Stillbirth, loss of a baby at delivery, is a painful challenge.  The suffering associated with the loss of a child, even before birth, can be overwhelming.  Especially acute for women that have conceived utilizing assisted reproduction, the loss of a pregnancy fought through reproductive technology can overwhelm a couple.  Stillbirth is a rare risk of pregnancy; the challenge facing us as reproductive medicine experts and obstetricians is how to reduce that risk.

The technologies of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) have enabled pregnancy for thousands of families with sperm, egg, and uterine problems.  With IVF, egg quality can be optimized using fertility drugs to produce more eggs.  Blocked fallopian tubes can be bypassed.  Weak sperm can achieve pregnancy by ICSI, where, using a microscopic needle, the sperm cell can be introduced into the egg.

No-one should expect these techniques to be foolproof.  While mechanical problems can be improved, other weaknesses in the reproductive system cannot.  Small deviations in the genetic code of the sperm or egg, missing chromosomes, aging, uterine defects, etc cannot be fixed by treating the sperm cell or embryo.

Thus the problem – these pregnancies established by high technology, are at higher risk.

A recent study from Denmark looked at stillbirth in children born after IVF/ICSI  and found that the risk was higher in children born after IVF/ICSI than natural pregnancy.  Out of 16,525 births to fertile women the chance of stillbirth was 0.37%, that is, 3.7 out of 1000 births.  Out of 742 babies born to women after IVF/ICSI there were 12 stillbirths, 1.62%, that is 16.2 out of 1000 births.

But more importantly to our patients, the liveborn baby rate after a successful IVF/ICSI treatment  and pregnancy is 98.4%.  The liveborn baby rate after a successful natural conception and pregnancy is 99.6%.  Almost all of the successful pregnancies after IVF/ICSI are liveborn.

Reproductive technologies, like IVF and ICSI, are enabling pregnancy and family building where it was not possible before.  All of our patients must be informed of and recognize the risks associated with fertility treatment.  These risks should not, however, dissuade anyone from considering these therapies.  On the contrary, the overwhelming likelihood is that, once a pregnancy is established, it will progress successfully to delivery and a healthy child.

We need to recognize these risks to provide help understand and take measures to reduce the risks to all children.  We will continue to watch these studies carefully in our ongoing effort to assure our patients of excellent pregnancy rates, at low risk.

Footnote:

1. K. Wisborg, H.J. Ingerslev, and T.B. Henriksen  IVF and stillbirth: a prospective follow-up study  Hum. Reprod. Advance Access published on February 23, 2010.

In vitro fertilization (IVF) is perhaps one of the most effective options available for the treatment of infertility. This procedure has been available in the developed world for approximately 30 years, and has been responsible for 1-4% of all conceptions. While IVF was originally developed for the treatment of female tubal factor, it has evolved to include treatment of male factor infertility via intra-cytoplasmic sperm injection (ICSI), as well as oocyte quality factor (Decreased Ovarian Reserve, or DOR). With the development of embryo biopsy techniques, IVF has also grown to incorporate pre-implantation genetic screening of embryos (PGD) to avoid genetic diseases in embryos and to screen for normal chromosomes. In the history of mankind, IVF will undoubtedly remain the greatest development for the treatment of human infertility for the foreseeable future.

Since the introduction of IVF, there has been a directly proportional increase in multiple gestation births. Traditionally IVF centers have measured success as the number of live births, irrespective of outcomes. This increase in multiple births is driven by the clinical incentives for live births, but some may also be driven by patient request. Two studies have shown that 20% of European and US infertile couples wanted a multiple birth^{(1, 2)}. Even after counseling regarding the risks of a multiple gestation, many patients still wanted to transfer 2 embryos. As IVF success rates have increased, and as the embryo freezing technologies have improved, a shift in the philosophy of IVF providers is occurring. Success rates are more likely to be measured as “live birth of a singleton (single baby) pregnancy”—in other words, “one healthy baby at a time”.

As the number of babies born after IVF has grown, there has been increased interest in looking at the pregnancy and birth outcomes in the successful IVF population. While potential complications for mother and babies are increased with any multiple gestation, there may also be an increased risk for complications even with IVF singleton babies. However, it may not be the IVF treatment itself that results in this increased risk for complications. The questions that reproductive endocrinologists and high-risk pregnancy specialists are trying to answer are primarily: 1) Is there a higher risk for a baby of any adverse birth outcome if that baby is conceived in an IVF laboratory? and 2) Is there something inherent about a past diagnosis of infertility which places even a singleton gestation at greater risk of pregnancy and birth complications?

IVF Singletons:

A number of large studies have addressed the question of increased risk to IVF babies ^(3-7). They echo a similar theme concerning birth outcomes, most importantly preterm birth <37 weeks, and low birth weight. One study compares the differences in degree of risk of poor outcomes with IVF babies vs. naturally-conceived babies. There appears to be a 93% increased risk for IVF singletons as compared to naturally conceived singletons, and a 57% increased risk for IVF twins versus naturally conceived twins⁽⁶⁾. Certainly the overall chance of a preterm delivery is much smaller for singletons than twins, and a twin pregnancy carries much greater risks overall.

A review of the US birth registry indicates that the proportion of IVF singleton babies born at full term with low-birth-weight is decreasing, but the proportion of IVF singleton babies born prior to full term with low-birth-weight is stable. In either case, the incidence of low-birth-weight is higher in babies born after IVF when compared with the general population. While outcomes of low-birth-weight babies may be getting better, there are still elevated risks for singleton low-birth-weight babies conceived via IVF.

For most of these studies looking at risks for IVF babies, factors known to influence pregnancy and birth outcomes are taken into consideration in the analysis. These important factors include maternal age and prior birth history. However, other factors may also be important but are not as well accounted for: factors such as previous poor obstetrical outcome, smoking status, socio-economic status, performance of fetal reduction procedure (especially for the analysis of the singleton data), types of ovarian stimulation protocols, media used in the IVF laboratory, and/or use of laboratory techniques (ICSI, etc.).

Infertility per se may itself be a risk factor for poorer pregnancy and birth outcomes. In an attempt to answer this important question, IVF outcomes have been compared with either non-IVF fertility treatments such as ovulation induction (OI) or to spontaneous conception outcomes. Numerous studies ^(8-15) have evaluated this question, and shown a higher risk of preterm birth for both IVF and OI babies as compared to spontaneously conceived singleton pregnancies. When evaluating outcomes for sub-fertile women (infertility for greater than 1 year) who spontaneously conceive, again we see a greater risk of preterm deliveries, obstetrical complications and adverse birth outcomes ^(16-18). These studies strongly suggest that there is an inherent characteristic of infertile patients which place them at greater risk of poorer pregnancy and birth outcomes. Whether this is due to uterine or embryo issues is not yet known.

IVF Twins:

Many studies have compared the outcomes for twins conceived via IVF versus spontaneous conception. These outcomes were summarized and reviewed in a meta-analysis of birth outcomes of IVF twins in studies up to 2003 ⁽¹⁹⁾. The specific findings showed an increase in the chances of a preterm birth (57% increase), admission to the neo-natal intensive care unit (two-fold increase), and Cesarean section delivery (33% increase). No other parameters were significantly different from spontaneously-conceived twins.

These differences between twin gestations conceived via IVF versus spontaneously-conceived twins were similar for cycles of twin gestation conceived via ovulation induction (OI). The rate of prematurity seemed to be higher for the IVF than OI group ⁽²⁰⁾.

In conclusion, when comparing singleton or twin gestations conceived via IVF or spontaneously, the degree of difference in the overall risk is greater for the singleton-baby births than twins. This is especially true with regards to preterm delivery which is increased two-fold in IVF singletons and by 40% (adjusted for age) in twins. While most studies have made adjustment for factors which can affect birth outcomes, such as maternal age, some other potential factors are difficult to measure, such as history of infertility or direct effects of IVF technology itself. It appears as though infertility prior to conception may play a larger role in IVF outcomes, for both singleton and twin gestations.  

1. Thurin A et al. Elective single-embryo transfer versus double-embryo transfer in in vitro fertilization. N Engl J Med 2004; 351:2392-2402.
2. Ryan GL et al. The desire of infertile patients for multiple births. Fertil Steril 2004; 81; 500-504.
3. Jackson RA et al. Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis. Obstet Gynecol 2004; 103; 551-563.
4. Helmerhorst FM et al. Perinatal outcomes of singletons and twins after assisted conceptions; a systematic review of controlled studies. BMJ 2004; 328; 261.
5. McGovern PG et al. Increased risk of preterm birth in singleton pregnancies resulting from in vitro fertilization-embryo transfer or gamete intrafallopian transfer: a meta-analysis. Fertil Steril 2004; 82; 1514-1520.
6. McDonald SD et al. Perinatal outcomes of singleton pregnancies achieved by in vitro fertilization: a systematic review and meta-analysis. J Ostet Gynaecol Can 2005; 27; 449-459.
7. Bower C et al. Assisted reproductive technologies and birth outcomes: overview of recent systematic reviews. Reprod Fertil Dev 2005; 17; 329-333.
8. French National IVF Registry. Analysis of 1986 to 1990 data. Fertil Steril 1993; 59; 587-95.
9. Frydman R et al. An obstetric assessment of the first 100 births from the in vitro program of Clamart, France. Am J Obstet Gynecol 1986; 154; 550.
10. McFaul P et al. An audit of obstetric outcome of 148 consecutive pregnancies from assisted conception: implication for neonatal services. Br J Obstet Gynecol 1993; 100; 820-5.
11. Tan S et al. Obstetric outcome of In vitro fertilization pregnancies compared with normally conceived pregnancies. Am J Obstet Gynecol 1992; 167; 778-84.
12. Wang JX et al. The obstetric outcome of singleton pregnancies following IVF/GIFT. Hum Reprod 1994; 9; 141-6.
13. Tanbo T et al. Obstetric outcome in singleton pregnancies after assisted reproduction. Obstet Gyncol 1995; 86; 188-92.
14. Rufat P et al. Task force report on the outcome of pregnancies and children conceived by in vitro fertilization (France 1987-1989). Fertil Steril 1994; 154; 550-5.
15. Friedler S et al. Births in Israel resulting from in vitro fertilization/embryo transfer. 1982-1989: National registry of the Israeli association for fertility research. Hum Reprod 1992; 7; 1159-63.
16. Basso O et al. Subfecundity and neonatal mortality: longitudinal study within the Danish national birth cohort. BMJ 2005; 330; 393-394.
17. Basso O et al. Infertility and preterm delivery, birthweight, and Caesarean section: a study within the Danish National Birth Cohort. Hum Reprod 2003; 18; 2478-2484.
18. Pandian Z et al. A review of unexplained infertility and obstetric outcome: a 10 year review. Hum Reprod 2001; 16; 2593-2597.
19. McDonald S et al. Perinatal outcomes of in vitro fertilization twins: a systematic review and meta-analysis. AM J Obstet Gynecol 2005; 193; 141-152.
20. Adler-Levy Y et al. Obstetric outcome of twin pregnancies conceived by in vitro fertilization and ovulation induction compared with those conceived spontaneously. Europ J Obstet Gynecol and Reprod Biol 2007; 133; 173-178.

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 #1: Ovarian Stimulation Techniques: Changes in ovarian stimulation techniques evolve as a better understanding of the medications and their effects on eggs and ovaries develops.

Letrozole (Femara) is increasingly being used as a mild stimulation for ovarian follicle growth and as an additional medication with gonadotropins (e.g. Follistim). In a study on the use of letrozole in preparation for IVF in breast cancer patients, a group from New York showed that breast cancer recurrence or the incidence of invasive carcinoma in the opposite breast does not appear to be increased after stimulation using letrozole and FSH for fertility preservation.

For patients with PCOS, researchers from France compared stimulation with a GnRH agonist, similar to Lupron, with oral contraceptives plus agonist. In these preliminary results, dual suppression does not provide any obvious effect in harmonizing the group of developing follicles nor in improving the quality of oocytes and embryos. This study is still ongoing in order to test these results in a larger population.

In patients that produce an excessive number of follicles in response to stimulation, ovarian hyperstimulation syndrome (OHSS) is possible. To prevent this, the fertility drugs are sometimes stopped mid-stimulation; the follicles are “coasted” – they grow without stimulation, with a lower risk of OHSS. An alternative to “coasting” is the use of Ganirelix, a GnRH antagonist, in a “salvage protocol.” Probability of live birth with the Ganirelix salvage protocol was similar to controls. High-grade embryos were more common with this regimen, in contrast to “coasting”. The miscarriage rate was slightly higher, but not statistically significant. These results suggest that the Ganirelix salvage regimen is a superior alternative to “coasting” in women at risk for OHSS.

A group in Montpelier, France is interested in gene expression in the follicle after use of fertility drugs. Using gene chips they measured gene expression in patients exposed to urinary FSH products and recombinant FSH. Significant differences were found meaning that different genes are being expressed in follicles of women receiving pure FSH (Gonal-f or Follistim) as compared to genes being expressed in follicles of women receiving urinary FSH (Repronex or Menopur)– the meaning of these changes will have to await further study.

On the other hand, a long debate about the effectiveness of urinary and recombinant FSH products is a bit closer to resolution. A meta-analysis from a group in Egypt examined pregnancy outcomes and risks in a group of previously published studies. No significant differences were found. Their conclusion was that urinary gonadotropin (hMG) is as effective as recombinant gonadotropin with regards to clinical outcomes and patient safety.

Philip Chenette, MD

The American Society for Reproductive Medicine (ASRM) is the largest organization in the United States for medical professionals in the field of Reproductive Endocrinology and Infertility. In 2002, ASRM published medical and psychological guidelines for ovum donation. The psychological recommendations for donors are general guidelines for addressing moral, ethical and psychosocial issues that may confront ovum donors. Included are standards for what should be included in a psychosocial screening of donors and reasons to exclude donors. A few of the objective reasons for donor exclusion include known substance abuse, positive family history of heritable psychiatric disorders such as schizophrenia or bipolar disorder, or instability in donors’ lives. To determine “inclusion” I take a psychosocial history and administer a psychological test that informs me about the donor’s personality profile, including just how much they are trying to impress me – the “fake good” factor. I am also assessing motivation to donate and the donor’s “need” versus “desire for” the compensation. Stability, stress levels, and reproductive history are also part of an ASRM assessment of donors.

Although I would like to base my entire decision on objective information, much of my decision on donor acceptance must, in fact, be based on intuition. Throughout my 25 years as a therapist, I have found that my intuition is quite accurate, but it is not fool proof.

There is one major controversy in the field that may hinder a psychotherapist’s ability to screen donors. That is the hotly debated topic on compensation of donors. In August 2000, the Ethics Committee of The American Society for Reproductive Medicine concluded that there is no consensus on the precise payment that oocyte donors should receive. It was suggested, “sums of $5,000 or more require justification and sums above $10,000 go beyond what is appropriate.” Due to costs of living and the scarcity of available donors, there are significant regional variations that affect these rates.

The Society for Assisted Reproductive Technology (SART) has attempted to assist clinics and patients by creating a list of Egg Donor Agencies that have signed an agreement stating that they will abide by the Ethics Committee Guidelines governing the compensation of egg donors.

The debate centers on the fact that donors could feel undue inducement and exploitation in the process if the fee is so high as to be coercive. Part of the job of the mental health professional is to provide donors with informed consent. Might donors conceal pertinent medical information that could be important for themselves or offspring if the monetary incentive is so high? Will donors discount risks to themselves? How can the donor actually give informed consent about the medical procedure and pay attention to the risks if $$ signs are floating before their eyes?

Ethicists and some in the field of women’s health advocacy express concern “that lucrative payments are enticing young women with credit-card debt and steep tuition bills to sell eggs without seriously evaluating the risks.” Can the payment cloud someone’s judgment and can we assess that? How much is too much? Where is that line?

When I began working with PFC in 1998, we were paying first time egg donors $2,500. Nine years later, the compensation is $6,500 for a first time donor and $7,000 for any subsequent donations. Even adjusted for inflation, the payment is rising at a phenomenal rate. Competition, supply and demand govern these rises.

As part of my objective/intuitive approach to interviewing donors, I discuss money with them. What would she use the compensation for? How does she support herself? What kind and how much debt does she have? While $25,000 in student loans points to a person’s drive toward positive goals, the same amount in credit card debt speaks to me of impulsive behavior. How much have they educated themselves on ovum donation? Whom have they talked with about their desires? Do they have their own children? Are they science majors who may be more likely to view gametes as DNA and not their own children? Are their answers well thought out?

My goal is to provide the recipients of donated eggs with intelligent, healthy, and thoughtful young women who understand the implications of ovum donation both for themselves and for the recipients. Donors who are motivated by the “need” for money are more likely to provide inaccurate information on their applications, or leave out information that could be pertinent to the recipients or their offspring. It is my job and the job of the Egg Donor Agency to determine motivation.

Although impossible to attain, we would all like donors to be motivated altruistically. We may diminish altruism by making the donation about eggs for money. However, I believe we can increase altruism by helping the donors to have a greater understanding of who the recipients are and what their struggles have been.

Peggy Orlin, MFT

Ms. Orlin served as 2006-7 chair of ASRM’s Executive Committee of the Mental Health Professional Group, is a member of Resolve’s National Mental Health Advisory Board. She co-teaches PFC’s Mind/Body workshops.

To register for the September 8th Mind/Body@PFC Workshop, please phone 415-834-3095.

Many couples, in the midst of their struggle with infertility and who may have undergone several cycles of fertility treatment, have a hard time visualizing success. They often have an even harder time believing they could conceive a multiple gestation. On the other hand, many fertility patients may see a twin gestation as a positive thing in that they can increase their family size all at once – a bargain!

In this country, we have seen an increase in the percentage of twin births that has become phenomenal and is mostly due to an increase in the use of fertility medications and assisted reproductive treatments. Of the 35,025 babies born from IVF in the year 2000, 44% were twins and 9% were triplets or more. Nationwide, the number of twins has increased by 65% since 1980 and by 38% since 1990. These numbers have not gone unnoticed by public health officials, insurance companies and increasingly, lawmakers.

Thankfully, although in the early 1990′s we saw astounding increases in the number of triplet and higher-order multiple gestations, the good news is that these numbers are falling. This change is felt to be due to increased awareness on the part of reproductive specialists and consequently better education of their patients about the desirability of avoiding triplet+ gestations.

Although most twin and even most triplet babies survive without serious problems, these pregnancies do involve significant increases in the risk for poor outcomes. This is because the gestational age at delivery (averaging 40 weeks for a singleton pregnancy) is decreased on average by 3 weeks for each additional fetus. Neonatal Intensive Care Unit admissions are significantly higher as a consequence. Only 9% of singletons end up in the NICU but 48% of twins and 78% of higher order multiples are admitted to the NICU. Intrauterine death (stillbirth) is increased 5-fold in twins. Neonatal death (death within the first month of life) is increased 7-fold for a twin as compared to a singleton. (See Table below.)

Treatment of prematurity has allowed even some of the lowest birth weight babies to survive. But survival may not mean disability-free living. Cerebral palsy is a devastating permanent brain injury that occurs either in the uterus or at the time of birth. For twins, the incidence is 4 times higher than singletons and the incidence is 17 times higher for triplets. Ultimately, the main worry is having a child with a severe handicap. This risk is 1.7 times higher for twins and 2.9 times higher for triplets. While the risks of twin gestation are definitely measurable, most high-risk pregnancy specialists do not advocate selective reduction of twin gestations. Most do advocate selective reduction of triplet+ gestations, however.

The maternal risks increase with multiple gestations and the risks rise with each additional fetus. These risks include high blood pressure, postpartum hemorrhage, excessive nausea, miscarriage, gestational diabetes, preterm labor, Cesarean section and even maternal death. Although obstetrics has come a long, long way in this country in the last 100 years, pregnancy and childbirth still pose medical risks to mothers and these risks are definitely affected by multiple gestation.

The purpose of this article is not to frighten patients considering fertility treatments. It is meant to educate our patients about these risks and to help our patients to understand why Pacific Fertility Center is doing its best to adhere to ASRM guidelines. However, we wish to retain the rights to individualize our treatments and adapt to the specific circumstances for each of our patients. We do not want to see the government interfere with medical decisions that should be made between physicians and their patients. This is why our motto is “Conception Solutions: One Healthy Baby at a Time.”

Carolyn Givens, MD

ICSI Overview: Intracytoplasmic sperm injection (ICSI) is a technique used in the IVF laboratory to inject individual sperm into eggs. The procedure was developed in Belgium in the early 1990′s (Palermo et al., 1992) and it revolutionized the treatment of male factor infertility. Prior to ICSI, men with moderate and severe fertility issues had little or no chance of having their own genetic children. ICSI has so revolutionized the treatment of infertility that it is used in the majority (55.6%) of assisted reproductive technology cycles in the United States (CDC National Summary and Fertility Clinic Reports, 2003).

When IVF is performed without ICSI, it is common to incubate individual oocytes in a petri dish with about 100,000 sperm. Usually these sperm have been obtained by processing the semen in such a way as to be able to isolate sperm that look normal and swim energetically. Only the best 10% of the sperm in a normal semen sample are used, and in the petri dish, these compete for the honor of fertilizing the oocyte.

When ICSI is employed, individual sperm are isolated and forcibly injected into the oocyte by an embryologist. The oocytes have to be incubated in the enzyme hyaluronidase to remove the cumulus cells that surround them (naturally, these cells would be dislodged by the many sperm that try to penetrate the oocyte). Prior to injection, the sperm may be processed (as above) but often there are so few sperm available that processing is minimal. Once selected, the sperm is immobilized by breaking its tail. This is accomplished by dragging the injection needle across the tail until a visible kink or break can be seen. The immobilized sperm is then aspirated into the needle, which is pushed through the shell surrounding the oocyte and then through the cell membrane. The elasticity of the oocyte membrane is such that the embryologist must be rough with it to get through. Piercing the membrane is usually achieved either by poking it several times or by aspirating the membrane into the needle until it breaks. Once the membrane breaks, the sperm can be dropped inside the oocyte.

Technically, ICSI is one of the most difficult procedures to perform in the IVF laboratory and it requires a talented embryologist to do it well. As well as being responsible for choosing “the sperm”, the embryologist must work quickly and be firm enough to break the sperm tail and oocyte membrane while not being so aggressive as to kill the oocyte. ICSI has been so successful as a technique that it is now widely used in cases where there is no male factor infertility. In fact, of all the ICSI cases performed nationally in 2003, only 53% had a male issue (CDC, 2003). While ICSI is absolutely indicated for low sperm counts, decreased sperm motility, abnormal sperm morphology (size and shape) and surgically retrieved sperm, its use has expanded to include cases with anti-sperm antibodies, previous low fertilization with IVF, low oocyte numbers, frozen-thawed sperm and ejaculatory dysfunction such as retrograde ejaculation. In addition, ICSI is being widely used for patients having preimplantation genetic testing because it avoids DNA contamination during embryo biopsy by the many sperm that are usually attached to the shell of the embryo.

ICSI Risks: In assessing the risks of ICSI, we must first look at the procedure itself. In piercing the cell membrane, our greatest concern is in avoiding the area within the oocyte where the DNA is located. This is done by orientating the oocyte such that the polar body (a small packet of discarded DNA) is placed at the 12 or 6 o’clock position and the needle inserted at 3 o’clock. The polar body is the most practical indicator of where the oocyte DNA is located since it is created by the division of the oocyte’s total DNA just prior to ovulation. However, the DNA may not always be in the assumed place so a theoretical risk of damage exists, and chromosome breakage has been observed as being higher in ICSI-derived embryos when compared to conventional IVF embryos (Bergere et al., 1995; Edirisinghe et al., 1997).

In addition to DNA disruption or damage, the physical and biochemical disturbance that occurs could be significant. The injection procedure could introduce foreign material into the oocyte such as culture medium, seminal fluid with or without bacteria (Michelmann et al., 1998), viruses (Brossfield et al., 1999), or in theory, even prions (Lacey & Dealler, 1994) or foreign DNA.

Following the ICSI procedure, the fertilization process is known to be different than with conventional IVF with atypical decondensation of the sperm head resulting in delayed replication of the male genome. This is thought to result from the injection of the intact sperm into the oocyte since such sperm retain their acromosomal cap and perinuclear theca, both of which are normally lost as the sperm penetrates the shell of the oocyte. There is marginal evidence that the sperm sex chromosome is preferentially located in the anterior head and therefore might be impacted by the delayed decondensation caused by retention of the cap (Luetjens et al., 1999).

Currently there is no evidence that the miscarriage rate is different between ICSI and IVF pregnancies, and the incidence of prematurity and low birth weight babies (7.6% and 10.3% respectively for ICSI) is similar to that for IVF in large studies (Wisanto et al., 1995; Aytoz et al., 1998), but slightly higher than rates found in natural pregnancies. These outcomes have been confirmed in a large US-based study (Schieve et al., 2002) showing overall lower birth weight and higher perinatal mortality in children conceived with the help of reproductive technologies, but no significant differences between ICSI and IVF.

In the mid 1990′s ICSI had become a routine procedure in the world of assisted reproductive technology (ART) and was being widely used. However, reports surfaced indicating that the resulting children had a high incidence of chromosomal abnormalities (In ‘t Veld, 1995; Van Opstal et al., 1997). The immediate response from the ART community was a flurry of scientific papers refuting the findings, but ultimately the conclusions of the studies were confirmed by large scale, prospective systematic follow up studies on the ICSI children. Instrumental in these studies was the Brussels University where ICSI was invented. Thorough pre- and postnatal testing showed an abnormal karyotype in 2.6% of the ICSI pregnancies (Bonduelle et al., 1999) and in a subsequent study, 3% showed a chromosomal abnormality (Bonduelle et al., 2002). Novel chromosome abnormalities increased threefold (1.6% in ICSI vs. 0.5% in the general population) and these were mostly comprised of sex chromosome aneuploidies with a smaller number of autosomal structural anomalies. Inherited chromosomal abnormalities increased fourfold in ICSI pregnancies (1.4% compared to 0.3% in the general population) and this was related to the higher rate of existing chromosome abnormalities seen in the parents (mainly the fathers). It is important to point out that the incidence of these sex chromosome aneuploidies and structural abnormalities is inversely related to the number of sperm in the ejaculate and is therefore higher in ICSI fathers (4.8% vs. 0.5% in the general population), and interestingly also higher in ICSI mothers (1.5%: Van Assche et al., 1996). The structural chromosome abnormalities include deletions of sections of the Y chromosome in some men with low sperm counts which will be passed directly to sons created by ICSI.

We are fortunate that the children of ICSI are being widely followed and many solid studies have appeared and continue to appear on the incidence of congenital abnormalities (these are problems that cause impaired function and require medical or surgical intervention). The most common abnormality appears to be hypospadias (a urological condition where the urethra opens under the penis instead of at the tip, and which is correctable with minor surgery) which is increased in ICSI births (Wennerholm et al., 2000). However, when evaluating these cases, the increased risk for congenital abnormalities is often reduced or eliminated when confounding factors (maternal age, infertility, multiple pregnancy, familial and pregnancy history) are factored in (Ericson & Kallen, 2001). Nonetheless, it does appear as though ICSI and IVF children do have an increased odds ration (2.77 and 1.8 respectively) for malformations that need medical or surgical intervention in early life when compared to naturally conceived children (Bonduelle et al., 2005).

Concerns have also arisen about developmental delays in ICSI children as a result of a single paper (Bowen et al., 1998) that had them scoring lower on the Bayley Scales of Infant Development at 1 year of age when compared to IVF and naturally conceived infants. However, a good number of solid papers have since been published indicating that this finding is not holding up and that ICSI children are performing normally in psychological testing as well as in their cognitive and verbal skills using the Bayley and other scales of intelligence (Bonduelle et al., 1998; 2003 Ponjaert-Kristoffersen et al., 2004; 2005).

Finally, it is worth asking if gene expression is normal for ICSI children and are problems likely to arise as the children get older? In looking at gene defects, there is emerging evidence that ART children might be at a higher overall risk for genomic imprinting errors when compared to naturally conceived children. Genomic imprinting is a process that silences one gene from a parent, specifically so that the gene inherited from the other parent can do the work. The classic example is placental growth, which is controlled largely by paternal genes. Maternal genes for placental growth are deliberately inactivated since it is considered a conflict of interest for Mom’s genes to be involved in the regulation of how much of her resources the fetus gets. Problems arise when an imprinted gene is defective, because the perfectly good copy of the gene from the other parent has been switched off and therefore cannot work. Diseases such as Beckwith-Wiedmann and Angleman’s syndromes result from not having a functioning copy of a gene and preliminary evidence suggests that these might be more prevalent in IVF children (Gosden et al., 2003). Abnormal spermatogenesis is associated with an increase in defective genomic imprinting (Marques et al., 2003), but it is probably too early to tell if imprinting errors will occur more frequently in ICSI children. Angleman’s syndrome for example occurs at most at a rate of 1/200,000 IVF births, so the impact of ICSI will be difficult to measure. Similarly, retinoblastoma (a type of cancer of the eye that is caused by a genetic defect similar to what causes imprinted diseases) has been reported as slightly higher in IVF children (Moll et al., 2003) but further studies will be required to substantiate this observation and to ascertain the specific risk of ICSI.

ICSI is an aggressively invasive procedure that deposits a single sperm, usually from an infertile father, into the oocyte of a woman who has undergone fertility treatments. The specific risk of ICSI in offspring is an increased incidence of chromosomal abnormalities which may be caused by the procedure or by the parents, or both. ICSI is a routine and overly used procedure and patients should be educated as to the risks. Of the studies cited here, none of the children examined were older than 5 years. The long term hazards of the procedure, if any, remain to be determined. See below for the complete bibliography.

– Joe Conaghan, PhD

Bibliography:

Aytoz A, Camus M, Tournaye H, Bonduelle M, Van Steirteghem A, Devroey P. Outcome of pregnancies after intracytoplasmic sperm injection and the effect of sperm origin and quality on this outcome. Fertil Steril. 1998 Sep;70(3):500-5.

Bergere M, Selva J, Volante M, Dumont M, Hazout A, Olivennes F, Frydman R. Cytogenetic analysis of uncleaved oocytes after intracytoplasmic sperm injection. J Assist Reprod Genet. 1995 May;12(5):322-5.

Bonduelle M, Wilikens A, Buysse A, Van Assche E, Wisanto A, Devroey P, Van Steirteghem AC, Liebaers I. Prospective follow-up study of 877 children born after intracytoplasmic sperm injection (ICSI), with ejaculated epididymal and testicular spermatozoa and after replacement of cryopreserved embryos obtained after ICSI. Hum Reprod. 1996 Dec;11 Suppl 4:131-55.

Bonduelle M, Aytoz A, Van Assche E, Devroey P, Liebaers I, Van Steirteghem A. Incidence of chromosomal aberrations in children born after assisted reproduction through intracytoplasmic sperm injection. Hum Reprod. 1998 Apr;13(4):781-2.

Bonduelle M, Camus M, De Vos A, Staessen C, Tournaye H, Van Assche E, Verheyen G, Devroey P, Liebaers I, Van Steirteghem A. Seven years of intracytoplasmic sperm injection and follow-up of 1987 subsequent children. Hum Reprod. 1999 Sep;14 Suppl 1:243-64.

Bonduelle M, Van Assche E, Joris H, Keymolen K, Devroey P, Van Steirteghem A, Liebaers I. Prenatal testing in ICSI pregnancies: incidence of chromosomal anomalies in 1586 karyotypes and relation to sperm parameters. Hum Reprod. 2002 Oct;17(10):2600-14.

Bonduelle M, Ponjaert I, Steirteghem AV, Derde MP, Devroey P, Liebaers I. Developmental outcome at 2 years of age for children born after ICSI compared with children born after IVF. Hum Reprod. 2003 Feb;18(2):342-50.

Bonduelle M, Wennerholm UB, Loft A, Tarlatzis BC, Peters C, Henriet S, Mau C, Victorin-Cederquist A, Van Steirteghem A, Balaska A, Emberson JR, Sutcliffe AG. A multi-centre cohort study of the physical health of 5-year-old children conceived after intracytoplasmic sperm injection, in vitro fertilization and natural conception. Hum Reprod. 2005 Feb;20(2):413-9.

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Brossfield JE, Chan PJ, Patton WC, King A. Tenacity of exogenous human papillomavirus DNA in sperm washing. J Assist Reprod Genet. 1999 Jul;16(6):325-8.

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Edirisinghe WR, Murch A, Junk S, Yovich JL. Cytogenetic abnormalities of unfertilized oocytes generated from in-vitro fertilization and intracytoplasmic sperm injection: a double-blind study. Hum Reprod. 1997 Dec;12(12):2784-91.

Ericson A, Kallen B. Congenital malformations in infants born after IVF: a population-based study. Hum Reprod. 2001 Mar;16(3):504-9.

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In’t Veld P, Brandenburg H, Verhoeff A, Dhont M, Los F. Sex chromosomal abnormalities and intracytoplasmic sperm injection. Lancet. 1995 Sep 16;346(8977):773.

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Luetjens CM, Payne C, Schatten G. Non-random chromosome positioning in human sperm and sex chromosome anomalies following intracytoplasmic sperm injection. Lancet. 1999 Apr 10;353(9160):1240.

Marques CJ, Carvalho F, Sousa M, Barros A. Genomic imprinting in disruptive spermatogenesis. Lancet. 2004 May 22;363(9422):1700-2.

Michelmann HW. Influence of bacteria and leukocytes on the outcome of in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). Andrologia. 1998;30 Suppl 1:99-101.

Moll AC, Imhof SM, Cruysberg JR, Schouten-van Meeteren AY, Boers M, van Leeuwen FE. Incidence of retinoblastoma in children born after in-vitro fertilization. Lancet. 2003 Jan 25;361(9354):309-10.

Palermo G, Joris H, Devroey P, Van Steirteghem AC. Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet. 1992 Jul 4;340(8810):17-8.

Ponjaert-Kristoffersen I, Tjus T, Nekkebroeck J, Squires J, Verte D, Heimann M, Bonduelle M, Palermo G, Wennerholm UB. Collaborative study of Brussels, Goteborg and New York. Psychological follow-up study of 5-year-old ICSI children. Hum Reprod. 2004 Dec;19(12):2791-7.

Ponjaert-Kristoffersen I, Bonduelle M, Barnes J, Nekkebroeck J, Loft A, Wennerholm UB, Tarlatzis BC, Peters C, Hagberg BS, Berner A, Sutcliffe AG. International collaborative study of intracytoplasmic sperm injection-conceived, in vitro fertilization-conceived, and naturally conceived 5-year-old child outcomes: cognitive and motor assessments. Pediatrics. 2005 Mar;115(3): 283-9.

Schieve LA, Meikle SF, Ferre C, Peterson HB, Jeng G, Wilcox LS. Low and very low birth weight in infants conceived with use of assisted reproductive technology. N Engl J Med. 2002 Mar 7;346(10):731-7.

Van Assche E, Bonduelle M, Tournaye H, Joris H, Verheyen G, Devroey P, Van Steirteghem A, Liebaers I. Cytogenetics of infertile men. Hum Reprod. 1996 Dec;11 Suppl 4:1-24.

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Wennerholm UB, Bergh C, Hamberger L, Westlander G, Wikland M, Wood M. Obstetric outcome of pregnancies following ICSI, classified according to sperm origin and quality. Hum Reprod. 2000 May;15(5):1189-94.

Wisanto A, Magnus M, Bonduelle M, Liu J, Camus M, Tournaye H, Liebaers I, Van Steirteghem AC, Devroey P. Obstetric outcome of 424 pregnancies after intracytoplasmic sperm injection. Hum Reprod. 1995 Oct;10(10):2713-8.

Infertility and OBGYN professionals across the U.S. and Canada appear to be united in agreeing that there is an undue amount of fear and controversy concerning the use of letrozole (under the trade name Femara) for fertility treatment. Letrozole is a drug that is used for the prevention of recurrence of estrogen-receptor positive breast cancer. Its “off-label” use for ovulation induction is increasingly common, although not approved by the FDA for this application.

In late 2005, Novartis Pharmaceuticals, the Swiss company that developed letrozole for treatment of breast cancer reacted to a single study that showed higher than normal adverse reactions. Novartis sent out a warning letter to infertility clinics asserting that the company does not advocate the use of this medication for infertility treatment. Despite the drug’s successful track record as an alternative to clomid for ovulation induction, at least one Canadian clinic has stopped using it.

As for the background, it started with the presentation of a study conducted by the Montreal Fertility Clinic at the 2005 annual meeting of the American Society for Reproductive Medicine (ASRM). The study reported a much higher rate of serious fetal abnormalities among patients who had been prescribed letrozole. The author’s analysis of only 150 babies born after letrozole therapy revealed a 4.7% rate of major anomalies. This rate was compared to the 1.8% rate of a “control group” of more than 36,000 babies born at a nearby hospital.

Our reading of this study leaves us skeptical about forming any conclusion that letrozole causes an increase in birth defects. First, it is generally agreed that within an unselected population, the background rate of birth defects is 3% for major anomalies and 6% when including minor anomalies. So the background rate in the “control” population seems low. Second, the comparisons between these groups are not indicative of a true controlled study whereby patients of like demographics and health are provided the same treatment protocol, ideally through a double-blind placebo study.

Common sense would remind us that infertility centers treat a higher percentage of women who have delayed childbirth and their older status is typically associated with higher rates of birth defects. The control group in the letrozole study of 36,000 women at a standard hospital would likely include a high percentage of younger women who, by nature, and backed by statistics, have fewer births with congenital anomalies. Indeed, in this study, the mean age of the women treated with letrozole was 35.2 years and the mean age in the control population was 30.5 years. Further, there may be “ascertainment bias” as there may have been under-reporting of defects in the “control” population. Comparing these two groups and drawing a conclusion that sends such alarm through the infertility community is questionable. Lastly, the limited size of the study makes drawing any conclusion very premature.

Novartis has not led any independent studies of its drug with applicability as an infertility medication. But it took the opportunity to analyze its own database with regard to safety. The company claims there were 13 cases involving “adverse reactions” involving letrozole and congenital birth anomalies.

No control groups or comparison to the background rates of congenital anomalies were made. Given this day and age of class action lawsuits, it is understandable for a pharmaceutical company to issue a warning at the hint of any trouble. In light of this, it has been up to the professional associations and communities of medical professionals handling infertility cases to sort through the data carefully, make up their own minds and provide full disclosure to patients.

Just this month, a new study on this subject is appearing in the primary infertility journal of the U.S., Fertility and Sterility. Again from Canada, researchers from Toronto reported on 911 babies conceived with the assistance of either letrozole or clomiphene. In this study, 14 of 514 newborns (2.4%) in the letrozole group and 19 of 397 newborns (4.8%) in the clomiphene group were found to have any congenital anomaly.

For major malformations, the rates were 6/514 (1.2%) for letrozole and 12/397 (3.0%) in the clomiphene group. These rates were not statistically significantly different, and were felt by the authors to be similar to rates of congenital anomalies seen in the general population.

In the field of medicine, there are hundreds of medications that were originally discovered to treat one condition and are subsequently found to be useful for other conditions. Once a drug is approved for a specific indication, most pharmaceutical companies will not go through the trouble and expense to have their drug officially approved for another indication. We at Pacific Fertility have carefully reviewed the data and circumstances around the controversy and we continue to believe that the use of letrozole is appropriate in certain circumstances and with full disclosure. Hundreds of infertility centers and OBGYN clinics worldwide are doing the same.

Although no broad scientific studies have yet established the efficacy of letrozole as the first course standard treatment for treating ovulatory problems, preliminary studies have shown letrozole to be useful, especially for women whose uterine lining may be thinned out by clomiphene (Clomid).

Please see the Science Pulse Extra to learn more about how letrozole works. The only other alternative to clomiphene for ovulation induction is the use of injectable fertility medications (gonadotropins). Use of these drugs in anovulatory women can be tricky, as it is often difficult to induce just one or two eggs to mature with these powerful drugs. So the risks of ovarian hyperstimulation and multiple gestation are significantly higher in anovulatory women on gonadotropins.

We at Pacific Fertility Center carefully explain to those women who might benefit from its treatment the controversy as well as the potential for adverse reactions. Letrozole is generally prescribed to be taken from days 3-7 of the menstrual cycle and has a short life span in the body. There are no traces of the medication in the body by the time an embryo will be implanting.

– Carolyn Givens, MD

The field of assisted reproduction is continually changing and this is a good thing because, for the most part, these changes have been for the better. Better medications, improved treatment strategies and a better understanding of laboratory techniques are resulting in constantly improving embryo implantation rates. This will allow us to transfer fewer embryos, reducing the risks for twins or triplets, which will result in better obstetrical outcomes for our patients. Our goal in assisted reproduction is to do all we can to ensure that chromosomally normal embryos have the opportunity to result in a healthy pregnancy.

More and more, Pacific Fertility Center is utilizing the day-5 embryo transfer procedure. The benefits of this are to 1) improve implantation and pregnancy rates and 2) lower the number of embryos transferred. Allowing embryos to remain in the laboratory for 5 days after egg retrieval (as opposed to the more standard 3 days) gives us an opportunity to choose those embryos most likely to carry normal chromosomes and those most likely to keep developing in the womb after embryo transfer. PFC utilizes low oxygen incubators almost exclusively. As such, we are seeing an improvement in the percentage of embryos that are developing well in the lab environment, as evidenced by their continued progression from a cleavage stage embryo to a blastocyst stage embryo.

Although Day-5 embryo transfer has been around for a while, we have been hesitant to use it exclusively for our patients. Clinical data suggests that unless a woman has a good number of nice looking embryos on day 3, the risks of having no well developed embryos on day 5 is fairly high. Therefore, the patient choosing to attempt a day-5 transfer might end up with virtually no embryos to transfer. One argument asserts that this is what would probably occur within the uterine lining anyway. However, there are studies suggesting that pregnancy rates in women with less than three or four nice 8-cell embryos on day 3 will have a higher chance of pregnancy with a day-3 transfer as compared to women with less than three or four nice 8-cell embryos who have a day-5 transfer. We are noticing that, with the use of our new low oxygen incubators, we are getting better developed embryos on day 3. These embryos, in turn, have a greater chance of being a nice embryo on day 5.

We are also seeing a small but growing number of couples interested in the transfer of only one embryo because they wish to avoid the risks of having a twin pregnancy. Although the over-whelming majority of babies born as a twin do well, there is a measurable increase in the incidence of perinatal death and cerebral palsy in twins as compared to babies born as a singleton. Also, we have many patients returning to us for baby #2 or #3 and they would like to avoid a multiple gestation. This has been particularly true for our patients using donor egg-derived embryos. Last year, we saw a 50% pregnancy rate in women electively transferring one embryo in the donor egg program. We will definitely support any patient that wishes to transfer only one embryo at a time, and we will likely encourage day-5 transfers to better select the one embryo most likely to implant.

One potential downside of attempting day-5 transfer is the question of whether or not we will increase the number of pregnancies in the fresh IVF cycle at the expense of additional attempts with frozen embryos. This is because embryos frozen at a cleavage stage [day 3] have historically done better with freezing and thawing as compared to day-5 embryos.

Pacific Fertility Center has always had a strong freezing program with excellent success rates with frozen embryo transfers, mostly at the day-3 stage of freezing and thawing. Many patients have asked us why we do not freeze some embryos at day 3 and culture some to day 5. One reason is that when we freeze some embryos at day 3, we are taking them out of contention for fresh embryo transfer and therefore, we may be losing some of the selective advantage of doing a day-5 transfer. With patients that have a very large number of embryos on day 3 that look good (say 15 or more), this may still be a viable strategy. Most patients don’t have many good quality cleavage stage embryos, however. So when we are planning to attempt a day-5 transfer, we will usually plan to culture all embryos to day 5 and select the best one or two for transfer and freeze the remainder as a day-5 embryo. As a result, we are now seeing a larger number of our patients returning for frozen embryo transfer with their day-5 frozen embryos. Our laboratory director, Dr. Joe Conaghan is currently reviewing the data on implantation rates from frozen-thawed day-5 embryos from 2005.

Listed below are some of the situations for which we are more likely to recommend a day 5 transfer. These include:

1. Any woman undergoing transfer with donor egg-derived embryos (anonymous donors)
2. Any woman less than 40 with a large number of eggs/embryos/good quality day 3 embryos
3. Any woman that has had poor success with freezing and thawing on day 3 in prior ART cycles
4. Any patient considering transferring only one embryo
5. Any patient with a history of multiple ectopic pregnancies (one recent abstract from the ASRM
meeting suggested a decrease in the ectopic rate after IVF with a day 5 vs. day 3 embryo transfer).
6. Any woman with unexplained IVF implantation failures with day-3 transfer.

– Carolyn Givens, MD

Related Posts:

Low O2 Incubators
Stages of Embryo Development
From Egg to Blastocyst
Day 3 vs. Day 5 Transfer – Photos

One of the most common questions from patients about to embark on any fertility treatment plan is “What are the side effects of the medications I will be taking?” This is a most appropriate question to which I’d like to provide an in-depth answer.

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

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.