A

PROJECT REPORT

ON

FERTILITY

SUBMITTED TO

AMITY UNIVERSITY

SUBMITTED BY:-

PREETI SINGH
 In Vitro Fertilization as A Medical Treatment for Male
or Female Infertility

Overview

Medical technology has developed a number of ways to bring the woman's egg and the
man's sperm together outside the woman's body. A Latin phrase, in vitro, meaning "in
glass," is often used to distinguish these methods from the natural method of fertilization.

When a sperm fertilizes the egg, the resulting embryo may continue to develop into a
baby. The popular press often refers to children conceived through in vitro fertilization
techniques as "test tube babies."

This issue brief describes in vitro fertilization and other related methods of assisted
reproductive technology (ART). Specifically, it focuses on in vitro fertilization involving
a couple unable to conceive a child through natural means. However, there are other
methods of becoming a parent which this brief does not address. These include
surrogacy, donated sperm and/or eggs, and adoption.

The topic of in vitro fertilization was chosen by HTAC because of general interest for
more information about these procedures, their costs, and their effectiveness. Some
aspects of in vitro fertilization are controversial and have raised medical, ethical, and
legal questions. These questions are currently under debate by health care providers,
payers, policy-makers and researchers as well as the general public.

Infertility

Couples who consider in vitro fertilization (IVF) have been diagnosed as infertile.
Infertility is defined as the inability to conceive a child or carry a pregnancy that results
in a live birth after one year of trying. Infertility is generally estimated at 15% of the
reproductive age population. However, IVF is used by less than 2% of those seeking
treatment for infertility.
Physician office visits for infertility services have increased dramatically since 1968. In
the U.S., there were 600,000 visits in 1968 and 1.35 million visits in 1988. Visits for
1995 are projected at 1.8 million. This increase reflects many factors-a higher incidence
of sexually transmitted disease which can cause infertility, less embarrassment about
seeking treatment for infertility, and acceptance that infertility can be a male or female
problem. In addition, many couples are postponing marriage or childbearing until they
are in their mid-30s when the chances of conceiving a child begin to decline.

Less than half of the couples who seek treatment for infertility have a child using fertility
drugs, surgery to unblock fallopian tubes, or artificial insemination.4 When these
conventional treatments do not work or are not practical, a couple may turn to
reproductive physicians working with laboratory scientists who specialize in vitro
fertilization (IVF).

Natural Fertilization Versus In Vitro Fertilization

The first child in the United States conceived in vitro was born in 1981. Although IVF
was originally developed as an alternative to surgery to correct for blocked fallopian
tubes in women, rapid technological advances in the last five years have extended the
scope of IVF treatment to infertile men. Some of these advances are summarized in the
section on in vitro fertilization with micromanipulation. To understand how IVF works,
the basic steps in an IVF treatment cycle are best compared to natural fertilization.

Natural Fertilization

A woman's fertile time is around mid-cycle, which is when ovulation occurs. The ovaries
release a single egg which is drawn into the fallopian tube where it awaits fertilization.
When a couple has intercourse during this time, sperm (produced in the male testes)
swim into the cervical mucus. If the sperm are compatible with the cervical mucus and
are sufficiently motile (able to move) they will swim through the cervix into the uterus
where they are drawn into the fallopian tube. If a sperm is able to penetrate the egg's
outer layer and fertilize it, the egg becomes an embryo.
After fertilization, the developing embryo moves down the fallopian tube to the uterus. If
the embryo is able to attach to the uterine lining, it will begin to develop into a baby.

Standard in Vitro Fertilization

The standard process begins with a woman taking human hormones to stimulate
ovulation. The hormones cause her body to produce many eggs instead of one. In a minor
surgical procedure, a doctor removes the eggs from the ovaries. The eggs are examined
under a microscope. The most mature eggs are selected, combined with sperm in a
laboratory culture dish, and then placed in an incubator. Fertilization is confirmed under
the microscope approximately 18 hours later. After 44-72 hours the laboratory scientist
selects 3 to 4 healthy embryos for transfer by the doctor back into the woman's uterus.8
the embryo transfer procedure does not require anesthetic and takes about 10 to 20
minutes.

Once the fertilized egg is transferred, a number of developments must occur to achieve a
pregnancy. The embryo must continue to divide and grow. It must also break out of the
hard protein shell surrounding it. The shell is called the zona pellucida, or more
commonly, the zona. Finally, the embryo must implant itself in the lining of the uterus
and continue to grow.

The selection of embryos to be transferred to the woman's uterus raises a number of

ethical concerns. For example, should scientists genetically screen or test embryos,
allowing prospective parents to select only embryos with genetically desirable traits to be
transferred? Should such tests be done in order to avoid having children with a
genetically transmitted disease?

Although clinics transfer 3 or 4 embryos into the woman's uterus, there is the possibility
that more embryos will implant than the woman can safely carry to term. If a number of
embryos successfully implant, selective abortion of one or more of the developing fetuses
may be chosen because of the risks associated with multiple pregnancies (for more
information, see the section on outcomes of in vitro fertilization). An ethical question is
whether the practice of multiple embryo transfer should be continued in light of this
knowledge.

In Vitro Fertilization with Micromanipulation

Although standard IVF offers hope to many infertile couples, it is not the answer for all
types of infertility. Micromanipulation techniques called ICSI (Intracytoplasmic Sperm
Injection) and assisted zona hatching, described below, are used for these difficult cases.

Intracytoplasmic Sperm Injection (ICSI)

In ICSI, a laboratory scientist, using a microscope and micro tools, injects one sperm into
an egg. This technique improves fertilization in cases of low sperm count or when sperm
are not motile or are irregularly shaped.

Assisted zona hatching

If the embryo is not able to break out of the zona, it cannot imbed itself in the wall of the
uterus, thus preventing implantation and pregnancy. With assisted zona hatching, a small
hole is made in the outer covering of the embryo before it is transferred from the
laboratory into the woman's uterus. This micromanipulation is sometimes helpful for
women who have eggs with very thick zona, women who have undergone IVF previously
and have not conceived, or older women.

Freezing embryos (Cryopreservation)

Often, after the first egg retrieval, there are many healthy embryos. The laboratory
scientist may freeze several in case the first cycle of IVF fails. When a woman uses a
frozen embryo, the IVF treatment process is simplified.

Freezing and storage of human embryos and other reproductive tissue raises additional
legal and ethical questions. For example, who owns an embryo? Who does, or should
have control over what happens to stored eggs, sperm, and embryos?
In Vitro Fertilization in Minnesota

There are four IVF clinics in Minnesota: three in the Twin Cities area and one in
Rochester. Three of the four clinics contacted for information reported that office visits
have steadily increased since mid-1995 as the availability of ICSI has increased. Over
500 IVF treatments were performed in the three Twin Cities clinics in 1995. In 1996,
there were over 700 IVF procedures in those clinics. In one Minnesota clinic, IVF with
ICSI procedures increased from 25 in 1995 to 270 in 1996.

Outcomes of In Vitro Fertilization

While natural pregnancy and child birth carry risks, IVF raises a number of additional
concerns. The frequency of complications, miscarriage or birth defects associated with
IVF is a matter of controversy. However, some studies have reported that these events are
no more common after IVF than in the general population. In addition, a recent study
found that ICSI does not cause more birth defects or miscarriages than standard IVF. No
long-term studies have been conducted on babies born as a result of the ICSI technique.
Consequently, the long-term effects of ICSI are unknown at this time.

However, the transfer of multiple embryos in IVF procedures causes approximately 38%
of all IVF pregnancies to result in multiple births (e.g., twins or triplets). Nationally, twin
births constitute approximately 2% of all births. Multiple births are associated with a
number of risks to the health of both mothers and their babies such as preterm birth, low
birth weight, long-term disability and early death.

In February, 1997, the Centers for Disease Control and Prevention (CDC) reported that
the risk of low birth weight is seven times higher among twins than for single births.
Twins account for 17% of all low birth weight infants, and 12% of all infant deaths. The
report added that fertility drugs and treatments, including IVF, have been associated with
the 30 percent increase in twin births in the United States during 1980-1994.

ICSI and other in vitro procedures can result in a variety of medical risks to a woman's
health. In about 10% of IVF procedures the use of hormones to induce ovulation can lead
to a condition called ovarian hyper stimulation syndrome. Mild cases of ovarian hyper
stimulation syndrome may cause the ovaries to become swollen and painful. Fluid may
accumulate in the abdominal cavity and chest, the woman may feel bloated, nauseous,
and experience vomiting or lack of appetite. Severe ovarian hyper stimulation syndrome,
which occurs in less that 1% of cases, can lead to stroke, kidney failure or heart attack
due to too much fluid in the body. In very rare cases, vaginal hemorrhage can occur
during egg retrieval.

Success Rates

To measure the success of an IVF procedure, clinics often report delivery rate, which is
defined as the number of live births divided by the number of egg retrievals. However, a
number of details are not available. These include: how many cycles of IVF were
necessary to achieve a live birth; whether frozen embryos were used; whether a
micromanipulation was employed in addition to standard IVF; or, how many pregnancies
resulted in multiple births.

The American Society of Reproductive Medicine (ASRM) and the Society for Assisted
Reproductive Technology (SART) compile success-rate data they receive from over 300
member clinics. The data are unstandardized, self-reported and unaudited. ASRM/SART
provides an overall delivery rate as well as separate statistics based on the woman's age
and whether male factor infertility is involved. In 1994, the overall delivery rate for
23,050 retrievals was 21.2%. Women over 40 have a much lower delivery rate (9.0%)
than women under 40.31 Fertility are negligible after the age of 45.

Some clinics report that they are able to help over 45% of the couples seeking infertility
treatment by using IVF with ICSI and assisted zona hatching. One Minnesota clinic
reports that the 1995 delivery rate for 218 retrievals was 42.2%.

Another factor that affects success rates is estrogen levels. The elevated estrogen levels
produced from hormone treatments during IVF because the uterine lining to mature at a
different rate than it would naturally. This may reduce the woman's chance of becoming
pregnant with each successive IVF cycle. Clinics offer to transfer frozen embryos in
order to reduce the number of hormone treatments, as well as the laboratory procedures,
necessary for each new cycle.

Costs

A standard cycle of IVF, including $200-$3000 in drugs, costs between $8,000-$10,000.

A couple generally goes through three cycles before they have a baby or decide that IVF
will not work for them. B Thus, for the average couple who may or may not conceive,
costs range from $24,000-$30,000. However, if costs are considered along with the
probability of becoming pregnant with each cycle of IVF (estimated at 21.2%-45%), the
cumulative costs of delivering a baby are much higher. For example, costs for three
cycles of IVF range between $47,667 to $132,463 per live birth

Most clinics do not charge extra for assisted hatching. However, an ICSI procedure adds
about $700-$900 per cycle. If a frozen embryo is used for a second or third cycle, the
charge may be reduced to $2000 per cycle because the procedure only involves a 10-20
minute embryo transfer.

A few clinics, including one in Minnesota, will provide a partial money back guarantee,
also called a "warranty" for couples seeking in vitro fertilization. For example, a couple
pays a fee up front. If the woman does not become pregnant after three cycles of
treatment, the clinic returns a portion of the fee.

Insurance Coverage

Relatively few insurers cover IVF because it is not considered a "medically necessary"
treatment. Although being a parent may be desirable from a social or personal standpoint,
IVF is not considered preventive medicine and it does not maintain health. While IVF
can help a couple to become pregnant, it does not cure the condition of infertility.

Coverage of IVF is inconsistent across Minnesota health plans. While a number of health
plan companies do not cover IVF, one plan offers an IVF premium package that
employers or groups, but not individuals, may purchase in addition to the standard
coverage package.
Since 1987, Massachusetts has mandated that insurers cover all infertility services
including IVF. Ten other states have mandates which cover all or some infertility
services. Minnesota has no state mandate.

Supporters of insurance coverage for IVF services assert that if IVF procedures were
used earlier in infertility treatment many less-effective procedures would not be used. As
a result, the length of treatment would be shorter, and costs of infertility treatment would
be lower. One research study estimates the additional cost to a typical employer health
plan would range between $2.79 and $13.95 per employee per year, depending on the
level of utilization of IVF.

Access to IVF services is also a concern. For example, should lifestyle, socio-economic
and/or marital status, age, medical condition or other criteria be taken into account when
deciding who should receive IVF?

Without health plan coverage, IVF is available only to those with adequate personal
finances to pay for the treatment. Additional questions arise, however, if health plans are
required to cover IVF. For example, is coverage of assisted reproduction the best use of
health care dollars given the high expenses of IVF? Should resources be focused instead
on conditions or diseases that are life-threatening or lead to permanent disability? If
coverage of IVF is required of state-regulated health plans, should coverage be extended
to Minnesota's public health care programs (e.g. Minnesota Care, Medicaid)?

Oversight of Assisted Reproductive Technology

IVF is a $350 million a year business that is largely exempt from government regulation.
However discussion concerning greater oversight of the infertility industry has grown as
the technology has advanced. The ASRM/SART has moved its publication of updated
ethical guidelines from 1998 to May, 1997 to address the changes in infertility treatment
and assisted reproduction that have occurred since its most recent report in 1994.

The Centers for Disease Control and Prevention (CDC) is currently implementing the
Fertility Clinic Success Rate Certification Act of 1992. In collaboration with
ASRM/SART and RESOLVE, the CDC's Assisted Reproduction Technology and
Epidemiology Unit will publish an annual report of fertility clinic success rates. A goal of
the process is to provide data collection and reporting that is consumer oriented and
addresses the information needs of consumers. The report, slated for publication in
summer of 1997, will include clinic-specific pregnancy success rates as well as data
variables such as the age and diagnosis of couples undergoing IVF, number of ART
initiations, oocyte retrievals, and embryo transfers.

Implementation of the 1992 Federal Act includes development by the CDC's Laboratory
Practice Standards Branch of the Division of Laboratory Systems, of a model program for
certification of embryo laboratories. The model is being developed in collaboration with
ASRM/SART, the College of American Pathologists (CAP), and with the assistance of a
variety of provider and professional groups, state and federal agencies. The model will
include standards for qualifications and training of personnel, quality assurance measures,
equipment maintenance, and record keeping.

Under the law states are encouraged, but not required, to implement the model either as a
state activity or through accreditation by organizations such as the CAP.

It is expected that the model will be made available for public comment in the Federal
Register before the end of 1997.

In October, 1995, the National Advisory Board on Ethics in Reproduction (NABER) held
a conference to consider legal and ethical concerns surrounding ART, and whether
increased oversight or regulation is necessary. The conference was held, in part, in
response to a number of allegations of improprieties at fertility clinics in California.

In its report, NABER stated that the professional standards set by ASRM/SART and CAP
is high, and that the best clinics follow those standards. NABER concluded, however,
that more oversight of IVF and ART is needed and that it should be formed out of broad-
based public input. Its discussion of oversight in the industry included the following:
 • Additional protection may be necessary for consumers in areas such as clinic
advertising, and ownership of eggs, sperm, and embryos, as well as in informed
consent procedures.
• The current voluntary system lacks "teeth" by which to guarantee compliance
with guidelines. In addition, there are currently no prohibitions against practices
"that may be morally objectionable or collectively dangerous, such as some
aspects of human embryo cloning and twinning, creation of hybrids, and a
commercial market in gametes."

Arguments against greater oversight of IVF providers were also discussed by NABER.
They include a concern that further regulation of already expensive ART procedures may
drive the cost even higher. In addition, greater oversight may not ensure quality and
adherence to ethical standards.