Science Pulse    Infertility Research Interview

Mary Croughan, PhD is a Professor in the Departments of Obstetrics, Gynecology, and Reproductive Sciences and in Epidemiology and Biostatistics at the University of California, San Francisco. In 1999 her research team received funding from the National Institute of Child Health and Human Development to examine the health outcomes of infertility treatment for both mothers and children. Two thousand women who conceived after a history of infertility or after receiving infertility treatment are being compared to 2,000 women without infertility from the general population. Dr. Croughan is comparing the frequency of pregnancy complications, neonatal complications, and childhood outcomes up to six years of age in both groups. • All our physicians at PFC have supported Dr. Croughan's research efforts for over a decade both at San Francisco Center for Reproductive Medicine and at UCSF. As a result, many of our patients have participated in her studies. We continue our research support as a participating clinic in this current study. Those women and children who are part of this or any other study must provide their consent. Under no circumstances will a patients' chart or personal information be provided for a study without their permission.

Q. In layman's terms, what makes your study so significant?
A. First, there hasn't been that much research in the field of infertility or assisted reproductive technologies looking at long-term outcomes. Most studies have focused on very early pregnancy losses or the newborn period with no long term follow-up. Our study is examining children up to 6 years of age who were born as a result of either infertility treatment or following a history of infertility, and comparing them to children born to women without infertility in the general population.

We are currently interviewing women for this study and abstracting information from their medical records. We are recording detailed information regarding each woman's infertility history, her medical history, her pregnancies, and her labor and delivery. We also are recording information about any conditions the child may have or any special services they might have received. We are particularly interested in looking at neurodevelopmental outcomes in the children.

Q. How is the study structured and what milestone have you reached?
A. In a previous study, we had gathered minimal information on a group of 52,000 patients who sought infertility services in California many years ago. Since we wanted to examine recent pregnancies in these women, we linked this existing information to birth certificates and fetal death certificates to determine which of these women had experienced a stillbirth or live birth between 1994-1998. We also selected a matched set of women from the general population using the same birth certificate and fetal death certificate database. We then mailed these women letters inviting them to participate in the current study. We are now in the process of interviewing these women and abstracting their medical records. We are about 60% complete in gathering our data. We hope to analyze it next summer.

Q. When do you expect to announce results?
A. In April 2006 we expect to be done with data collection. By June of next year we hope to see results completed. We are now nearly done with data collection for the infertile women in this study and we're interviewing women from the general population comparison group. (Article continued-back page)

Q. It is interesting that standard comparative data for common medical conditions are not already known.
A. While we do know the incidence rates for many conditions in the general population, these numbers refer to everyone. In other words, the general population numbers include cases among children conceived using infertility treatments. In order to have comparative data, it is important to look at the groups separately.

Q. What do you mean by “examining infertility etiology?”
A. In trying to determine if there is an increased incidence of any adverse outcomes in these pregnancies or in the children, it is important to be able to tease out the effects of infertility per se from infertility treatments, other medical conditions, and advanced parental age. By looking at the reason(s) for infertility (the etiology) in combination with different treatment modalities and different conception methods, we can begin to tease out the independent effects of each.

Q. Is there any accounting for multiples vs singletons?
A. We are examining both singleton gestations and multiple gestations in this study. It is important to compare these two groups to each other, and to compare them across fertility groups (e.g., infertile vs. fertile). In a previous study I did with Dr. Rebecca Jackson here at UCSF, we performed a meta-analysis of singleton children conceived using IVF. These children had a significantly increased risk of low birth weight and prematurity as compared to singleton children in the general population. In our current study, we will be able to examine the same outcomes for multiple gestations.

Q. Why did you choose to identify patients from 11 different clinics?
A. By using many different institutions, we can examine different protocols and different types of patients. We are examining IVF with and without ICSI, IUI with and without ovarian hyperstimulation, as well as natural conceptions in infertile women and men. By including four Kaiser facilities, we also are able to look at a more diverse patient population. This is in contrast to the majority of other studies in Europe, Israel, and Australia that have focused solely on outcomes following IVF.

Q. Nine months ago a journalist revealed in an article that you already identified increased autism and ADD in children conceived using assisted reproductive technologies. Is this accurate?
A. No. The data was misinterpreted from a talk I gave at a professional meeting, and it was published without permission. We still have a lot of work left to do in this study and I don't know what the final results will indicate.

Q. What led you to such a specialized field?
A. I have been interested in reproductive and perinatal epidemiology since high school, and have worked in it ever since. But having gone through infertility treatment myself, I was frustrated by the lack of information available to help me make decisions. I knew that I could help other women by providing information to help them make the best decisions possible.

Q. Can you comment on your ideas for future studies?
A. We just submitted a grant application for our next study. In this study, we hope to have the children and their parents come to UCSF to be evaluated in person. The children in our study are now between 10-12 years of age, so it will be important to follow these children through adolescence and adulthood. Of particular interest is looking at the children's reproductive outcomes.

Conception Health    Fertility Medications and Side Effects

When discussing any medication, it is important to keep in mind some concepts when discussing “side effects.” Side effects are really those symptoms, usually minor, most commonly suffered by a significant proportion of patients taking the medication. Typically, this would include nausea or headaches.

There are also “adverse effects.” These are more serious events, usually rare and often unpredictable. Examples would be a stroke or a heart attack. An example of a less severe adverse effect would be ovarian hyperstimulation syndrome. If a drug has been found to have a significant incidence of severe adverse effects, it is not likely to pass FDA approval. If the adverse effect is extremely rare, it may not be discovered until very large numbers of patients have taken the drug and the medication may be pulled from the market after approval (e.g. Bextra).

Separate from side effects and adverse effects, are “long term effects.” These are generally serious adverse effects not discovered until well after the drug therapy is undertaken. An example of this is the effect on the uteri of daughters of mothers who took the drug DES during pregnancy. When patients ask us about the safety of fertility drugs, they are usually referring to adverse or long-term effects as much as concerns about side effects.

When reading the FDA-approved package labeling for almost all medications, fertility drugs included, it's important to be aware that any possible adverse effect anyone has ever experienced on the drug will be reported. Unfortunately, this almost renders this information useless because there are virtually no drugs that someone somewhere has taken without something happening at the same time. It is often impossible to prove whether or not that medical event was related to taking the drug or not.

None of the medications that are in use for fertility treatment are known to have such serious adverse effects that the FDA has even considered withdrawing its approval.

Overall, we believe fertility medications to be very safe, usually associated with only very mild side effects, relatively rare and treatable adverse effects (mostly commonly ovarian hyperstimulation) and no known significant long term effects.

Below is a list of some of the most common side effects our patients mention, as well as some of the more common adverse effects. It is by no means an authoritative or exhaustive list.

THE MOST COMMON SYMPTOMS AND SIDE EFFECTS:

Clomiphene (Clomid, Serophene®)
• FDA: FDA-approved for ovulation induction in anovulatory women, but widely used for unexplained infertility in women who do ovulate regularly on their own.
• Most common side effects: Hot flashes, night sweats, dizziness, mood swings
• Adverse reactions: ovarian hyperstimulation, abdominal pain or bloating, temporary visual disturbances.
• Long term effects: Possible increased incidence of noninvasive (“borderline”) ovarian tumors – not proven to be causative. Most recent studies find no link with invasive ovarian cancer.

GnRH agonists (Lupron, Synarel)
• FDA: Although Lupron and Synarel are not FDA-approved for IVF use, they are widely used in the U.S. to prevent premature ovulation in IVF cycles.
• Most common side effects: Mild headache
• Adverse reactions: Patients with unrecognized pituitary tumors can experience a type of pituitary “stroke” when on Lupron. This is very rare but potentially serious.
• Long term effects: bone loss in long-term users, not significant for the short courses used for IVF.

Gonadotropins (Follistim, Gonal-f, Repronex, Menopur)
• FDA: FDA-approved for super-ovulation and in IVF to recruit multiple eggs.
• Most common side effects: Tiredness, local injection site skin reactions such as pain and redness (especially Repronex), abdominal fullness, bloating. Contrary to popular belief, we rarely hear our patients complaining of mood swings on gonadotropins.
• Adverse reactions: Ovarian hyperstimulation, multiple pregnancies (twins or more).
• Long term effects: Some concern was raised in the early 1990's about whether these drugs could increase a woman's risk of ovarian cancer. Most recent studies are reassuring that there is not an increased risk. These studies are ongoing because this class of drugs has only been in wide use for about 25 years.

GnRH Antagonists (Ganirelix, Cetrotide)
• FDA: FDA-approved for use in IVF to prevent premature ovulation.
• Most common side effects: None that we have seen.
• Adverse reactions: Earlier (pre-FDA approval) versions of these medications were sometimes associated with severe allergic reactions but we have not seen any yet in our practice.
• Long term effects: bone loss in long-term users, not significant for the short courses used for IVF.

hCG (Novarel, Pregnyl)
• FDA: FDA-approved for ovulation induction. Commonly used in clomiphene, gonadotropin and IVF cycles to time insemination or egg retrieval.
• Most common side effects: Some increased discomfort, rarely outright pain, at the time of ovulation.
• Adverse reactions: If a patient has multiple follicles on gonadotropins, hCG can be the final kick to the ovaries to tip someone over into hyperstimulation syndrome. This is not seen in natural cycles or in most patients on clomiphene.
• Long term effects: None known.

Progesterone (Prometrium, Progesterone suppositories, Progesterone in oil)
• FDA: Only Prometrium is FDA approved and it is approved for use in menopause in conjunction with estrogen hormone replacement. It is pure oral micronized progesterone. Progesterone suppositories and Progesterone in oil are usually compounded by individual specialty pharmacies (pharmacies that specialize in distributing fertility drugs). Most progesterone packaging advises not to use in pregnancy but these drugs are the exact same progesterone produced by the human ovary in the luteal phase and in early pregnancy so are widely used in fertility treatment.
• Most common side effects: Mostly very minor things like breast tenderness or mild bloating. For patients on progesterone in oil, local pain and redness at injection sites is common.
• Adverse effects: Local vaginal reactions such as irritation or itching from suppositories. Severe local skin reactions to progesterone in oil are fairly rare.
• Long term effects: Questions have been raised as to whether high doses of progesterone in early pregnancy may be associated with urinary tract abnormalities in the fetuses of the mothers taking progesterone. There has never been any such association proven.

Carolyn Givens, MD

Patient Odyssey    Cindy and Heidi: Their Story

One of the first things that my partner Cindy and I discussed when we started to date was a strong desire to have children. As we talked about building a life together, we clearly imagined ourselves as parents, much to the relief of our families who were eager for grandchildren. We even started talking with Dr. Ryan about starting a family at the same time that we started planning our wedding. We had selected an anonymous sperm donor that we hoped to use for each of us, so that our children would be partially related to each other. We were very excited. We decided Cindy would begin first, as she was older, so the month after we returned from our honeymoon, we started trying.

Cindy was started on Clomid, which, although it worked relatively well, also had the unfortunate side effect of making her feel completely crazy at times. After a few months on Clomid, we decided that trying to balance pregnancy efforts with two demanding and stressful jobs with a lot of travel was enough to make anyone crazy, and we didn't actually need the additional variable of Clomid. We moved on to injectables (gonadotropin), which although not perfect, ended up being a great deal easier on both of us. Once again, although everything looked like it was working relatively well, no pregnancy. At this point, we had been trying for almost a year with absolutely no success, and we were trying very hard not to act as frustrated and upset as we felt. It was a tough year -- our friends and family were very supportive, but the monthly calls to our parents and close friends letting them know we still weren't pregnant were getting harder and harder and the financial and emotional toll was starting to weigh on us. We decided to move on to IVF and that if IVF didn't work I would start trying.

In the egg retrieval for IVF, we ended up with ten viable embryos of varying degrees of quality, and in consultation with Dr. Ryan we decided to be as aggressive as possible, and put all of the embryos back. Two weeks later, we learned what we had suspected, which was that none of the embryos had implanted. We took a few months off - spent several months remembering what it was like not to split your month into binary segments, not to have hypodermic needles in your kitchen cupboard and to drive down the Embarcadero without worrying we were late to an appointment.

When we felt ready, we went back to PFC. It was my turn. Everyone welcomed us back with sympathetic hugs and although we were ready to start trying again, it was a somewhat different experience - our excitement was tempered by our awareness that pregnancy simply doesn't happen for everyone. I started out on Clomid for six months with great results - except no pregnancy. At that point, we both decided we didn't have it in us to continue the same trajectory for the next few months with injectables. We decided to go right to IVF, which had the highest chance of success for us. We also started seriously discussing adoption, which was comforting to us as we were able to tell ourselves that we would be parents in the next year, one way or another, and that really helped.

We ran into out-of-town friends in the IVF waiting room (we knew they had been trying, but hadn't discussed where and how in depth with them, so we had no idea they were also doing IVF at PFC) and we both agreed to hope the coincidence was a lucky sign. Three days later, we put back three embryos and froze five. After two nerve-wracking weeks in which I fluctuated between wondering if I could be pregnant and worrying it was all jet lag, we found out on January 14, 2005, that we were pregnant! It was suggested to us that since my HCG numbers tripled very quickly, we might want to think about the possibility of twins, and our five week ultrasound revealed two sacs. Those two sacs have developed into a boy and a girl, who are due this October 6, and look, thus far, completely healthy. (Even better, our friends also succeeded on their try, and their baby is also due on October 6.)

We are thrilled beyond all measure, and these babies are so loved and wanted by so many people that it is ridiculous. We have taken every possible step to ensure that Cindy is also legally recognized as their parent so our family is as legally and emotionally solid as it can possibly be. We will always wish that Cindy could have gotten pregnant and we don't think that sense of loss will ever go away completely. On the other hand, as this experience has reminded us, you don't always get to live the life narrative you had hoped to write and these are the children that we are blessed with. We could not have had our family without PFC and especially not without Dr. Ryan's support and encouragement. We look very much forward to meeting our children when they arrive. • Heidi (Names have been changed at the author's request)

Post Script: Heidi and Cindy recently welcomed a healthy boy and girl into their family!

From Us To You    PFC to Study Progesterone Gel vs Tablet

Some women benefit from direct delivery of progesterone to enhance the implantation process.

The current protocol for direct progesterone application is via vaginal suppositories. Endometrin is an effervescent tablet that is inserted vaginally and absorbed locally to provide progesterone to the developing uterine lining and to provide support of pregnancy. The study aims to demonstrate the equivalence in maintaining pregnancy of the new medication to an existing FDA approved medication.

PFC is currently recruiting up to 25 women experiencing infertility to take part in this clinical research study.

The participants must be non-smokers between the ages of 18 and 42, with two functioning ovaries and a Body Mass Index of 34 or below. Additional screening will be conducted to determine if a patient is eligible to participate. Women who qualify and undergo an IVF treatment cycle will receive free medications and a reduction in IVF fees. Individuals interested in participating are invited to contact Dr. Philip Chenette at (415) 834-3000, or (888)-834-3095.
• Philip Chenette, MD

Announcement    PFC MDs are the "Best Doctors"

Left to right: Front Row: Carl Herbert, MD, Isabelle Ryan, MD Back Row: Joe Conaghan, PhD, Eldon Schriock, MD, Carolyn Givens, MD, Philip Chenette, MD

The physicians at Pacific Fertility Center are internationally recognized specialists in reproductive endocrinology and infertility. They have completed top-level medical education, published groundbreaking professional papers, and held positions on the faculty of leading research universities. They continue to participate in reproductive research. All MDs are Board Certified by ABOG as Reproductive Endocrinology and Infertility Specialists. Our state-of-the-art laboratory has one of the most highly trained teams in the country with every embryologist board certified and licensed in their specialty.

Thank you for your interest in subscribing to Pacific Fertility Center's free monthly newsletter. In order to better protect your privacy, we have a new secure subscription/log in form. We respect your privacy: Your email remains confidential and will not be shared or sold. Please click here to change your subscription preferences.

-- Best regards from all of us at Pacific Fertility Center.