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Tufts OpenCourseware
Author: John Petrozza, M.D.

I. Introduction

A. Epidemiology

Infertility is defined as the inability to conceive after 1 year. Ten to fifteen percent of couples are infertile. Twenty-five percent of all women will have at least one episode with infertility. In contrast, fecundability or the ability to get pregnant per couple per month, averages 20-25%.

In general, infertility rates have risen. Some reasons for the increase in infertility include:

  • changing aspirations of women (delaying pregnancy until after college or job success)
  • postponing marriage
  • concern over the environment in which that child may grow up
  • unfavorable current economic conditions to raise kids
  • increasing delay in reproduction

Delaying pregnancy increases a couple’s chance of infertility because aging poses specific risk factors for infertility. Some of these include:

  • endocrine changes such as an increase in FSH and a decrease in inhibin by age 40 and a steep decrease in eggs after 30 (human females have the best egg number before 30 and have a very low egg count by 40)
  • FSH and inhibin both represent the magnitude follicular loss
  • older pregnant females have more difficulty in maintaining pregnancy - rate of miscarriage in pregnant females who are over 40 is about 35-75%, due to declining oocyte quality and increase in aneuploidy in remaining oocyte

B. Common Causes of Infertility

Thirty-five percent of the time there is a medical problem with the male (low sperm count, low motility, misshaped sperm.) Other infertility causes include problems with the female such as tubal disease (40%), ovulatory problems (40%), unexplained (10%) and other (10%).

C. The Physician’s Role in Infertility

The physician must address certain issues unique to treating infertile couples. In addition to seeking out and correcting causes of infertility, the physician should also provide accurate information and dispel myths, provide emotional support/counseling to couples, provide support to families and finally perform the difficult task in advising a couple that current fertility technology will not benefit them anymore.

D. The Role of Assisted Reproduction Technicians (ART) and Laboratories

ART centers perform semen/sperm analysis in the andrology labs. In the IVF embryology labs, they work on IVF, ICSI, cultures, AH, embryo transfers and embryo cryopreservation. These techniques are explained below (section II).

E. Increased Use in Fertility Technology

Infertility is not as stigmatized as it used to be and more infertile couples are turning to infertility clinics in hopes of having their own children. Some of these reasons include:

  • an insurance mandate in Massachusetts which requires fertility methods to be covered
  • an increase in publicity and therefore an increase in public awareness of fertility technology
  • an increase in social acceptability
  • an increase in the number of fertility clinics

In addition, there has also been a decrease in the number of children adopted because in vitro fertilization is becoming cheaper, easier and increasingly legally easier than adoption.

II. Alternatives to Traditional Pregnancies

Infertile couples are started on simple treatments before complex and more expensive treatments are tried. These treatments are listed below:

A. Semen Analysis

Thirty five percent of infertility problems are due to the man. Because male factors of infertility are easier to diagnose than female factors, semen analysis should be done initially to rule out male infertility. In semen analysis, count, percent of motile sperm, volume of ejaculate, progression, morphology, viscosity, agglutination, antibodies, viability, pH and the presence of other cells are measured. Infertile men have <20 million sperm per ml, <14% of sperm morphologically normal, sperm motility of <40%, <2 ml in volume (normal 3-4 ml), rapid progress <25%, and total progression <25%. Sperm also are tested for their survival ability by passing a density gradient test and by the swim-up technique. These additional tests help determine the types of treatment to prescribe. For example, if sperm cannot pass these tests, then ICSI is done. Some causes of abnormal sperm include cancer treatment, significant anti-sperm antibodies, or congenital abnormalities in sperm.

B. Timed Intercourse

The best day to try to become pregnant is the day of ovulation or 1-2 days before. Most sperm are lost in the vagina/cervix and only 5-10 per million sperm make it to the fallopian tubes!

C. Intrauterine Insemination (IUI)

Intrauterine insemination is used in cases where males have low viable sperm. In this procedure, motile sperm are separated and concentrated at least 3 million total motile sperm and introduced by a catheter into the uterus. The clinical pregnancy rate is 13% per cycle, compared to 20% in normal couples and 2% if you did not treat the infertile couple. If IUI does not work and male factors of infertility have been accounted for, then the complicated treatment of female factors of infertility are considered.

D. In Vitro fertilization (IVF)

The physician should counsel the patient about psychological issues such as:

  • pressure from cultural demands for parenthood (is the couple doing this for themselves or for others such as parents)
  • motivational discrepancy between partners
  • sense of inadequacy due to infertility
  • deferred career goals
  • painful memories due to prior abortion
  • religious/ethical concerns regarding IVF

The first step in IVF is stimulating the ovaries to release eggs that are normally lost anyway (more than 30 eggs are made each cycle). The typical IVF stimulation protocol is as follows: the patient is given hormones that suppress the hypothalamus so it has no control over the ovaries; after this is done, she is started on recombinant FSH and LH to stimulate those eggs that have been selected for that month. After about 9-12 days of medication, the patient is given HCG to mature and loosen the eggs within the follicles and finally, the eggs are removed 36-40 hours later. This procedure involves sedation and the ultrasound guided removal of eggs through the back of the vagina through a puncture with a 16 g needle. Ideally, 8-15 eggs are obtained and patients have a quick recovery time with only some cramping.

The next step is sperm preparation and selection utilizing a swim-up technique.

Third, eggs are incubated in culture and fertilized in vitro. About 10,000 sperm are introduced to each egg. Three days later, 2-3 embryos are deposited into the uterus and the patient is given progesterone to maintain adequate priming of the uterine lining. Finally, 14 days later a pregnancy test is done.

Some possible problems regarding IVF include:

  • no eggs
  • no ovulatory stimulation
  • no fertilization
  • failure of the fertilized egg to divide
  • failure of implantation

Risks with IVF include:

  • miscarriage in 20% of cases for women under 40
  • miscarriage in 50% of cases for women older than 40
  • ectopic pregnancies
  • multiple
  • ovarian hyperstimulation syndrome

Thirty-five percent of couples who become pregnant use this method. The biggest criticism of IVF is multiple pregnancies. There is a 20-30% risk of multiples.

E. Intracytoplasmic Sperm Injection (ICSI)

In ICSI, sperm is injected into egg. This technique is used in cases where:

  • the male has very low sperm count, motility, or normal morphology
  • poor fertilizations in previous IVF cycles
  • sperm antibodies

The male factor may be due to sexually inherited genetic abnormality and there is sufficient concern about passing defects to children. Adequate genetic counseling is provided.

ISCI involves immobilizing the sperm and injecting it into the eggs. In ISCI, 97% fetuses are normal, 2.8% have major congenital abnormalities and 1-2% have chromosomal abnormalities. Factors in ICSI outcome include method of retrieval, motility, egg quality and technique.

F. Percutaneous Needle Aspiration (PESA)

PESA involves obtaining sperm from the epididymis using a needle.

G. Testicular Sperm Aspiration (TESA)

TESA involves obtaining sperm from testicular tissue.

H. Gamete In Vitro Fertilization (GIFT)

GIFT is the implantation of gametes within fallopian tubes.

I. Zygote In Vitro Fertilization (ZIFT)

ZIFT is the implantation of zygotes into the fallopian tubes.

J. Microdrop Insemination

In this procedure, the egg is in a reduced volume solution, and more sperm is injected, providing for a higher concentration of egg/sperm for fertilization.

III. Significant Milestones in Fertility Technology

Besides IVF and ICSI, several other techniques have revolutionized fertility technology.

A. Sequential Culturing to Blastocysts

The development of a sequential culture system allows eggs to grow to blastocysts which is the stage of development eggs are normally in when they arrive to the uterus in natural cycles. These blastocysts can now be put back in 5 days and not 3 days. This allows less embryos (hopefully the best) to be implanted and thus less risk of multiple births.

B. Assisted Hatching (AH)

In AH, the zona pellucida of the egg is opened to assist in implantation. This procedure is done in older females, if eggs were frozen and if the couple has been though several unsuccessful IVF cycles.

C. Embryo Cryopreservation

Embryo cyropreservation involves the slow freezing of embryos for storage. Embryos can be frozen at the 2PN, the multicellular or blastocyst level. Post-thaw survival rate is 70%; post-thaw pregnancy rate is 25%. Some patients who are interested in embryo cryopreservation include leukemia patients who must undergo severe chemotherapy.

D. Egg Cryopreservation

Egg cryopreservation does not work as well but it has been done. Eggs do not freeze as well as sperm and embryos because of the large volume of cytoplasm (predisposes to ice crystal damage) and the delicate nature of the spindle body and microtubal architecture. Post-thaw eggs are fertilized using ICSI (due to hardening of the zona pellucida)

E. Preimplantation Genetic Diagnosis (PGD)

In PGD, PCR analysis or FISH is done to see if the embryo would have genetic abnormalities before IVF. The procedure is typically done at the 8 cell or blastocyst stage and a couple of blastomeres are analyzed in the process. This process is not 100% accurate in predicting an outcome because it is believed that embryos at these stages may actually have a small mosaic component. Polar bodies may be used from unfertilized eggs as well.

IV. Guidelines for Most IVF Labs

  1. No one over 43 due to low chance for pregnancy
  2. No egg donors over 50
  3. One procedure at a time to avoid matching error
  4. Patients need to file many consent forms to avoid lawsuits and to protect the lab
  5. Freeze the unused embryos (unless the owners indicate that they should be discarded, and keep track of the owners)

V. Controversies

  1. Uses of preimplantation diagnosis:
    • Designer embryos
    • HLA typing
    • Improving success rates in older women
    • Screening for non-life-threatening diseases
  2. Uses of donor eggs:
    1. Women over age 50
  3. Uses of traditional IVF:
    1. HIV+ couples
    2. Stem cell research