don’t want transmitted to their kids.

Previously: The end of sex?, Sex without babies, and vice versa: Stanford panel explores issues surrounding reproductive technologies, and Stanford’s IVF research on Time’s top ten list

We’ve written before about autoimmune disease and pregnancy, and the fact that having children seems to be safe - and even beneficial - for women with one such disorder. Now comes research showing that having lupus or rheumatoid arthritis may affect how many children a woman has: In a survey of 578 patients, more than half said they wound up with fewer children than what they had hoped for.

As The Checkup reports:

According to [the study] it appears that some women diagnosed with RA or lupus during their childbearing years consciously choose not to have children after they’ve been diagnosed. Those choices may be based on concerns that they may pass their disease on to a child, that the medication they take to manage their condition may harm a child, or that their condition might render them unable to properly care for a child.

Beyond those understandable concerns, the study found that women with RA who had had fewer children than they had once planned had experienced higher rates of infertility and those with lupus who’d had fewer children than planned had higher rates of miscarriage than women who had the number of children they had originally planned.

In a WebMD article, first author Megan Clowse, MD, MPH, from Duke University Medical Center, noted that potential fertility problems among RA patients haven’t been studied - and need to be. And:

She adds that women with rheumatoid arthritis who wish to have children need to know that their ability to conceive may be compromised.

“This needs to be part of the conversation,” she says. “Women with rheumatoid arthritis who want to have children may be better off trying to conceive sooner rather than later if their family circumstances support this.”

The study is being published in Arthritis Care & Research.

Previously: Multiple sclerosis doesn’t appear to pose pregnancy-related risks, Childbirth may be beneficial for MS patients and Encouraging news for pregnant women with MS or epilepsy

Somebody, somewhere, must have been having sex during the noon hour yesterday. But inside a small classroom in Stanford’s Li Ka Shing Center, about 30 attendees were sitting in a U-shaped formation listening intently as Stanford law professor Hank Greely, JD, made an astounding prediction: Within the next 50 years or so, Greely said, the majority of babies in developed countries will be spawned in IVF clinics.

Greely is chair of the of Stanford Center for Biomedical Ethics’ steering committee chair as well as director of Stanford’s Center for Law and the Biosciences. He sat in on a panel discussion I moderated last year about the societal issues posed by new reproductive technologies. Clearly, he’s been thinking about this a lot.

The provocative title of Greely’s talk, “The End of Sex,” was not meant to imply the demise of sexual relations or gender differences or the basic one egg/one sperm requirement. Rather, he said, sexual intercourse as a mode of conception will become outmoded, thanks to steady improvements and cost reductions in whole-genome sequencing, analyzing an embryo’s genome in a dish without impairing the embryo’s viability, and making gametes from iPSCs (induced pluripotent stem cells) generated from easily reached tissue such as skin. Like embryonic stem cells, iPSCs can differentiate into every one of the 200-odd cell types that make up the human body. (And if gametes can be begotten from skin via iPSCs, age and even gender will no longer pose a barrier to creating thousands of embryos to pick from.)

Four or five decades is a long time in the life-science business. And so a half-century hence, said Greely, “most children will be conceived in IVF clinics” - as selecting your kids for health traits gets not only cheap and easy but outright encouraged by insurance companies and governments trying to rein in health-care expenses. Tossing a measly $5K into the kitty for prenatal genetic diagnosis to predict other, not strictly medical traits from height to sociability to IQ will prove irresistible for people already ready to fork over an extra twenty grand a year for the right preschool, Greely suggested.

Putting aside some truly gnarly ethical issues (eggs or sperm from two-year-old girl’s skin? a dead man’s? a pilfered toothpick?) not to mention profoundly deeper concerns (see The Abolition of Man, by C.S. Lewis), I’m skeptical for other reasons. The notion that a majority of babies will originate from a lab procedure depends on the procedure’s perceived utility: People have to believe that optimizing embryos absent serious health concerns actually makes for better babies. But would it?

Here’s the thing: PGD, properly performed, hasn’t yet been shown to impair embryos’ progress to babyhood. And the follow-up necessary to ensure that no long-term harm occurs awaits several more decades of careful follow-up. In PGD, one cell is teased from the eight or so that compose an early embryo, then subjected to genetic scrutiny. The assumption that the remaining cells can fill in for the missing one, is just that: an assumption. Serious researchers, such as Magdalena Zernicka-Goetz, PhD, of the Gurdon Institute, have shown position-dependent differences in embryonic cells at the earliest stages of development.

Plus, many of the most interesting inherited human traits owe to not one, but scores or hundreds of genes working in concert. Many genes are pleiotropic, so an improvement in one desirable trait (say, athletic prowess) comes at the expense of another (say, intelligence). Besides, there’s more to a human cell’s hardwiring than mere DNA. Cells’ properties (and those of the person those cells compose) depend on activation levels of each gene in each cell, which in turn depend on epigenetic settings - chemical rheostats - that are themselves inherited, to some degree, along with the DNA.

Anyway, no amount of genetic selection can forecast with any accuracy the environment in which a newborn’s genetic program will play out. Today’s “lethal disease” becomes tomorrow’s nuisance. I suffer from a genetic defect that surely would have caused my early death 3,000 years ago. It’s called “nearsightedness”. Big deal; I wear contact lenses. Who knows what “the just-right genome” will look like 50 years from now?

Previously: Sex without babies

Cancer survivorship has been on my mind since writing a Stanford Medicine article on the topic. The (amazing) woman on whom my story focuses was in her late 30s and had two small children when she was diagnosed with lymphoma, and she has spent the last decade-plus living with the consequences of her disease and subsequent treatment. From her I learned of the great hurdles and challenges that can face survivors; pain, fatigue, depression, organ damage, sleep disruption, sexual dysfunction, cognitive disarray and financial struggles make up just a partial list of potential problems.

For people who are diagnosed at a younger age than the patient I featured, fertility is often also a real issue - and that’s something explored by a recent paper in the Journal of Cancer Survivorship. UC San Francisco researchers studied the fertility-related concerns of a small group of female cancer survivors between the ages of 18 and 34 and identified six main themes from their discussions. Among them, as outlined by Medical News Today:

• A hopeful but worried approach to fertility and parenthood: While participants expressed hope about having a family, many also felt anxious that they would be unable to have their own children.
• Frustration with lack of choice or control over fertility: Even though the young women acknowledged that a discussion about fertility at the time of diagnosis would have been overwhelming, they felt strongly that they (or their parents) should have been told about both the impact of treatment on their fertility, and the options available before treatment to preserve fertility e.g. freezing eggs.
• Young survivors want information about their fertility: Several women reported with regret that their doctors had not talked to them about fertility and they felt that a young woman was old enough to have this discussion anytime after puberty.

The researchers concluded, as others also have, that there’s a need for medical professionals to provide young female survivors with information on their options and to offer help in “navigating both emotional and practical issues that arise when considering fertility and future parenthood.” I hope clinicians hear the message: I know from researching and telling my cancer patient’s story that survivors could truly benefit from additional support.

Previously: Unique challenges face young women with breast cancer, A need to provide infertility counseling to cancer patients, Programs help cancer patients at risk of losing their fertility
Photo by quinn.anya

Married or formerly married men who have had no children are at a higher risk of cardiovascular-related death than those who have become fathers. Why this is true, it’s too early to say. But Stanford urologist Michael Eisenberg, MD, wonders whether this may be because of a higher prevalence, among the childless men, of fertility problems that ultimately could be tied to some of the same factors responsible for heart disease.

In a 10-year study of some 135,000 men, all of them over 50 years old and basically healthy when the study began, Eisenberg and his colleagues observed a 17 percent increase in cardiovascular-related (heart-disease and stroke) deaths among men with no children, compared with those who’d had two or more.

To make sure that the men they were looking at had both the intent and the opportunity to reproduce, Eisenberg and his colleagues, whose work appears in the journal Human Reproduction, restricted their sample population to those who were married or had once been married. They reasoned that the absence of children among currently or formerly married men might suggest a reduced ability to conceive.

And indeed, in another recent, much smaller study that was widely reported - no doubt because of its provocative main conclusion that men’s testosterone levels sink upon becoming fathers - one finding was that men with higher testosterone levels seem to have better luck finding mates and producing offspring.

I lean toward another theory, myself: Having kids is just plain good for you. It’s not so much that the drop in a man’s testosterone count after having kids (especially among highly nurturing dads, as that smaller study found) is good for the heart (which, according to the medical literature, it may or may not be). It’s that the cumulative blessings accruing from taking care of kids overwhelms the acute brain damage arising from those early sleepless nights and, shall we say, “arms-length transactions” of early parenthood.

Photo by Michelle Brandt

In today’s San Francisco Chronicle, Erin Allday is reporting on experts’ belief that chemotherapy has a greater impact on fertility than previously suspected - and that female cancer patients should be given the option to freeze their eggs or embryos before undergoing treatment:

Infertility is increasingly being addressed soon after a woman is diagnosed with cancer, but gaps still exist in the accuracy of information given to patients and how much access they’re given to procedures like egg- and embryo-freezing that could help them preserve their ability to become pregnant later, [UCSF's Dr. Mitchell Rosen] and other fertility experts said.

“I don’t think that everyone who has cancer needs to have fertility preservation,” Rosen said. “But they need to be counseled and look at whether this is a possibility for them and whether they want to do it.”

…

“Especially young patients who are otherwise healthy, many of them have very good life expectancy after treatment, and they want to be able to think past their cancer,” said Dr. Lynn Westphal, a reproductive endocrinologist at Stanford. “For many patients, (fertility) is a key quality of life issue.”

Allday also discusses a recent UCSF study showing that receiving pre-treatment infertility counseling led to greater post-treatment quality of life for cancer patients.

Previously: Programs help cancer patients at risk of losing their fertility