Infertility Research

• New research on how infertility affects women long term who do not go on to become a mother through infertility treatment, adoption, or third party reproduction. "[Infertility] is, essentially, an assault to a woman’s identity. Although most women are forever changed by the infertility experience, many issues begin to resolve once you have a child. For those who decide not to have children after ceasing treatment, this issue –- this assault to identity -- remains very much alive.” Over time, most of the women in the study reported tremendous growth after stopping fertility treatment. “Several ongoing issues remain, of course, but most participants had integrated the loss into their narratives, had actively reimagined their lives and were embracing life once again.”The study found that on average it took three to four years for study participants to fully emerge from feeling like infertility was their primary identity.
• Conditional embryo relinquishment: choosing to relinquish embryos for family-building through a Christian embryo ‘adoption’ programme. Forty-three people (18 couples and 7 wives) who had chosen to donate their unused frozen embryos to a Christian embryo ‘adoption’ program in the US were interviewed on why they chose this method of handling their unused embryos. The following factors contributed to the participants choosing an embryo ‘adoption’ program: how they conceptualized their embryos; dislike of alternative disposition options available; conceptions of their parental responsibility towards their embryo and a desire to have an ‘open’ relinquishment with (varying) degrees of information-sharing and contact arrangements between themselves and recipient couples. The researchers acknowledged that there is a diversity of views on embryo relinquishment. Some couples’ desire the approach that treats embryo donation more like an “adoption” so that they can relinquish in ways that are both morally and practically acceptable to them. They concluded that “[t]he current polarized debate concerning the language of embryo ‘adoption’ detracts attention from the practical considerations of formulating ‘best practice’ in this area.” They suggest using “less politically charged terminology such as ‘conditional relinquishment’”. Published in Human Reproduction Volume 26, Issue 12 Pp. 3327-3338
  
• Fishing Games Gone Wrong: Trial-And-Error Behind Important Cause of Female Infertility. Our cells have two copies of each chromosome, one inherited from our mother and the other from our father. An oocyte, the cell that matures into an egg cell, has to discard half of its chromosomes, keeping only the maternal or paternal copy of each. New research has found that the cellular machinery which separates chromosomes is extremely imprecise—they liken it to the children’s game of playing fish with a magnet on the end of a string. These chromosomal errors result in infertility and miscarriage. These results provide a very plausible explanation for the high rate of errors during egg formation especially as women age. Researchers hope that this information will lead to ways to prevent some age-related female infertility.
• Croen LA, et al. Arch Gen Psychiatry. 2011 July 4. New study shows a possible link between the use of some antidepressants during pregnancy and the risk for autism in the offspring. According to this study, the offspring of women who receive selective serotonin reuptake inhibitors (SSRIs) during pregnancy may be at increased risk for autism.

  For this population-based, case-control study, researchers compared the medical records of 298 children with autism spectrum disorders, and their mothers, and 1507 randomly selected children and their mothers (control group) from the Kaiser Permanente Medical Care Program in Northern California.

  Among the children with autism, 20 (6.7%) were prenatally exposed to antidepressants. In the control group, 50 (3.3%) had been exposed to antidepressants in utero. The use of SSRIs was associated with a 2-fold increased risk for autism in the offspring of mothers who received SSRIs during the 1 year before giving birth. The strongest effect on autism risk in the offspring was related to maternal SSRI treatment during the first trimester of pregnancy.

  The investigators noted that further research is needed to confirm these findings, and that clinicians must balance the possible SSRI exposure risk with the risks that may come with untreated mental health disorders, including during pregnancy.

• Researchers have found the first direct evidence that early embryos with genetic abnormalities can correct their faults as they develop, marginalizing cells with an incorrect number of chromosomes, while allowing the growth of normal cells. The findings have significant implications for fertility treatment and stem cell therapies. The complete report can be read here.
• Dr Kaltum Adam reported at the 2011 European Society of Human Reproduction and Embryology Conference about new research that provides a reliable way of predicting the outcome of pregnancies that are threatening to miscarry
• New studies reported at the 2011 European Society of Human Reproduction and Embryology Conference in Stockholm suggest that frozen embryo transfer leads to larger and heavier babies. Two studies from France and Denmark have shown that children born after frozen embryo transfer are larger and heavier. The risk for a baby to be too heavy for its gestational age at birth is increased 1.6 fold compared to IVF children from fresh embryo transfer and 1.5 fold compared to naturally conceived children.
• In a report from the 2011 European Society of Human Reproduction and Embryology Conference in Stockholm, "vanishing twin" explains the increased risk of birth defects in the surviving baby after infertility treatment. According to Professor Michael Davies, “vanishing twin” phenomenon, in which only one child is born from a pregnancy that originally starts as a multiple pregnancy, is linked to a nearly two-fold increased risk in any congenital malformation and to a nearly three-fold risk of multiple malformations.
• Women taller than 5‘8” are more likely to have twins after double embryo transfer during IVF, according to recent research from the Netherlands and reported at the 2011 European Society of Human Reproduction and Embryology Conference in Stockholm. The complete report can be found here.
• "The impact of cross-border reproductive care or ‘fertility tourism’ on NHS maternity services" is an article in BJOG: An International Journal of Obstetrics and Gynecology that talks about the need for more regulation on infertility treatment across jurisdictions as seen in a recent study on high order multiple pregnancies in the UK where patients received cross-border fertility treatment.
• A study by a Danish research group has found no evidence of declining sperm numbers. The study took the data of 5,000 eighteen-year old Danish men taking their military physicals and spanned fifteen years. These findings reverse the claims of the same research group who, in 1992, published a study claiming that sperm count had declined by 50 percent worldwide from 1938 to 1991 and that the trend would continue. The originally study was widely criticized for flaws like a lack of standardized methods of collecting semen, methodological issues in semen analysis and biases in the ways men were selected, but was highly influential and has been one of the few studies available on the topic. The new study was taken with far more rigorous standards and scientists hope that once the data is analyzed, it will help researchers come to a consensus about sperm count numbers.
• Creating a Family blog titled "Good News about Health of Kids Conceived through IVF" summarizing the report by the journal Fertility and Sterility on “The risk of cytogenetic abnormalities in the late first trimester of pregnancies conceived through assisted reproduction”. Conway, et al. Fertility & Sterility Vol. 95, No. 2, 2011 p. 503-506. , and "Pubertal development of the first cohort of young adults conceived by in vitro fertilization in the US”. Beydoun, et al. Fertility & Sterility Vol. 95, No. 2, 2011, p. 528-533
• Intracytoplasmic Sperm Injection (ICSI) Reverses Natural Gender Ratio. Researchers at Michigan State University have found that the use of intracytoplasmic sperm injection (ICSI) reverses the natural gender ratio at birth. The usual ratio of boys to girls at birth is 105 boys to 100 girls. Boys are considered more fragile and likely to not survive childhood, thus the higher percentage assure a more even ratio by early adulthood. When ICSI is used, this ratio was reversed. In many clinics ICSI is standard for most IVF cycles regardless of the cause of infertility. This research was summarized in "The sex ratio of singleton offspring in assisted-conception pregnancies" Fertility and Sterility Volume 92, Issue 5, Pages 1579-1585 (November 2009)
• Rocking Embryos May Improve Pregnancy Rates. New study in mice shows that changing the shape of the petri dishes where the embryos grow and adding a rocking motion pre-transfer to mimic the motion of a woman's body improves pregnancy rates by 22 percent. University of Michigan researchers changed the shape of the petri dishes from flat to funnel shaped and added a gentle rocking motion during the pre-transfer growth period. The study showed that prior to transfer the rocked embryos were more robust after four days. The rocked group had 109 cells compared to 67 cells for the static group. Embryos growing naturally inside a female mouse had an average of 144 cells at the four day stage. After transfer, approximately 77 percent of the rocked mouse embryos led to ongoing pregnancies, compared with 55 percent of the statically-grown embryos. In a control group of mouse embryos conceived naturally, 83 percent led to ongoing pregnancies. Although this research was done in mice, it is hoped that it will lead to higher IVF success rates in humans. Reported in Science Daily.
• Mediterranean Diet May Increase Success with Infertility Treatment. The March 2010 journal Fertility and Sterility reported on a fascinating study of the effect of diet on success in infertility treatment. Researchers in the Netherlands followed 161 couples undergoing fertility treatment. Two-thirds underwent in-vitro fertilization (IVF), while the rest had IVF and intracytoplasmic sperm injection (ICSI). Before treatment, the couples completed detailed questionnaires on their eating habits over the past month. The following diet patterns were identified among the women:
  
  • The Mediterranean diet- High in vegetables, vegetable oils, fish and beans, and low in snack foods.
  • The "health-conscious" diet,- High in fruits, vegetables, whole grains, beans and fish, and low in meat and snack foods.
  
  The primary finding was not all that surprising for those of us who follow research on diet. Women whose eating habits most closely matched the traditional Mediterranean diet were 40 percent more likely to become pregnant than those with the least Mediterranean-like diets. What really surprised me, however, was that researchers found no increase in pregnancy rates for the group that ate the health-conscious diet. Researchers speculate that the high intake of vegetable oils in the Mediterranean diet may be the important distinction. This study was not designed to prove cause-and-effect, but it is certainly a first step. Reuters had a good review of this research.
• Acupuncture to Treat Depression in Pregnancy. In a study published recently in the journal Obstetrics & Gynecology, acupuncture was found to be effective to treat depression in pregnancy. Depression in pregnancy is a risk factor for postpartum depression and low birth weight. Postpartum depression is associated in some studies with poorer cognitive and emotional development in children. Many woman and their doctors would prefer to avoid antidepressant medications during pregnancy.
  
  This study is the largest to date examining the effectiveness of acupuncture to treat depression in pregnant women. 150 clinically depressed pregnant women who weren't previously taking antidepressants were randomly assigned to get either acupuncture for depression, acupuncture not specifically designed for depression, or massage for eight weeks. Those who got acupuncture targeting depression had a significantly greater decrease in depressive symptoms, compared with the other women. Some 63% of women in the acupuncture-for-depression group responded to treatment, compared with 44% in the other groups. A good summary of the study can be found in The Wall Street Journal.
• Health of Children Conceived through Assisted Reproductive Technology. In the February issue of Fertility and Sterility, a study was published on how the first generation of IVF kids are doing in adulthood. Researchers followed 173 children who were conceived at the IVF program at Eastern Virginia Medical School between 1981 and 1990. These “kids” are now 18- to 26years old.
  
  The study found that young adults born via IVF were generally "healthy and well adjusted." However, their rates of certain psychological conditions, including attention-deficit hyperactivity disorder (ADHD), depression and binge-drinking, were elevated. On the other hand, they were less likely to smoke and more likely to exercise than other U.S. adults their age.
  
  I’m not sure what to make of this study. While interesting, I was left with questions. The study did not compare these children to others of similar socioeconomic and demographic backgrounds. The study was not designed to tease out the cause of these rather unusual differences. Were these children disproportionately multiple births (likely), and could these differences be attributable to prematurity or low birth weight? Were these kids in families with access to health care; therefore, more likely to be diagnosed with ADHD and depression. The researchers speculated that perhaps these differences could have been caused by the heightened stress levels that past studies have found among parents undergoing IVF or the overprotective parenting that some studies have found in parents who conceived after years of trying.
  
  The researches acknowledged some of the limitations of their study. They originally hoped to study the over 500 children born during the time span of the study in the IVF program, but less than one-third responded. This raises the possibility that only those in the best health participated in the study or perhaps only those who were struggling. .
  
  There is much need for more study of children conceived through assisted reproductive technology and this is a good beginning. This study was summarized in Reuters on March 5, 2010.
• The largest study to date of pregnancies and subsequent births of children conceived after undergoing preimplantation genetic diagnosis (PGD) was published in the January 2010 issue of the journal Human Reproduction. This study attempts to determine whether removing a cell or two from an embryo to screen it for inherited conditions or genetic abnormalities can, in itself, impair the health of the subsequent pregnancies or births. This research was summarized in a Dec. 23, 2009 article in Science Daily.
  
  The current study looks at the health of all pregnancies, deliveries and babies born after preimplantation genetic diagnosis and screening (PGD/PGS) at one Dutch infertility clinic between 1992 and 2005. In all, 581 babies were examined at two months old and questionnaires were sent to parents and physicians at the time of conception and delivery. The PGD/PGS babies were compared with a control group of IVF/ intracytoplasmic sperm injection (ICSI) children to determine if any differences in outcomes were related to the embryonic biopsies required in PGD and not to other standard IVF/ICSI procedures.
  
  There was no statistically significant difference in outcome between the two groups in the gestational ages at delivery, birth weights and major malformations. There was no difference in the numbers of deaths around the time of birth between PGD/PGS and ICSI babies if they were born as a result of singleton pregnancies. "[T]he health of the singleton children born after embryo biopsy for PGD is similar to the health of singleton children born after IVF/ICSI." However, there were five times more perinatal deaths after multiple pregnancies in the PGD/PGS babies compared to the ICSI babies (11.73% versus 2.54%) "A point of concern in this study was the multiple PGD/PGS children being more often premature and of low birth weight."
  
  In the editorial that accompanied the study in Human Reproduction, Dr. Joe Leigh Simpson, Professor of Human and Molecular Genetics and Professor of Obstetrics and Gynecology at the Wertheim College of Medicine, Florida International University, USA, wrote: "PGD is not the purview of amateurs or the inexperienced, nor is any technical procedure. Inferential data suggest that less than fully experienced embryologists or diagnosticians may do more harm than good when performing PGD, especially PGD aneuploidy testing."
  
  Although this is the largest study to date, only 581 children were studied., and the data was only collected through two months of age. Long term studies that follow children for many years are needed to fully assess the risks of PGD/PGS.
• A study in the July issue of Molecular & Cellular Proteomics suggests that Preimplantation Genetic Diagnosis (PGD) may have some negative neurological consequences in adulthood. This study was summarized in the July 22, 2009 issues of Science Daily.
  
  There have been few long term studies of the safety of PGD and embryo screening in humans. Researchers used mice studies to try to predict safety issues and found that PGD may increase risks of weight gain and memory decline in adulthood. Scientist examined how biopsies of embryos at the blastocyst could affect fetal, neonatal and adult development. They found that successful births from biopsied embryos were significantly lower than in controls. After birth, they found that “mice in the biopsied group on average had higher body weight and poorer memory in maze tests. To get a more detailed picture of these memory defects, the authors performed a proteomic analysis of adult mouse brains; 36 proteins displayed significant differences between biopsied and control groups, 17 of which are closely associated with neurodegenerative disorders like Alzheimers and Down Syndrome.”
  
  Keep in mind that this study was on mice and has not been confirmed in humans. More long term research is needed.
• In a meta-analysis of 20 studies on in-vitro fertilization or intracytoplasmic sperm injection using either fresh or frozen embryos, researchers found no difference in rates of prematurity , low birth weight, or birth defects between kids born from frozen or fresh embryos. Interestingly, they found that for embryos in the early cleavage stage, frozen embryos actually had slightly better rates of preterm birth and low birth weight than those born after fresh cycles.

The researchers speculate that these better outcomes for children born out of cryopreservation might be because of the "adverse effect of hormone stimulation in fresh cycles” or because "embryos surviving freezing and thawing might be of better quality than fresh embryos, and this may have a positive influence on child outcome."

• In the September 2008 issue of The Archives of General Psychiatry a well developed study found a strong link between the father’s age at conception and later development of bipolar disease in their children. Past research has found a similar link between father’s age and autism and schizophrenia in their children. The highest risk was for fathers over the age of 55. The study is not available free online, but the NYT ran an article on the findings.

• Assisted Reproductive Technology Surveillance --- United States, 2005 published by the Center for Disease Control (http://www.cdc.gov/mmwr/preview/mmwrhtml/ss5705a1.htm)

  The CDC recently published an analysis of multiple births resulting from Assisted Reproductive Technology (In Vitro Fertilization or IVF). This study was based on 2005 data.
  
  Here are some eye popping statistics from this study:

• 49% of births from IVF and other forms of assisted reproduction were twins, triplets or higher multiples.
• The multiple-birth risk was highest for using fresh embryos from donor eggs (41%), but it was still high for women using fresh embryos from their own eggs (32%).
• Approximately 1% of U.S. infants born in 2005 were conceived through ART.
• IVF accounts for 17% of multiple births nationwide.
• 47% of IVF procedures using fresh, nondonor eggs transferred three or more embryos. 18% transferred four or more, and 6% transferred five or more embryos
• Approximately 9% of ART singletons, 57% of ART twins, and 95% of ART triplets or higher-order multiples were low birth weight.
• Approximately, 15% of ART singletons, 66% of ART twins, and 97% of ART triplets or higher-order multiples were born preterm.
• 
  

It is easy for us to forget the health risks of twins, with the media focus on celebrity twin births such as Julia Roberts, Jennifer Lopez, and Angelina Jolie. Let me summarize—the majority of twins are low birth weight and pre-term, and thus, are subject to very serious long term health risks including a substantially increased risk for perinatal and infant mortality. We should do everything possible to reduce the number of twins born through IVF or any form of assisted reproduction.

• British Medical Journal August 7, 2998 (BMJ 2008;337:a716)

  Infertility affects one in seven couples and the cause is unexplained in about 25% of these cases. Infertility is “unexplained” when semen analysis, tubal patency tests, and assessment of ovulation are all normal.

  A study published on August 7, 2008 in the British Medical Journal found that the two most common “first-step” treatments for unexplained infertility were no more affective than doing nothing.

  In the study, 580 women were randomly assigned to one of three groups: doing nothing (aka “expectant management”), oral clomifene citrate (often sold as Clomid) or unstimulated intrauterine insemination (aka artificial insemination). The three randomized groups were comparable in terms of age, body mass index, duration of infertility, sperm concentration, and motility. With “expectant management, the coupled were basically just told to have sex regularly. They were not instructed on enhancement techniques such as basal temperature charts or luteinising hormone kits. They did not come in to the infertility clinic for a follow-up for six months.

  At the end of the study, live birth rates were 17% for the expectant management group, 14% for the clomifene citrate group, and 23% for the unstimulated intrauterine insemination group. These differences were not significantly different. Satisfaction rates did differ depending on the group. More women randomized to clomifene citrate (94%) and unstimulated intrauterine insemination (96%) found the process of treatment acceptable than those assigned to expectant management (80%).

  The researchers concluded that in couples with unexplained infertility popular treatments such as empirical clomifene and unstimulated intrauterine insemination are unlikely to offer superior live birth rates compared with having sex regularly.

  This study was summarized in a Aug. 11, 2008 NYT article.

• Predicting Success with IVF (Jun S, et al "Defining human embryo phenotypes by cohort-specific prognostic factors" PLoS One 2008; DOI: 10.1371/journal.pone.0002562.)

  A fascinating new study found four key variables that were 70% accurate in predicting whether a woman undergoing in vitro fertilization treatment would become pregnant. Stanford researchers found that, taken together, four variables -- the total number of embryos produced during the treatment cycle, the number of eight-cell embryos, the percentage of cells that stopped dividing, and the level of follicle stimulating hormone on day three -- were the most effective predictors of the outcome.

  "Remarkably, these four variables all describe the embryo cohort rather than individual embryos, and were more informative than age, clinical diagnoses, or any measures of the transferred embryos," the researchers said. The method is not yet ready for clinical use, however, because the researchers defined successful pregnancy as a positive serum beta-human chorionic gonadotropin test and not an actual pregnancy. Further research will consider actual pregnancy outcomes.

  It has been difficult to predict the success of IVF before embryos are transferred because embryos can fail to implant and up to this point, the characteristics of individual embryos have not been predictive of success. This complicates the process and makes it more difficult to determine the number of embryos to transfer.

  Among other findings, the Stanford researchers found that

  It has been difficult to predict the success of IVF before embryos are transferred because embryos can fail to implant and up to this point, the characteristics of individual embryos have not been predictive of success. This complicates the process and makes it more difficult to determine the number of embryos to transfer.

  Among other findings, the Stanford researchers found that

  • Embryo cohorts that had fewer than six embryos were 3.9 times more likely to result in no pregnancy compared with those with six or more
  • Among cohorts with six or more embryos, those with a cleavage arrest rate greater than 14.6% were three times more likely to result in no pregnancy than those with a lower rate .

  A number of news articles have covered this research, including http://www.medpagetoday.com/OBGYN/Pregnancy/tb/9996; http://www.newsdaily.com/stories/n01259037-pregnancy-invitro/

• Preterm birth is a major cause of infant mortality, but few studies have assessed long-term health among survivors of preterm birth, particularly their health status in adulthood. A study ("Association of Preterm Birth With Long-term Survival, Reproduction, and Next-Generation Preterm Birth") published in the Journal of the American Medical Association on March 2008, analyzed data from 1.1 million singleton births that occurred from 1967 to 1988 in Norway, to determine the effects of preterm birth on survival, reproduction, and next-generation preterm birth. Norway's homogenous population and its universal access to medical care make the findings a "best case scenario,"

  The study found that compared with persons born at term, participants who were born preterm had diminished long-term survival and reproduction, and women born preterm were at increased risk of having preterm offspring. As expected, babies born early were more likely to die during the first year of life compared with babies born at term. Unexpectedly, their increased risk of death persisted as they aged.

  The children who were born five to nine weeks early (28 to 32 weeks into the pregnancy) showed a doubled risk of death from ages 1 to 5 compared with children born at normal term. (The overall risk of death was low: 33 of the 5,880 children in the premature group died.) When the researchers looked at boys and girls separately, they found a stronger link in boys between premature birth and higher death rates in childhood. The causes of childhood deaths are still being analyzed, but birth defects and childhood cancers played a role.

  In adulthood, other differences showed up. Prematurity was linked to lower levels of education and more childlessness in both men and women in a subset of more than 580,000 births from 1967 through 1976. Women who were preemies had a higher risk of giving birth to premature babies themselves. The risk of next-generation premature births increased with the severity of prematurity in the mothers.

  JAMA. 2008;299(12):1429-1436.

• Currently, embryologists can not tell which embryos are likely to implant and grow once transferred. A recent study, “Novel strategy with potential to identify developmentally competent IVF blastocysts”, published online in Human Reproduction on May 13, 2008. provides evidence that may soon change this.

  Hum. Reprod. Advance Access published online on May 13, 2008

  Human Reproduction, doi:10.1093/humrep/den123

• Proceedings of the Summit on Environmental Challenges to Reproductive Health and Fertility: executive summary from Fertil Steril 2008;89:281-300.
• New study shows that using a single more mature egg increases pregnancy rates and decreases risk of multiple births. http://news.bbc.co.uk/1/hi/health/7254973.stm
• IFFS Surveillance 07: a survey of the current status of assisted reproductive technology procedures around the world from Fertil Steril 2007;87:(Supplement 1). -Maybe because I'm a geek or maybe because I love to research, but for whatever reason, I found this report fascinating. If you've ever wondered how infertility treatment differs around the world, this is the place to find the answers.
• Induction of ovulation and ovarian cancer: a critical review of the literature from Fertil Steril 2006;85:819-26.