SCIENCE PULSE    IVF Birth Outcomes: How Much Do We Understand?

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.  Isabelle Ryan, M.D.

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.

Isabelle Ryan, M.D. is recognized by prestigious medical associations for her pioneering research leading to new insight into the important clinical problem of endometriosis related infertility. Dr. Ryan is medical director of PFC’s Third Party Parenting Program and Egg Donor Agency.

               
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FROM US TO YOU    What's New @ PFC

FISH (flourescence in situ hybridization) uses molecular DNA probes that have colored fluorescent dyes; blue for the X and pink for the Y chromosomes.

Sex Selection: What Type Of Services Are Available And Should We Do It?

For many people, the dream of having a family also includes the dream of having children of both sex. Since most families today are much smaller than in generations past, the odds of having two or three or even four children of the same sex is fairly high.

Throughout human history, there always has been interest in methods to sway the chances of conceiving a child of a particular sex. Today, in the 21 st century, it is quite clear that many of these sometimes bizarre and sometimes simple home remedies have no basis in fact.

There are ways to significantly shift the odds of having a child of one sex or another. Sex is conferred on an embryo by whether an X-bearing sperm (for a girl) or a Y-bearing sperm (for a boy) enters the egg. Unfortunately, despite highly publicized claims, there are no proven effective "at home" methods of sperm separation. Nor does timing of intercourse relative to ovulation affect the 50:50 sex ratio. By natural methods, the ratio remains a flip of the coin.

The only commercially available method for sperm separation that appears to be effective is the sperm sorting process available through Microsort.net. This method involves using a fluorescent DNA dye that attaches to either X or Y chromosomes. The sperm then passes through a cell sorter that separates the sperm based on the fluorescence. This method is still under FDA investigation for safety and efficacy but does appear to do a reasonable job in separating sperm, especially if the desired sex is female.

Mirosort reports a 90% success rate with separating X-bearing sperm and a 73% success rate in separating Y-bearing sperm. There have been only a few hundred babies born thus far, but there does not appear to be any increase in birth defects. Because this process is still considered “experimental,” couples wishing to participate, will have to travel to either Fairfax, Virginia (Microsort headquarters) or an affiliated clinic in Southern California for fresh sperm insemination.

Unfortunately, after Microsort processing, the number of sperm available for insemination is severely decreased. Freezing and thawing of sperm, which would allow the sample to be shipped to another location, reduces these numbers even further. Because sperm counts are so low after sorting, it is usually necessary to do in vitro fertilization with sperm injection (IVF-ICSI) to significantly improve the fertilization in the IVF laboratory. PFC is a participating site in the FDA investigation for Microsort. We have used sperm specimens that had been previously Micro-sorted for IVF-ICSI.

Researchers at UC Irvine recently published a study describing the use of lasers to “trap” the heavier and slower moving X-bearing sperm to separate it from the lighter Y-bearing sperm. In the future, this process may provide an alternative to Microsort. However, it is not yet commercially available.

Beyond the Microsort technique, the only way to improve the odds of selecting one sex over another at close to 100% accuracy is to undergo Pre-Implantation Genetic Screening (PGS). PGS uses a DNA-binding technique to determine if there are a correct number of chromosomes in the embryo at the time of IVF. To complete this screening, embryos on Day 3 of culture (5-10 cells) undergo a biopsy to remove a single cell. The rest of the embryo remains in culture in the IVF laboratory. The removed cells are analyzed for the correct number of chromosomes. Currently, PFC with its cytogenetic partner, Genetics and IVF Institue screen embryos for 3-12 chromosomes. This screening is called "aneuploidy screening." We allow our patients to know and select the sex of their normal embryos for transfer if they so wish.

Although IVF with PGS is the most effective method for sex selection, it is certainly the most expensive and there is no absolute guarantee that the transfer of the screened embryos will result in pregnancy. A PFC physician can best discuss the odds of success, based on the woman’s age and the couple’s history of childbirth.

Many couples undergoing PGS are doing so to screen for specific genetic defects or are specifically undergoing sex selection because of their risks of having a genetic disease that only affects males (X-linked diseases).

On the other hand, PGS for elective sex selection, either for "family balancing" or even for having a first child of a particular sex poses difficult ethical issues. Just because we have the ability to choose the sex of a child, should we? What will the couple do with normal embryos of the undesired sex? At PFC, we do not encourage PGS for elective sex selection. However, if a couple is undergoing IVF and wishes to undergo aneuploidy screening, we do allow them to select to transfer embryos by sex. We encourage all patients to consider donating excess embryos of the undesired sex for adoption by other couples.

Women or couples interested in this procedure should discuss it with their Reproductive Endocrinologist. At PFC, we also refer our PGS patients for a special genetic counseling session at California Pacific Medical Center in preparation for this process.  Carolyn Givens, MD

Carolyn Givens, M.D. was the first in San Francisco to successfully initiate a pregnancy using intracytoplasmic sperm injection (ICSI). She currently co-directs the Bay Area Pre-Implantation Genetic Diagnosis Program (PGD) and is director of PFC’s PGD program.

               
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CRITICAL REVIEW    At Home Fertility Test Kit For Couples

Interested in self-diagnosis of fertility? The ability to screen for fertility in private, on one’s own schedule, with an at home diagnostic kit is an appealing option. A company from the UK, Genosis, has developed such a kit, called Fertell.

Fertell is a testing kit that offers a basic assessment of male and female fertility.

Fertell for the male is a specimen collection and testing kit that measures the concentration of motile sperm. A sperm specimen is collected into a cup and allowed to liquefy and then warmed to body temperature. Motile sperm pass through a filter and are colored red by exposure to a gold-coated antibody. Appearance of two red lines in a testing chamber indicates a sperm count over 10 million total motile.

Fertell for the female is a conventional urine test strip very similar to an ovulation prediction kit. The female places the absorbent tip in her urine stream for 5 seconds. FSH in the urine reacts with antibodies on the test strip and shows as a red line in the result window. The intensity of this line reflects the FSH concentration (the darker the line, the more FSH present in urine). High FSH levels are indicated by two dark red lines.

Traditional semen analysis measures sperm volume, count, and motility. Multiplied together, these numbers yield the total motile sperm count, that is, the number of moving sperm in the ejaculate. Total motile sperm count is a reasonable predictor of fertility for men. Fertell establishes that the sperm count is over a specific value of 10 million total motile, a reasonable threshold for male fertility.

The male test kit is not able to determine subtle gradations of male fertility. It cannot detect the effects of treatment or change in lifestyle that may cause improvement in sperm count, nor can it detect alterations in sperm morphology (shape). More sophisticated testing is available at a sperm lab.

The female test kit is used as a screening test, and cannot detect subtle gradations in FSH levels, or the relationship of FSH to other important hormones such as estradiol. Such issues have dramatic effect on the patient’s prognosis.

Neither of these tests can replace an expert’s opinion. An expert’s ability to interpret test results with a broad knowledge base and experience remains the best way to diagnose and treat infertility problems.

Of primary importance is that, while both test kits have been correlated with existing assays, neither has been evaluated for its ability to predict pregnancy. Such research takes time, and hopefully will be forthcoming. For now, Fertell is an interesting option for those seeking a private screening assessment of their fertility. Philip Chenette, M.D.

Philip Chenette, M.D. has spent over a decade specializing in the treatment of patients with complex infertility diagnoses, especially in women with decreased ovarian reserve and women over 40.

               
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BOOK REVIEW    The Joy of Pregnancy

Title: The Joy of Pregnancy
Subtitle: The Complete, Candid, and Reassuring Companion for Parents-to-Be
Author: Tori Kropp, R.N.

For many of our patients, who successfully conceive at PFC, a major shift in thinking follows the moment they realize that their pregnancy is viable. Shelving all the fertility literature, now it’s time to get educated about pregnancy. Hundreds of books on the subject of pregnancy can be found, but which one to read?

Finally we have a thoroughly enjoyable, informative and readable book by Tori Kropp, a labor and delivery nurse for many years at our own California Pacific Medical Center. “The Joy of Pregnancy” celebrates the miracle of pregnancy, labor, birth and brand-new parenthood. It embraces these experiences for what they should be: a time of joy and excitement, not of fear and guilt.

Tori has not only worked in Labor and Delivery at California Pacific Medical Center in San Francisco for many years, but she has also taught childbirth classes for thousands of expectant parents. As a mother herself, she has experienced pregnancy and birth first hand. She really has seen it all. Her calm, reassuring manner, helped many parents-to-be welcome the birth experience with knowledgeable assurance.

This book is written in an honest and open style. The medical terminology is minimized and practicality is emphasized. The many “Tori’s Tips” in the book are gems resulting from her knowledge and experience. They serve as little pearls of pregnancy wisdom. A glossary of medical terms at the end of the book is very useful. The questions and answers sprinkled through the book are entertaining, yet filled with practical and informed answers. Special sections for fathers are also included.

The last section of the book is one that is often missing in books about pregnancy: it is all about the first few weeks of parenthood. Breast-feeding and caring for your new baby are covered, again with an eye to being relaxed and enjoying the experiences.

We highly recommend this new book as you journey from infertility to family.

Carolyn Givens, MD

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