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Dr. Kreiner has received national ASRM awards for his IVF work on ovulatory monitoring. In addition he has presented at a national ASRM meeting his highly successful and innovative two step ultrasound guided embryo transfer.

Egg Donation
Dr. Kreiner has extensive experience in oocyte donation since assisting in the development of the oocyte donation program at the Jones Institute in 1986. During his tenure at the pioneering Norfolk program, he noted a number of pregnancies among patients with recent ovarian failure who were being treated with estrogen therapy. This observation led to his publishing his findings in Fertility and Sterility. In addition, he has performed research involving oocyte donation and ovarian failure.

In vitro fertilization (IVF)
Modern IVF generally involves controlled ovarian hyperstimulation with exogenous gonadotropins, harvesting the eggs via transvaginal ultrasonographic-guided aspiration, co-culture of eggs and sperm in culture (or intracytoplasmic injection of sperm into the oocyte), and placement of the resultant zygotes (2-5 d later) directly into the uterus.

The first IVF pregnancy was achieved in 1978. Since then, the number of IVF centers and IVF procedures performed has increased dramatically. An intense effort to obtain insurance coverage for these services has also occurred. With the support of organizations such as RESOLVE (ie, the National Fertility Association), 15 US states provide coverage for these services. Currently, 3 states (Massachusetts, New Jersey, and Rhode Island) offer full coverage. Other states exempt health maintenance organization programs, private insurers, or companies with few employees. Other states offer limits to their coverage. In states that provide full coverage, the actual cost per paid subscriber is not substantial. A recent study in Massachusetts calculated that the increase is only $25 per year per subscriber.

As a result of the Fertility Clinic Success Rate and Certification Act, the US Centers for Disease Control and Prevention (CDC) gathers information from 422 of the 475 clinics throughout the United States. Information from 2005 shows that 134,260 assisted reproductive technique (ART) cycles were performed resulting in 38,910 live births (deliveries of one or more living infants) and 52,041 infants.

Other assisted reproductive techniques
Gamete intrafallopian transfer (GIFT) was developed in 1984 for women with unexplained infertility. GIFT is much less utilized, but to certain religious and ethnic communities (in which fertilization inside the woman's body is the only type allowed), it is considered more acceptable. During this procedure, the patient undergoes a controlled ovarian hyperstimulation. The oocytes are retrieved transvaginally under ultrasonographic guidance, and 3-4 oocytes are placed via laparoscopy into one of the fallopian tubes along with sperm.

During zygote intrafallopian transfer (ZIFT), oocytes are retrieved similar to IVF and GIFT and they are allowed to fertilize in vitro in the laboratory as in IVF. A day after fertilization (2 cell stage), 3-4 embryos are transferred via laparoscopy into one of the fallopian tubes. If the embryos are allowed to develop to greater than a 2-cell stage, the procedure is termed tubal embryo transfer (TET). The only benefit to a ZIFT or TET versus the more traditional IVF is for women who are thought to have compromised embryo quality due to embryo in vitro culture. Placing these zygotes or embryos back into their own natural incubators is thought to enhance subsequent development with improved pregnancy rates.

With the development of enhanced culture media, the success rates for IVF are now comparable, if not better, to those of GIFT and ZIFT, and IVF is less invasive than GIFT and ZIFT.

Interpreting IVF success rates
Comparing one program's success rate to another is difficult because of all the variables involved, including the program's selection criteria, patient demographics, and insurance coverage. In general, like any statistical analysis, the more IVF cycles a program has performed, the more valid the numbers are. The cancellation rate is a critical number. If the rate is high, the program is possibly very selective for the patients it allows to proceed to egg retrieval. This type of program would rather cancel the patient's procedure than have a low chance for success. The implantation rate refers to the pregnancy rate divided by the number of embryos transferred. If the implantation rate is low and the pregnancy rate is high, this suggests that the program is transferring a large number of embryos per patient to achieve that success. Chances are good that the program's multiple pregnancy (eg, twins, triplets, and higher order multiples) rate is high. Optimally, the better programs have a low cancellation rates, good pregnancy and implantation rates, and high singleton pregnancy rates compared with multiple pregnancy rates.

The ultimate critical number is the birth rate because this represents the final goal of the patient and the physician. This goal is also less vulnerable to misinterpretation than the pregnancy rate (single positive hCG vs serial increases) or the clinical pregnancy rate (gestational sac vs fetal pole vs fetal pole with heartbeat).

IVF outcomes
2007 data for IVF outcomes are summarized and results can be viewed on the CDC and Society for Assisted Reproductive Technology Web sites. Outcomes are stratified based on cycle type (fresh IVF, frozen embryo IVF, donor IVF, and maternal age). Overall, 134,260 ART cycles were performed in the United States in 2005 resulting in 38,910 live birth deliveries. For reference, in 1996, 14,507 deliveries resulted from 64,681 ART cycles. Because more than 1 infant is born during a live-birth delivery (eg, twins) in some cases, the total number of infants born is larger than the number of live-births. From 1996-2005, the percentage of transfers resulting in live births for fresh–nondonor cycles increased from 28% in 1996 to 34% in 2005. See East Coast Fertility success rates on this website.

Guidelines for embryo transfer
Multifetal gestations are associated with greater risks for both mothers and infants, including higher rates of caesarean section, prematurity, low birth weight, and infant disability or death. In response to the significant numbers of higher order multiple pregnancies generated from ART, the American Society of Reproductive Medicine (ASRM) released guidelines for the number of embryos transferred in 1999. These were modified in 2006 based on newer data.

In 2005, the percentage of multiple-infant live births decreased from 38% of all live births in 1996 to 32% in 2005 for fresh-nondonor ART cycles. Note the much lower per cent for multiples at East Coast Fertility with virtual absence of more than twins.

Increasing the number of embryos transferred from 1 to 2 not only increases the chance for a live birth but also increases the likelihood of a multiple-infant pregnancy. However, transferring more than 2 embryos may not increase the overall live birth rate.

Many variables affect the decision of how many embryos to transfer. Factors such as the patient's age, embryo quality, number of prior failed IVF cycles, and use of frozen-thawed embryos are important to consider. New data from Europe suggest that a single embryo transfer in the appropriate patient results in approximately a 35% pregnancy rate with a less than 1% multiple pregnancy rate. These patients typically have embryos that are frozen, ensuring that their cumulative pregnancy rate using either fresh or frozen embryos is similar to transferring 2 or more embryos. Single embryo transfer is appropriate in certain situations where the likelihood of a multiple pregnancy is high. This may include women younger than 35 years, women who conceived with first IVF cycle, women with only tubal factor infertility, women with concerns about multiple gestation, and donor egg recipients.

Factors contributing to IVF success
The most important factor that determines a successful cycle is the female patient's age. As mentioned previously, decreases in fecundity rates are observed beginning as early as age 30 years. The dramatic effect that age has on fecundability is also observed in ART. Our egg donors are aged 21-31 years, allowing for an optimal control group to observe these differences.

Ultimately, the success of ARTs mimics the overall fecundity trend observed in the general fertile population. That is, pregnancy and live birth rates start to decrease beginning around age 30 years and continue to decrease until the chance of having a live birth is so low that the benefit of ARTs must be evaluated. In women older than 40 years, the chance of having a liveborn infant with a chromosomal abnormality also increases.

Oocyte retrieval
Oocyte retrieval is performed approximately 36 hours after 10,000 U of hCG is administered to allow for the resumption of meiosis, cytoplasmic maturation, and loosening of the oocytes within the follicle. This allows for a lower optimal vacuum pressure during aspiration and ultimately less oocyte damage.

The 3 basic methods to retrieve oocytes are laparoscopic, transabdominal, or transvaginal. The laparoscopic approach was used frequently in the 1980s, especially when a GIFT procedure was planned. Often, only the follicles that could be seen on the surface of the ovary were removed, and, if the ovary was very mobile, traction was required to support the ovary as the follicles were aspirated. Associated morbidity occurred with the procedure, which included infection and injury to the pelvic organs. General endotracheal anesthesia was usually used, and the patient's recovery often lasted 2-3 days. As the quality of ultrasonographic images and culture media improved, the need for laparoscopy decreased.

In 1981, ultrasonographic-guided aspiration was first described. Initially, the transabdominal approach was used, usually with the aspirating needle going through the bladder, which, when full, provided a window of visualization for the person operating the abdominal ultrasonographic probe.

Although still used for retrieval of oocytes from ovaries that are adhered high up in the pelvis or to the fundus of the uterus, the transabdominal approach was superseded by the transvaginal approach. The first transvaginal retrieval was performed in 1984 and has now become the procedure of choice because of its ease and low morbidity.

ICSI
Intracytoplasmic sperm injection (ICSI) is the treatment of choice for couples in whom the male partner has azoospermia or severe oligospermia. ICSI is also indicated for men with significant antisperm antibodies, low sperm motility, or significantly abnormal sperm morphology (Kruger strict morphology <14%).

ICSI is used when poor fertilization occurs with regular insemination techniques in the laboratory. ICSI may be used when a limited amount of sperm is available. In cases of azospermia, no sperm, sometimes sperm can be obtained directly from the epididymis or through a testis biopsy (TESE procedure).

The potential transmission of a genetic abnormality is a possibility when ICSI is performed. The normal barrier for morphologically abnormal sperm that tend to have genetic abnormalities (ie, zonal pellucida) is bypassed with ICSI. Morphologically normal sperm may also have genetic abnormalities. Approximately 10% of sperm from healthy men have chromosomal abnormalities. Men who are infertile have a 5-7% chance of having a chromosomal abnormality. Chromosomal abnormalities include microdeletions of the long arm of the Y chromosome in areas AZFa, AZFb, and AZFc (DAZ or deleted in azoospermia region). These deletions can be passed on to male offspring, with resulting oligospermia.

Some data suggest a 30% increase in birth defects in children conceived with ICSI. Overall, this implies that the risk of having a child with a birth defect from ART with ICSI goes from a normal baseline of 3% to, at most, 4%. This is thought to be due to the increased incidence seen in males with low sperm counts transmitting the slight increase in birth defects.

Approximately 1-2% of men with azoospermia have genetic translocation, Klinefelter syndrome (47,XXY), or a congenital bilateral absence of the vas deferens, which is associated with mutations in the cystic fibrosis transmembrane regulator (CFTR) gene or the 5T allele.

In the situation where the male partner has the CFTR mutation, the female partner should also be screened for cystic fibrosis. In any couple undergoing ICSI for male factor infertility where the sperm count is less than 5 million/ml, a referral to a urologist is recommended. In addition to an examination he may consider checking the karyotype and Y-DNA. Prenatal testing of ICSI pregnancies has revealed an incidence of 0.83% of sex chromosome abnormalities (higher than those reported for spontaneous pregnancies).


Injection Teaching

The following materials outline the step by step procedures for the reconstitution and administration of Follistim AQ, Bravelle/Repronex and Gonal-f RFF:


IVF Consent
Click here to download and print the IVF Consent packet