Every year, several Pacific Fertility Center professionals participate in ASRM’s national meeting. They evaluate the research and share their findings with PFC and Fertility Flash.

Among those attending the conference from PFC were Dr. Philip Chenette and Dr. Isabelle Ryan and Peggy Orlin, MFT. Their reviews cover the following topics: Update #1: Ovarian Stimulation Techniques, Update #2: PGD and Aneuploidy Screening Techniques, Update #3: Egg Freezing, Update #4: Acupuncture, and Update #5: Men and ART.

Update #2: PGD and Aneuploidy Screening Techniques

Preimplantation genetic diagnosis (PGD) has been one of the hallmark technologies of modern reproductive medicine. The ability to look inside a cell, beyond its visual appearance to the actual genes controlling the cell, has provided insight into the workings of the embryo and a valuable clinical tool to improve fertility care.

The most common use of PGD is to count chromosomes using FISH probes. Using labels that glow under ultraviolet light, a limited number of chromosomes can be identified and counted. Missing or duplicated chromosomes are indicators of abnormalities in the embryo, a condition known as “aneuploidy.” FISH has a significant error rate, and while clinically useful, results must be interpreted with caution.

A new technique discussed at the ASRM meeting is SNP analysis. SNPs are common tags in DNA that can be measured by automated systems. Microarrays of thousands of SNPs have been prepared that provide a clear picture of the chromosome structure of a cell. Microarray-based aneuploidy screening has excellent reliability and accuracy, and holds enormous promise for identifying genetically normal embryos. This study represents the first validated method of analyzing the entire set of chromosomes in a single cell. Stay tuned for more on this exciting technology.

Array CGH uses thousands of very small DNA probes along with computer software to describe the structure of DNA in a single cell. A very sensitive test, it is fast enough to be used during an IVF treatment cycle, and far more accurate than conventional fluorescent probe (FISH) analysis. Array CGH may lead to improved IVF outcomes as embryos containing an error in any chromosome can be detected, which would allow better selection of healthy embryos.

PGD has proven useful for the treatment of recurrent miscarriage. In an analysis of 279 patients with recurrent miscarriage (women who had previously experienced 3-5 miscarriages), researchers in New Jersey found an improved miscarriage rate of 19.5% after PGD versus their 40.9% expected rate.

Philip Chenette, MD

Polycystic ovary syndrome (PCOS) is the most common endocrinologic disorder in women of reproductive age. Approximately 5-10% of reproductive age women have PCOS. The various symptoms of PCOS can be irregular or absent menstrual cycles, infrequent or absent ovulation, excess facial and body hair, obesity, and infertility. The key components defining this disorder are chronic anovulation (inability to ovulate an egg), clinical hyperandrogenism (elevated male type hormones) and more recently discovered, insulin resistance.

Insulin resistance, the precursor state to diabetes, is present in 35-40% of women with PCOS, even if they are not overweight. Insulin resistance is diagnosed by blood testing, either as fasting glucose to insulin ratio, or as a complete glucose tolerance test. Long term follow up of women with PCOS reveals that up to 40% develop impaired glucose processing or diabetes by age 40. The prevalence of diabetes in women with PCOS is seven times higher than for the non-PCOS population. Excessive insulin production is thought to promote excess male hormone production, though the actual mechanism explaining this observation is still unclear. Insulin resistance may increase the long-term risks of heart disease and hypertension.

Interventions that reduce circulating insulin levels in women with PCOS may restore normal reproductive endocrine function. Non-pharmacologic methods, such as weight loss and exercise, have clearly led to reduced insulin and male hormone levels, resulting in resumption of ovulatory function. However, these regimens are at risk for poor compliance and, over time, the benefit of weight loss is rarely maintained.

Insulin-sensitizing (anti-diabetic) medications can be used to decrease insulin levels, which may help restore the normal ovarian hormone profile (i.e. reduce male hormone), thus allowing for spontaneous ovulation to occur in about 75% of patients. The most commonly used medication is metformin (Glucophage®). Side effects of metformin include gastrointestinal symptoms, which are dose-related and tend to resolve after several weeks. While there are no well-controlled studies of safety during pregnancy, metformin has been administered to a small number of women with diabetes throughout their pregnancies, and no fetal abnormalities have been described⁽¹⁾.

Clinical studies have shown that metformin (500 mg three times per day or 850 mg twice daily with meals) administration to women with PCOS increased the frequency of spontaneous ovulation, menstrual cyclicity, and ovulatory response to clomiphene citrate (CC) (Clomid^®). Benefit has been demonstrated with metformin treatment in PCOS patients both with and without insulin resistance⁽²⁾. Metformin alone may be less effective in obese PCOS women.

Women with PCOS are considered to be at increased risk of miscarriage, as high as 30 – 50 %. When women were treated with 1000-2000 mg daily of metformin throughout pregnancy, rates of early pregnancy loss were 11.6% in the metformin group compared with 36.3% in the control group (p < 0.0001). Administration of metformin throughout pregnancy to women with PCOS may decrease miscarriage rates⁽³⁾.

Controversy exists when comparing metformin to clomiphene citrate (CC) for treating infertility. A well-designed study showed metformin is better for ovulation induction than CC alone and equivalent for pregnancy achievement. The authors suggest that metformin can be used first for ovulation induction in patients with PCOS regardless of their weight and insulin levels because of its efficacy and known safety profile⁽⁴⁾. Alternatively, another study found benefit with metformin if obese (BMI >30 kg/m⁽²⁾ subjects and women older than 34 years were excluded⁽⁵⁾. Another paper pooled the results of 6 studies to examine whether metformin is efficacious when given to patients resistant to CC. They found the addition of metformin in the CC-resistant patient is highly effective in achieving ovulation induction⁽⁶⁾. Most studies showing benefit were small with fewer than 100 patients.

Conversely, two large multicenter trials, one conducted in the US (PPCOS)⁽⁷⁾ and one in the Netherlands⁽⁸⁾, have shown no benefit from metformin either as a single agent or as adjuvant therapy in combination with clomiphene for the treatment of infertility in women with PCOS. They found metformin increased the occurrence of ovulation but did not increase the chance of becoming pregnant. The PPCOS study is large and well designed, with 626 participants. It differs from other studies by using the extended release form of metformin. One very notable result was the absence of any statistically significant effect of this extended release form of metformin on insulin levels or insulin resistance. There were none of the expected metabolic effects of metformin. Extended-release metformin has not previously been studied in women with PCOS. Thus, it has not been ascertained that its efficacy is comparable to regular metformin in PCOS⁽⁹⁾.

Additionally, metformin and clomiphene citrate (CC) differ in their therapeutic time frames (the period of time from initiating therapy to achieving maximum effectiveness). CC produces higher rates of ovulation and pregnancy in the early months of treatment than that of metformin and might be preferable to women who wish to become pregnant quickly ⁽⁵⁾. However, a patient with more time to become pregnant may benefit from metformin’s metabolic effects. During the 3 to 6 months that it takes for metformin to become maximally effective, the patient can prepare for pregnancy by losing weight through diet and exercise. Reducing a patient’s weight might considerably optimize her pregnancy⁽⁹⁾.

Metformin induces normal ovulation, and the risk of multiple gestation is no more than that in the general population. Conversely, CC can precipitate the release of multiple eggs in a given menstrual cycle and carries a risk of multiple gestation: in the PPCOS study, multiple gestation was 6% in the clomiphene group and 0% with metformin.

Metformin may significantly increase the incidence of multiple pregnancy when used in combination with gonadotropins⁽¹⁰⁾.

Short-term co-treatment with metformin for patients with PCOS undergoing IVF/ICSI cycles does not improve the response to stimulation but significantly improves the pregnancy outcome and reduces the risk of ovarian hyperstimulation⁽¹¹⁾.

Conclusions:

• PCOS patients should be screened for diabetes before becoming pregnant. Hemoglobin A1c levels should be normal.
• Metformin alone can induce ovulation and may improve the effectiveness of CC. Extended release metformin may not be as effective.
• Metformin may decease miscarriage rates.
• Weight loss may improve the effectiveness of metformin.
• Time to achieve pregnancy may be longer with metformin than CC.
• Metformin may be less effective in older women.
• Metformin does not increase multiple pregnancy rates when used alone.
• Metformin may increase multiple pregnancy rates and decrease ovarian hyperstimulation when used with gonadotropins.
• Long-term benefits of metformin in preventing hypertension and heart disease need further study.

Eldon Schriock, MD

References:

1. The Practice Committee of the American Society for Reproductive Medicine Committee Opinion. Use of insulin sensitizing agents in the treatment of polycystic ovary syndrome. Fertility and Sterility
2. Nawrocka J, Starczewski A. Effects of metformin treatment in women with polycystic ovary syndrome depends on insulin resistance. Gynecol Endocrinol. 2007 Apr;23(4):231-7.
3. Khattab S, Mohsen IA, Foutouh IA, Ramadan A, Moaz M, Al-Inany H. Metformin reduces abortion in pregnant women with polycystic ovary syndrome. Gynecol Endocrinol. 2006 Dec;22(12):680-4.
4. Neveu N, Granger L, St-Michel P, Lavoie HB. Comparison of clomiphene citrate, metformin, or the combination of both for first-line ovulation induction and achievement of pregnancy in 154 women with polycystic ovary syndrome. Fertil Steril. 2007 Jan;87(1):113-20.
5. Palomba S, Orio F Jr, Falbo A, et al. Prospective parallel randomized, double-blind, double-dummy controlled clinical trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in nonobese anovulatory women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90:4068-4074.
6. Siebert TI, Kruger TF, Steyn DW, Nosarka S. Is the addition of metformin efficacious in the treatment of clomiphene citrate-resistant patients with polycystic ovary syndrome? A structured literature review. Fertil Steril. 2006 Nov;86(5):1432-7.
7. Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356:551-566.
8. Moll E BP, Korevaar JC, Lambalk CB, van der Veen F. Ovulation induction in women with polycystic ovary syndrome: A randomized double blind clinical trial comparing clomiphene citrate plus metformin with clomiphene citrate plus placebo. BMJ. 2006;332:1485.
9. Baillargeon JP, Legro RS. Should metformin be used as front-line therapy for fertility in women with PCOS. Sexuality, Reproduction, and Menopause 2007; 5(2):17-19.
10. Shibahara H, Kikuchi K, Hirano Y, Suzuki T, Takamizawa S, Suzuki M. Increase of multiple pregnancies caused by ovulation induction with gonadotropin in combination with metformin in infertile women with polycystic ovary syndrome. Fertil Steril. 2007 Jun;87(6):1487-90.
11. Tang T, Glanville J, Orsi N, Barth JH, Balen AH. The use of metformin for women with PCOS undergoing IVF treatment. Hum Reprod. 2006 Jun; 21(6): 1416-25.

Many people who get pregnant easily but have experienced recurrent miscarriages may not realize that they may actually have an “infertility” problem. The rubric of infertility includes not only helping couples establish a pregnancy but also achieving a viable pregnancy, which will grow to full term. So the diagnosis and treatment of recurrent miscarriages is indeed an area that is managed by infertility experts.

Recurrent Miscarriages, also called recurrent pregnancy loss (RPL), is diagnosed after at least 2 or 3, or more, consecutive pregnancy losses in the first or early second trimester (less than 15 weeks gestation). It is one of the most common clinical problems in reproduction, yet a definite cause can be established in only about 50% of the cases, often leaving patients distraught and frustrated. Consequently, some patients will turn to alternative therapies of unproven benefit. Medically known causes and treatments are described in this article.

Egg Quality Factor
The normal biological aging process of the egg causes the egg to function less accurately during the fertilization process at the critical time of chromosomal duplication and pairing. The resulting chromosomally abnormal embryos have a lower chance of implanting in the uterine lining. If implantation does occur, these embryos have a higher chance of leading to a first trimester miscarriage. We test for egg quality by performing a blood test for the FSH and Estradiol hormones on menstrual cycle day 2 or 3. For some patients we may recommend a more extensive test called a Clomid Challenge Test.

Other Hormonal Factors
Other hormonal abnormalities that result in miscarriage must be very subtle because the cycle is normal enough to allow egg development, ovulation, fertilization, and implantation, yet the pregnancy is lost at a later time. The amount of progesterone produced by the follicle after ovulation and the effect of that progesterone on the lining of the uterus may be of importance. A low progesterone level or an inadequate maturation of the uterine lining is called a luteal phase defect.

Abnormalities of other metabolic hormones can cause a luteal phase defect. If the prolactin level is elevated, it is important to evaluate for prolactin-elevating drugs, hypothyroidism (check the TSH), and pituitary tumors. The prolactin level can be lowered to a normal range with medications.

Women who have polycystic ovary syndrome (PCOS) are at higher risk of miscarriages because of an intraovarian hormonal imbalance. If PCOS is suspected, checking for LH, androgens and insulin resistance can be helpful in discussing treatment with insulin-sensitizing agents (metformin).

Anatomical factors
The anatomical factors are a variety of structural abnormalities of the cervix and uterus that are found in about 15% of women with recurrent pregnancy loss. These factors are diagnosed by performing a hysterosalpingogram (HSG), mid-cycle ultrasound or saline hysterogram, with attention directed to the shape or contour of the uterine cavity.

Potential abnormalities that may be found and associated with recurrent miscarriages are polyps, fibroids, and uterine septums. These anatomical abnormalities can lead to an unfavorable uterine environment for the embryo at the time of implantation and early embryo development. These can lead to early pregnancy loss. All of these abnormalities can usually be corrected with minor surgery.

Chromosomal Factor
There are 2 types of chromosomal factors. One is a random event; the other is genetically inherited by the fetus. At least 60% of all miscarriages are chromosomally abnormal embryos that arose from sporadic, random genetic defects in the sperm or the egg. These are defects that would not have been detected by analysis of the couple’s chromosomes (karyotype). However, these defects become more common as the woman ages. The miscarriage risk increases from about 15% of pregnancies before age 35, to 35% by age 40 and to 50% by age 45. About 99% of the time a chromosomally abnormal embryo will be miscarried. Because perhaps 1% will continue to develop, amniocentesis or chorionic villus sampling, which determine the genetic makeup of the fetus, is suggested for women over 35. When the genetic makeup of the fertilized egg is very abnormal, no embryo forms. On ultrasound examination an empty sac or a “blighted ovum” is seen in the uterus.

Some patients have chromosomal abnormalities in each cell, including eggs and sperm, which place them at greater risk of making a larger proportion of abnormal embryos. The fetus then genetically inherits this abnormality. Every cell in our body other than eggs and sperm has 46 chromosomes arranged in 23 pairs. It is possible that between the two chromosomes of a designated pair there could be a mix-up in the sequence of genes that make up these chromosomes, but the total number of genes is still normal. This mix-up is called a “balanced translocation” and causes no symptoms, diseases, or abnormalities in the patient or partner. However, if this genetic rearrangement occurs in a sperm or egg, the embryo will be chromosomally abnormal, and a miscarriage will follow. Balanced translocations can be detected by performing a chromosomal analysis. Chromosomal analysis requires a blood sample from both partners. The white blood cells are cultured to produce an analysis, or karyotype, of the chromosome pairs. The karyotype will be abnormal in about 5% of cases of couples that have suffered from three or more miscarriages. It is difficult to say what the risk of repeated miscarriages will be with a balanced translocation, however a normal full term pregnancy is still possible.

Immunologic factors
The immune system protects our bodies against foreign micro-organisms by recognizing any cells that are different from our own and making antibodies that attack and destroy those cells. Some women with recurrent pregnancy loss have autoantibodies. These are antibodies in their blood vessels that are made to attack their own tissues (e.g., antiphospholipid (anticardiolipin), antinuclear, or antithyroid antibodies). Antiphospholipid antibodies, along with lupus anticoagulant, may interfere with the formation of a normal placenta early in pregnancy and increase the risk of abnormal blood clotting in the placenta later in the pregnancy. This compromised placenta will lead to compromised growth of the fetus and an eventual miscarriage. If one has a positive antibody test, the test should be repeated 6-8 weeks later. If both sets of tests are positive, the recommended treatment may include one “baby” aspirin tablet per day, and sometimes the addition of daily heparin.

Thrombophilia Factors
Various enzymes regulate effective flow and clotting of blood. If there is a deficiency in some of the clotting enzymes, then small blood vessels of the placenta may be at greater risk of forming clots. Clots of the placenta will compromise blood flow to the growing embryo, placing the pregnancy at greater risk of a miscarriage. There are now a number of clotting enzymes that are recommended to be tested for in patients with recurrent miscarriages. If specific combinations of these enzymes are found to be in an abnormal range, then recommended treatment is a “Baby” aspirin per day with the possible addition of heparin.

Most miscarriages are the result of a random genetic defect leading to abnormal chromosomes for that particular fetus. This random event is unlikely to recur. For patients who have had three consecutive first-trimester miscarriages, and normal results after full evaluation, the chance of the next pregnancy leading to the delivery of a child is approximately 65%. Therefore, despite having had three recurrent miscarriages, the odds are still in favor of the next pregnancy being a normal pregnancy. While it can be incredibly frustrating both for patient and physician, to face repetitive failed pregnancies, it is still important to understand that the odds are still in the patient’s favor of eventual success. This may require fertility treatment, from low-tech intervention such as Clomid to high tech intervention such as IVF with preimplantation genetic screening (PGS), but in general, success is in our favor. If you are, or know someone who is experiencing recurrent miscarriages, please discuss this with a fertility specialist who may be able to recommend treatment options.

– Isabelle Ryan MD

When a woman is not able to conceive after one or more attempts at IVF with no apparent reason, she may feel heightened anguish. She may then broaden her research efforts with a determined resolve, even exploring unconventional treatments. She may end up considering immunological testing and treatment.

It is easy for patients to scapegoat the body’s immune system when apparently healthy looking embryos fail to implant, or a pregnancy is thwarted for unknown reasons. Autoimmune factors related to recurrent pregnancy loss (RPL) have been fairly well studied, resulting in treatment methods that are relatively standard.

On the other hand, implicating the immune system for repeated IVF failures represents an area of medicine that can be subject to abuse. Practitioners of reproductive endocrinology in the U.S. as well as Great Britain consider this one of the more controversial topics in their field.

There is no shortage of data analyzing the role of immunology in reproductive success or failure. A number of comprehensive studies in the mid- to late1990s were undertaken to identify a potential cause and effect relationship between abnormal immune test results associated with reproductive failure. Yet the tests reached the same conclusions; the most rigorous studies failed to provide a correlation.

Today many years after most reproductive endocrinologists might have thought the topic was put to rest, women with greater research capabilities on the internet who actively seek answers for their fertility problems continue to come across offers of clinical immunological investigations and treatments that lack true scientific basis. As pointed out by the Royal College of Obstetricians and Gynecologists, “Praying to Artemis of Ephesus, a goddess associated with fertility, might be as useful as undergoing some of the fertility tests offered on the Internet”.

The market for potential abuse is considerable, given that nearly 15% of American couples suffer from infertility, 10% of whom suffer from unexplained infertility. Additionally 2% of childbearing women may experience recurrent pregnancy loss or RPL, (generally defined as three or more consecutive pregnancy losses before 20 weeks gestation) and as many as 60% of such RPL will demonstrate no cause. Despite the costs, the lack of scientific evidence and the majority of skeptical practicing reproductive endocrinologists, people nevertheless seek treatment for purported immune imbalances.

Many such patients might be genuinely mixed up, finding it difficult to distinguish potential immunological causes of RPL from failed implantation following IVF procedures. Indeed, there is some evidence that RPL can occur as a result of an imbalance of some immune factors. But RPL is very different than a failed pregnancy at the implantation stage. If patients are given the impression that studies will support unproven treatments, it is understandable that frustrated patients may agree to experimental treatments.

What is clear, however, among the majority of practicing reproductive endocrinologists is the myriad of studies conducted in the 1990s demonstrated a sound scientific approach to the question, and no causal relationship was found. The American Society for Reproductive Medicine (ASRM) also summarized the literature and published an opinion paper concluded scientific evidence is not sufficient to suggest immune therapies are valuable for IVF. The Royal College concurs: “It is clear that the advice given on many sites is strongly influenced by the personal prejudices of doctors practicing non-evidence based medicine. Much of the data they provide has never been exposed to the rigorous scrutiny of peer review. The couples are emotionally vulnerable, and there is currently no scientific evidence to justify the use of these tests and treatments.” Nevertheless, a highly visible, albeit controversial industry exists, comprised of just a handful of practicing physicians and associated laboratories offering panels of immunological tests and subsequent treatment.

Patients are rarely informed that there is no standardized testing methodology among laboratories, so the interpretation of test results (normal, borderline, or abnormal) is frequently inconsistent. If and when therapies are administered, many are designed to modify the immune system (i.e. glucocorticoid treatment, intravenous immunoglobulin, and peripheral leukocyte immunization) or to compensate for the suspected effects of the immune defect (i.e. heparin or aspirin to reduce thrombophilia from thrombogenic autoantibodies).

Given the lack of strong scientific proof of meaningful associations between abnormal immune testing and adverse reproductive outcome, combined with the poor quality of the standards of such tests, PFC physicians maintain a packet of information for our patients who inquire about potential immunological causes to their infertility.

In the next issue of Fertility Flash, we will provide a follow-up article that will include more detailed descriptions of the tests that have been conducted as well as an introductory description of what is considered viable immunological tests and treatments for RPL, versus those that are considered more controversial for repeated IVF failure.

My husband and I were married for 6 years before we started trying to have a baby, and essentially got pregnant on the first attempt. Unfortunately, I miscarried in the second month. Our doctor told us not to worry; we tried again, got pregnant again, and miscarried early again. We still weren’t particularly worried, but had some tests performed and nothing in particular seemed to be inhibiting fertility. Over the next 5 years we went through phases of trying and not trying as we moved twice to accommodate dual careers, worked with 3 different fertility specialists in 2 states, negotiated a variety of insurance policies, endured the gamut of fertility tests, and suffered 3 more early miscarriages. Along the way I also struggled with mild depression, and guilt that perhaps the stress and travel associated with my job was the culprit, but we generally remained optimistic that we would someday have a baby.

Gradually we attempted more intense treatments, from Clomid to ovulation induction injections to intrauterine insemination (IUI). When our second IUI attempt failed last spring, our hopes really started to fade. I was 36, and while my husband and I are blessed with the resources to try several assisted fertility cycles, there were limits to what we could withstand financially and emotionally. Although I liked my doctor (a specialist at a teaching hospital), the support staff seemed to be in flux, the office environment had a high chaos factor, and I didn’t feel as though my particular case was significant to them.

On the recommendation of my primary care physician, I set up a consultation with Pacific Fertility Center and met with Dr. Ryan. I was immediately encouraged by the thorough review of my history and finally felt that someone was really listening to me, unfortunately this is not a given with all practices. After discussing a range of options it was crystal clear to me that we should try IVF with PGD, in order to screen the embryos (since we had experienced so many early miscarriages). We figured even if PGD told us that none of the embryos were viable, at least we would have valuable information about our next steps.

We embarked on a cycle of IVF this past winter, and with each successful step of the cycle, were amazed and encouraged. When the results of PGD came in we found that the majority of our embryos had a chromosomal abnormality, but several also appeared perfectly normal. We transferred 3 embryos, and I’m delighted to report that I’m now in the 5th month of my pregnancy (one baby, a boy, due in August). So 6 years after we began our quest for a baby we see the proverbial light at the end of the tunnel, and it is an amazing feeling. We can’t thank PFC enough for their combination of expertise and compassion. They restored our confidence and hope.

– Name withheld upon request

Alcohol and pregnancy don’t mix.

This article includes contributions from Isabelle Ryan, MD and Beth Schriock, MD

Studies have tied alcohol consumption during pregnancy to increased risk for stillbirth and first trimester miscarriage. Indeed – alcohol abuse by women who are expecting is the number one cause of birth defects, premature births, low birth weight and mental retardation. A shocking 12,000 babies each year are born with Fetal Alcohol Syndrome (FAS) and at least twice that many with the milder Fetal Alcohol Effects (FAE) associated with learning disabilities and lower alcohol intakes.

While the tragedy of FAS is well established, less certain is whether casual consumption of alcohol while trying to conceive either hinders or helps a woman’s chances. Past published studies have been mixed as to whether there is an association between moderate alcohol consumption and waiting time to pregnancy. One study did show decreased probability of conception in women imbibing 1-5 drinks per week. Another study saw no effect of 7 or more drinks per week in younger woman but women over 30 were more likely to be infertile. None of these studies have stratified the data to see if any type of alcohol might benefit or hinder. Yet a recent study drew a mildly positive correlation between moderate wine drinking and pregnancy.

The study, published in the September Journal of Human Reproduction was conducted at the Danish Epidemiology Science Center in Copenhagen by Mette Juhl, who had already researched the impact of moderate alcohol consumption on conception. Her past survey work concluded that moderate consumption of alcohol (up to 7 glasses per week) does not reduce a woman’s chances of purposefully getting pregnant.

For this study, the researcher set out to take a closer look at specific types of alcohol consumed by the 29,844 pregnant women who had participated in the first survey. Researchers discovered that wine drinkers had a nearly 30 percent greater chance than nondrinkers of getting pregnant within one year of trying. Woman who exclusively drank wine became pregnant sooner than those that drank only beer or hard liquor (spirits). Interestingly, drinking all three types of alcohol was associated with the shortest time to pregnancy.

Again, the study confirmed that heavy drinking of spirits actually decreases conception chances. Women who drank more than seven shots per week were 240 percent less likely to conceive. However, it is important to note that many of these women also had other risk factors for subfertility (smoking, greater incidence of pelvic infections or abdominal surgeries).

Ms. Juhl is cautious to point out that it may not be wine consumption per se, causing the increase or decrease in pregnancy success, but rather other lifestyle influences that may go along with wine drinking. For instance, some oenophiles enjoy healthier food than nondrinkers and beer or liquor drinkers. They also are more likely to be of average weight, and practice healthier lifestyle habits. The wine drinkers were less likely to smoke; smoking has been shown to prolong time to conception. Other confounding factors such as caffeine consumption, partner’s age and frequency of intercourse were not evaluated. She cautioned against drinking alcohol specifically to try to conceive, since this benefit was quite mild.

As little as one drink per day in pregnant women has been linked to decreased cognitive performance in their infants. Alcohol can have detrimental effects on the fetus as early as three weeks gestation – before a woman even knows she is pregnant. The “safe” amount of alcohol intake for pregnant women has not been established. Given that wine drinking could just be a proxy for a healthier lifestyle and the known negative effects of alcohol on the fetus, it is premature to encourage the consumption of wine to enhance conception.

For now we at PFC endorse the positions of the Centers of Disease Control (www.cdc.gov/ncbddd) and the American Academy of Pediatrics (www.AAP.org) advising that women attempting pregnancy should abstain from alcohol.

References:

American Academy of Pediatrics: Preventing Fetal Alcohol Syndrome. www.aap.org/advocacy/chm98pre.htm

CDC: Alcohol Use and Pregnancy. www.cdc.gov/ncbddd

National Institute on Alcohol Abuse and Alcoholism: Fetal Alcohol Exposure and the Brain. www.niaaa.nih.gov/publications/aa50.htm

Barefoot JC, Gronbaek M, Feaganes JR, McPherson RS, Williams RB, Siegler IC. Alcoholic beverage preference, diet, and health habits in the UNC Alumni Heart Study. American J of Clinical Nutrition 2002;76 (2): 466-472.

Bolumar F, Olsen J, Boldsen J. Smoking reduces fecundity: a European multicenter study on infertility and subfecundity. The European Study Group on Infertility and Subfecundity. Am J Epidemiol. 1996; 143 (6): 578-87.

Bolumar F, Olsen J, Rebagliato M, Bisanti L. Caffeine intake and delayed conception: a European multicenter study on infertility and subfecundity. The European Study Group on Infertility and Subfecundity. Am J Epidemiol. 1997; 145 (4): 324-34.

Jacobson JL, Jacobson SW, Sokol RJ, Martier SS, Ager JW, Kaplan-Estrin MG. Teratogenic effects of alcohol on infant development. Alcohol Clin Exp Res. 1993; 17 (1): 174-83.

Jensen TK, Hjollund NH, Henriksen TB, Scheike T, Kolstad H, Giwercman A, Ernst E, Bonde JP, Skakkebaek NE, Olsen J. Does moderate alcohol consumption affect fertility? Follow up study among couples planning first pregnancy. BMJ. 1998; 317: 505-510.

Juhl M, Andersen AM, Gronbaek M, Olsen J. Moderate alcohol consumption and waiting time to pregnancy. Human Reproduction. 2001; 16 ( 12) 2705-2709.

Juhl M, Olsen J, Andersen AM, Gronbaek M. Intake of wine, beer, and spirits and waiting time to pregnancy. Human Reproduction. 2003; 19 (9): 1967-1971.

Kesmodel U, Wisborg K, Olsen SF, Henriksen TB, Secher NJ. Moderate alcohol intake during pregnancy and the risk of stillbirth and death in the first year of life. Am J Epidemiol. 2002; 155 (4): 305-12.

Kesmodel U, Wisborg K, Olsen SF, Henriksen TB, Secher NJ. Moderate alcohol intake in pregnancy and the risk of spontaneous abortion. Alcohol Alcohol. 2002; 37 (1): 87-92.

Rosenberg A. Brain Damage Caused by Prenatal Alcohol Exposure. Scientific American. July/August 1996; 42-51

A new study, just published in the British Medical Journal has received quite a bit of press attention. This study, conducted at Kaiser Permanente in Northern California, suggests there may be a relationship between the use of aspirin and aspirin- like medications (called non-steroidal anti-inflammatory drugs, or NSAIDs) and first trimester miscarriage. We at PFC took a closer look at the study and determined that it has severe shortcomings.

NSAIDs, including aspirin, ibuprofen, naproxen and others, have not as yet been strictly forbidden during pregnancy, although most doctors, PFC physicians included, recommend acetominophen (Tylenol) if needed for headaches and other minor ailments during pregnancy.

Research has long established the impact of aspirin on women trying to get pregnant. At low doses (e.g. 81 mg), aspirin has markedly different effects on such things as platelet function as compared to higher doses (325-1000 mg). At low doses, some studies have suggested that aspirin may improve uterine blood flow and enhance embryo implantation. At higher doses, NSAIDs may inhibit prostaglandins, substances important for ovulation and implantation. This is the basis upon which we, at PFC, have designed our medication treatment protocol. We suggest patients not take drugs such as ibuprofen and naproxen during treatment, yet we do recommend patients undergoing infertility treatment take a daily baby aspirin.

This recent study surveyed 1055 women immediately after their pregnancy was diagnosed, and the women were followed up to 20 weeks of pregnancy. Only 53 women reported using NSAIDs around the time of conception or during pregnancy (5% of those surveyed). Of these, 15 (25%) miscarried. Of the 980 women who reportedly did not use NSAIDs, 149 (15%) miscarried. The 95% confidence interval was 1.0-3.2. When the 95% confidence interval is less than 1.0, the results are not considered statistically significant. Therefore, these results just barely achieved statistical significance. If the study had been able to find more women who had used NSAIDs, it might be more conclusive.

With so few women reporting NSAID use, and with results barely in the statistically significant range, more questions than answers are raised. It is disappointing that the authors did not include the average age of the mothers in their data presentation. Miscarriage is strongly associated with maternal age, as more embryos are genetically abnormal and will likely miscarry, as the mother is older at conception. Is there a possibility that the average age of the women using NSAIDs was greater, by chance or not? The study did not specify the maternal ages or how the data was adjusted to eliminate this potential important bias.

However cautiously we must review these results, PFC will continue to recommend a daily dose of baby aspirin to our patients undergoing infertility treatment. At such a low dose, baby aspirin improves uterine blood flow and this study does not warrant alarm. The primary conclusion from this Kaiser study strongly suggests that further research is needed.