Reproductive Endocrinology and Infertility A
subspecialty of obstetrics and gynecology which concentrates on
treating infertility and on female endocrinologic problems that affect
reproduction and reproductive hormones.
In Vitro Fertilization An
advanced treatment for many types of infertility that involves
fertility drugs to produce multiple eggs, removal of the eggs,
fertilization outside the body and transfer of the resulting embryos to
the mother's womb.
Polycystic Ovarian Syndrome A common endocrine disorder that can cause irregular menses and infertility.
Preimplantation Genetic Diagnosis A
procedure that removes a cell from an embryo created by in vitro
fertilization and analyzes it, looking for genetic abnormalities. Read
more about it on the Saint Barnabas web site. Saint Barnabas is a world
leader in this advanced technique.
Oocyte Donation A
form of in vitro fertilization using eggs obtained from a donor. This
technology can help women who have no ovaries, whose ovaries are not
working and women who have failed in vitro fertilization using their
own eggs. If you are interested in donating eggs, see "Becoming and Egg Donor".
ICSI ICSI
or IntraCytoplasmic Sperm Injection has revolutionized the treatment of
male infertility. ICSI is the process of injecting a single sperm into
the egg to assist fertilization during an IVF cycle.
Recurrent Miscarriage Women
who have 2 or more miscarriages should have specialized testing. Saint
Barnabas is pioneering the use of preimplantation genetic diagnosis to
help many women with unexplained first trimester miscarriage have a
better chance of having a normal healthy pregnancy.
Staff Information
Sharon
Taylor, my administrative coordinator, will help schedule your
appointments, Hysterosalpingograms (HSG's) and surgery. She can be
reached at 973 322 2682 or email: SharonT@sbivf.com.
Polycystic Ovarian Syndrome
Polycystic
Ovarian Syndrome or PCOS affects 6% of women of reproductive age. Many
women with chronically irregular periods may have PCOS without
realizing it. It is important to know about PCOS because it can affect
not only your ability to conceive but your general health as well.
While the cause for PCOS is unknown and there is no “cure” for this
condition, you can lower your health risks by knowing about PCOS and
taking advantage of the management options available. Irving Stein
and Michael Leventhal first recognized PCOS in the 1920’s when they
noted an association between no menstrual periods or infrequent
periods, bilateral polycystic ovaries, obesity and excessive male
pattern hair growth or hirsutism. As a result, PCOS was formerly known
as Stein-Leventhal syndrome. However, other names given to this
condition include: Hyperandrogenic Chronic Anovulation and PCOD or
Polycystic Ovarian Disease. Today PCOS is preferred because researchers
do not know the cause of this syndrome and not all women with PCOS have
all the symptoms described by Stein and Leventhal. How do you know
if you have PCOS? Unfortunately, there is no single test that will tell
you that you have PCOS. Women with this syndrome usually have irregular
menses from the time they start having periods. Therefore, this is the
most common and reliable symptom of PCOS. Irregular menses are
classified as cycles that are longer than 35 days from the first day of
bleeding to the day before the next bleed, or less than 8 cycles per
year. In response to this common symptom, many women with PCOS
are given oral contraceptive pills to regulate their menses, but are
not formally diagnosed with PCOS. To obtain a diagnosis, the physician
must rule out other possible causes for irregular menses. Usually this
involves checking a pregnancy test, checking your thyroid function with
a TSH (thyroid stimulating hormone) level, and checking a prolactin
level as well. These are all simple blood tests. If your physician
suspects PCOS, you may be given medroxyprogesterone acetate (brand name
Provera) to see if it will induce a period. This can help differentiate
PCOS from other causes of no menses such as ovarian failure and
hypothalamic amenorrhea. Women with these conditions have low estrogen
levels and usually will not bleed in response to Provera. Women with
PCOS will have normal to slightly elevated estrogen levels and will
usually have a full period after this medication. Many women with
PCOS will have problems with acne and hirsutism – excessive hair growth
on the face, chest and abdomen. These are signs of elevated levels of
male hormones or androgens and are seen in up to 80% of women with
PCOS. If you have these symptoms your doctor may order testosterone,
DHEAS and 17 hydroxy progesterone blood levels. If your symptoms are
mild, these are not necessary. If they are moderate to severe, these
tests will rule out hormone producing tumors and adrenal disorders that
can look like PCOS. Other characteristics of PCOS include excess
weight, multiple small follicles on ovarian ultrasound and an elevated
LH:FSH ratio in the blood. About 50% of women with PCOS are overweight,
making this characteristic consistent with PCOS, but not conclusive
from a diagnostic standpoint. About 80% of women with PCOS have
polycystic ovaries on ultrasound, but 20% of women with PCOS will have
normal appearing ovaries on ultrasound and 20% of normal women will
have polycystic ovaries on ultrasound. Therefore, like excess weight,
ultrasound can support a diagnosis of PCOS but not make it. Another
supporting test is the LH:FSH ratio. LH is luteinizing hormone and FSH
is follicle-stimulating hormone, both of which are made by the brain.
Dysfunctional signaling between the ovary and the brain in women with
PCOS leads to elevated LH:FSH ratios (greater than 3). These are
indicative of PCOS because elevated LH levels cause elevations in male
hormones and irregular ovulation, which leads to irregular periods. In
ovarian failure, FSH levels are elevated. In hypothalamic amenorrhea,
FSH and LH levels are normal or low. Why is it important to know
whether you have PCOS? PCOS not only causes irregular menstrual cycles,
it puts you at increased risk for other health problems. However, these
risks can be decreased or minimized if managed correctly. Irregular
menses are a result of chronic anovulation. The ovary produces
estrogen, but it does not release eggs and does not produce
progesterone. Not only is progesterone necessary for pregnancy, but it
also prevents overgrowth of the lining of the uterus. Overgrowth of the
lining of the uterus can lead to heavy bleeding, and after years of
irregular periods, to cancer of the lining of the uterus. Irregular and
infrequent ovulation leads to problems conceiving for most women with
PCOS. Recently researchers have found that many women with PCOS
have elevated insulin levels or hyperinsulinemia and are resistant to
insulin action. Insulin resistance can lead to a variety of health
problems including obesity. Obesity in turn worsens insulin resistance,
but even thin women with PCOS have higher than normal insulin levels.
Because of this resistance to insulin, PCOS patients have an increased
risk of developing diabetes, high blood pressure, high cholesterol and
heart disease. In the past, physicians have considered PCOS to be a
gynecologic disorder, but we now know that PCOS can have a negative
impact on a woman’s overall health. How is PCOS treated? Because
PCOS can affect many different aspects of a woman’s health, a
multi-pronged treatment plan is often necessary. The treatment for
irregular menses depends upon whether or not a woman with PCOS is
trying to conceive. For women not trying to conceive, the oral
contraceptive pill is a safe and effective treatment for most women.
The birth control pill can regulate your period, provide very effective
protection against endometrial cancer and can improve symptoms of
hyperandrogenism such as hirsutism and acne. An alternative is periodic
treatment with progesterone to induce menses. For women
attempting to conceive, the first line of therapy is often clomiphene
citrate, a pill that can induce ovulation in 80% of patients with PCOS.
For women who do not repond to clomiphene citrate, more advanced
treatment with insulin sensitizing agents and/or injectable
gonadotropins may be recommended. These more advanced treatments should
be monitored by a specialist with experience in using these drugs in
women with PCOS. PCOS patients are very sensitive to stimulation with
gonadotropins and at high risk for ovarian hyperstimulation syndrome if
not properly monitored. For treatment of hirsutism and acne, a
combination of medication to lower androgen levels and local treatment
such as electrolysis may be necessary. The oral contraceptive pill is a
very effective treatment for lowering androgen levels in the skin. It
is even more effective when combined with spironolactone, a mild
diuretic that also acts as an antiandrogen in the skin and hair
follicle. Spironolactone must be used with an effective contraceptive
since it can feminize a male fetus if used in early pregnancy. There
also are many other agents that are effective in treating hirsutism and
acne in PCOS. These include flutamide, cyproterone acetate (not
available in the USA), ketoconazole and finasteride. However, none of
these agents has been shown to be more effective than the birth control
pill and/or spironolactone. All are more expensive and many have a
higher rate of significant side effects. So the oral contraceptive pill
and/or spironolactone remain the first choice for treatment of
hirsutism and acne. What about the effects of PCOS on metabolism?
Is there a way to lower the risk of diabetes, high blood pressure, high
cholesterol and heart disease? The high insulin levels seen in PCOS
increase the risks for these serious health problems and make weight
loss more difficult for overweight PCOS patients. However, weight
control is critical for your health if you have PCOS and as few as 5 to
10 pounds can make measurable improvements in insulin levels, glucose
tolerance, blood pressure and cholesterol levels. All patients with
PCOS should make a balanced diet and regular exercise a top priority.
Although it may be difficult reaching an ideal weight, you should be
encouraged knowing that even small improvements can make significant
differences in your health. What about the new drugs for PCOS?
Researchers have demonstrated very promising results with
insulin-lowering agents that improve hormonal and metabolic parameters
in patients with PCOS, induce ovulation and improve pregnancy rates.
The most studied of these agents, which can be used alone or in
combination with fertility drugs, is metformin (brand name Glucophage).
Metformin, used for the last 20 years to treat diabetics, lowers
insulin levels without causing hypoglycemia, so non-diabetic women with
PCOS can tolerate the drug. This drug may help a patient lower her
insulin levels so her body will be more responsive to diet and
exercise, and it has been used successfully to induce ovulation in PCOS
patients who were very resistant to fertility drugs. However, it
remains to be seen whether long-term use will be beneficial and, while
the drug is unlikely to cause serious side effects, many people
experience nausea and diarrhea. This requires that the drug be started
in low doses and gradually increased and that the patient be monitored
carefully. Troglitazone (brand name Rezulin), which is more effective
than metformin in lowering insulin levels, has been used effectively in
PCOS. However, the FDA has withdrawn it, due to concern about side
effects. Other agents related to troglitizone may be safer and
available in the future. Another promising agent that seems to be well
tolerated is currently in clinical trials: D-chiro-inositol, which also
lowers insulin levels. PCOS, a common cause for irregular menses,
can have serious consequences for a women’s reproductive and general
health. If you think you may have PCOS it is important to have a
thorough evaluation. Weight control through a sensible diet and
exercise plan is crucial for women with PCOS and may improve symptoms
and response to treatment. While there is no cure for PCOS, there are
effective treatments available to manage the symptoms. Speak with your
doctor about the options that are best for you.
Copyright Serena H. Chen, 2000, all rights reserved.
New Patient Information
To schedule an appointment: 1. Please call my secretary Rasheeda at 973 322 2682. 2.
Fill out the New Patient Forms (you can down load these from this web
site by going to "New Patient Information" under "Patient Education" on
the home page). 3. Request any relevant medical records from your doctor.
If
you live out of state, you may want to schedule a phone consultation
first. Paula, or any one of our administrative coordinators can help
you to arrange this.
We look forward to meeting you soon!
Serena H. Chen, MD
Recurrent Miscarriage: Will PGD help?
Published in THE FEMALE PATIENT. Volume 27, December 2002:
Recurrent First Trimester Pregnancy Loss: Is PGD the Answer?
Serena H. Chen MD, Tomas Escudero PhD, David B. Sable MD
Introduction
Preimplantation
Genetic Diagnosis or PGD is a new technology that can detect genetic
abnormalities such as disease-causing mutations and chromosomal
abnormalities to prevent the conception of abnormal pregnancies or
children. PGD has made the headlines recently in some controversial
cases: such as the use of PGD to prevent transmission of adult-onset
diseases such as Alzheimer?s1; or the use of PGD to help conceive an
HLA-matched child to donate bone marrow for a sibling with Fanconi?s
anemia2. While this may seem like an exotic and cutting edge technology
that has no practical applications for the general
obstetrician-gynecologist, in fact, PGD may be a reasonable treatment
option for many of your patients with recurrent first trimester
pregnancy loss or a history of a chromosomally abnormal pregnancy. PGD
can be used to detect aneuploidy, an abnormal number of chromosomes,
the cause of 50 to 70% of first trimester miscarriages3, 4, 5, 6. By
preventing the transfer of abnormal embryos, the risk for miscarriage
and aneuploidy can be significantly reduced in these patients.7 The
Institute for Reproductive Medicine and Science at Saint Barnabas is
one of only a few centers have significant experience with this
technique, and this article will review our experience and results.
However, the availability of this technique is increasing rapidly and
as a primary care physician or general obstetrician gynecologist, it is
important to understand the technique and know which patients it may
benefit. This article will examine the indications, benefits and
limitations PGD of aneuploidy and demonstrate why it should be
considered a treatment option for patients with recurrent miscarriage.
How is PGD performed?
PGD
requires the creation of embryos in the laboratory. So, patients must
undergo in vitro fertilization or IVF. This involves ovarian
stimulation of multiple oocyte development using injectable
gonadotropins. While the patient is under sedation or anesthesia,
oocytes are retrieved transvaginally using a needle to aspirate the
ovarian follicles under vaginal ultrasound guidance. The oocytes are
then inseminated with the husband?s sperm in the laboratory. Once
fertilization occurs, embryos are cultured in the laboratory for a
total of 3 days after egg retrieval. After 3 days of culture, normal
embryos will divide and should reach the 6 to 8 cell stage. At this
stage of development, prior to differentiation, analysis of the
chromosomes of a single cell or blastomere should reflect the
chromosomes of the entire embryo.
An embryo biopsy is performed
by creating an opening in the zona pellucida, the ?shell? around the
embryo, using either mechanical means, dilute acid solution or a laser.
A single blastomere is removed through this opening using gentle
suction and a micropipette. The procedure is performed using a special
microscope with micromanipulators ? special devices designed for
delicate microscopic procedures. The blastomere is then fixed upon a
slide and the embryos that have been biopsied are placed back into an
incubator to await the results of the biopsy.
For the
diagnosis of aneuploidy a technique called fluorescence in-situ
hybridization or FISH is used. This technique uses commercially
available small pieces of DNA (probes) attached to fluorescent labels
that bind to specific chromosomes in the blastomere. Once the probes
are bound, the signals are read under a fluorescent microscope, so that
the number and type of chromosomes present in that cell can be
determined. The analysis takes approximately 1 day to accomplish.
Embryos that are normal by the analysis are then transferred to the
woman?s uterus on day 4 or 5 after the oocyte retrieval.8,9 Due to the
limited amount of material being analyzed and the limited window of
time in which to obtain a diagnosis, only 8 out of the 24 types of
chromosomes can be analyzed. The chromosomes most commonly analyzed are
13, 15, 16, 18, 21, 22, X and Y.9,10 These particular chromosomes are
thought to be responsible for the majority of clinical pregnancy
losses.11
What are the results of PGD of aneuploidy?
PGD
of aneuploidy can reduce spontaneous abortion rates. In a group of IVF
patients matched for maternal age, number of previous IVF cycles and
response to fertility drugs, there was a significant reduction in the
rate of spontaneous abortions in the group that underwent PGD of
aneuploidy compared to the control group (23% to 9%, p < 0.05)7,
along with a subsequent higher ongoing pregnancy and delivery rate in
the PGD group. The rate of trisomic pregnancies is also
significantly reduced by PGD12. In addition, in patients undergoing
IVF, PGD of aneuploidy may improve the chance of conception by
increasing embryo implantation rates7. It is thought that PGD improves
the process of selecting embryos for transfer, allowing embryologists
to choose embryos most likely to result in a normal pregnancy. By
improving embryo selection, and allowing fewer embryos to be
transferred, PGD can also assist in reducing the frequency of high
order multiple births after IVF.7, 12
What are the risks and limitations of PGD?
The
risks of PGD include the risk that the embryo will be damaged during
the biopsy procedure. The risk of embryo damage at our center is
currently 0.9% and is affected by the experience and skill of the
person performing the biopsy.7
As discussed earlier in this
article, PGD of aneuploidy is currently limited to 8 out of the 24
types of chromosomes. An embryo that is deemed normal by PGD could have
an abnormality in one of the other 16 types of chromosomes that were
not analyzed by PGD. In addition, because the analysis is performed
using FISH, the abnormalities that are detected are in chromosome
number only. Other types of structural abnormalities, such as
additions, deletions or translocations may not be detected as they
would be in a routine karyotype or chorionic villus sampling (CVS) or
amniocentesis. Since only a single cell is analyzed, mosaicism may lead
to misdiagnosis. A mosaic embryo does not have the same chromosomal
component for all cells, so that a single cell will not reflect the
karyotype of the entire embryo. Because of these limitations, the error
rate for the chromosomes analyzed (including mosaics, false positive
and false negative results) is approximately 7% at our center, while
the error rate for CVS and amniocentesis is typically less than 1%. PGD
cannot be considered a substitute for prenatal diagnosis and the
decision to forgo CVS or amniocentesis should not be based upon normal
PGD testing. At this time, our center recommends that patients at high
risk for aneuploidy have CVS or amniocentesis even if PGD has been
performed.
Which patients should have PGD?
Recurrent first trimester pregnancy loss
Recurrent
pregnancy loss (defined as 3 or more consecutive miscarriages) affects
approximately 1% of the population. The evaluation of these patients
should rule out genetic, anatomic, endocrine, and immunologic causes
for recurrent miscarriage. Many clinicians will also rule out
inheritable thrombophilias, although this testing remains
controversial.13 The evaluation of the recurrent loss patient should be
individualized, but typically includes history and physical exam,
pelvic sonogram, hysterosalpingogram or saline hysterosonogram, CBC,
TSH, antithyroid antibodies, prolactin, lupus anticoagulant,
anticardiolipin and antiphosphostidylserine antibodies, karyotyping of
both partners and possibly an endometrial biopsy and screening for
inheritable thrombophilias.13
Approximately 5 to 8% of couples
with a history of recurrent pregnancy loss will have an abnormal
karyotype, usually a balanced translocation. PGD can be performed for
couples with a balanced translocation, allowing them to implant only
normal or chromosomally balanced embryos, thus reducing their risk of
miscarriage.14, 15 PGD for translocations is technically more
complicated than PGD of aneuploidy. Patients with a translocation
should be referred to a genetics counselor to review their options. A
referral for PGD at a center with experience performing this type of
analysis can then be made if the couple desires it.
Once the
work-up is complete, many patients will not have an identifiable cause
for their miscarriages and therefore, no obvious treatment options.
Without any treatment, couples with this history have a 55 to 70%
chance of a successful live birth, depending upon how many miscarriages
they have had and whether they have any previous live births13. Thus,
expectant management with close follow up is a reasonable option for
these patients. For couples that desire a more aggressive approach, PGD
may be offered to significantly reduce (by over 50%) the risk of first
trimester loss due to aneuploidy.
Previous chromsomally abnormal child or pregnancy
For
patients with a previous child or pregnancy with a chromosomal
abnormality, PGD can reduce the risk of certain abnormalities in the
patient?s next pregnancy. This may be an attractive alternative to post
conception testing for patients as they may be able to avoid
termination of an abnormal pregnancy.
Advanced maternal age
As
a woman ages, her risk for both miscarriage and aneuploid pregnancy
increases markedly. For women 37 years of age and older undergoing IVF,
our center has demonstrated that PGD of aneuploidy significantly
improves pregnancy rates, reduces miscarriage rates and reduces
trisomies if 6 or more embryos of good quality are available for
analysis.16
Summary
PGD of aneuploidy is a new
technology that is quickly becoming available at more and more IVF
centers around the country. In order to undergo PGD, patients must
conceive via in vitro fertilization. PGD of aneuploidy is a limited
chromosomal analysis of early stage embryos prior to implantation.
Obstetrician-gynecologists should understand the technique and consider
offering PGD of aneuploidy as an option for their patients with a
history of recurrent first trimester loss that is unexplained or due to
a chromosomal abnormality. PGD can significantly reduce miscarriage
risk in these patients. If a patient wants to consider PGD of
aneuploidy, she should have a consultation with a genetics counselor
for a more extensive discussion on the procedure and its limitations.
The primary care physician, obstetrician-gynecologist or the genetics
counselor can then refer the patient to a center with experience using
this technique. While PGD can have significant benefits, it is a
limited genetic test and is not a substitute for CVS or amniocentesis.
References
1.
Verlinsky Y, Rechitsky S, Verlinsky O, Masciangelo C, Lederer K, Kuliev
A. Preimplantation diagnosis for early-onset Alzheimer disease caused
by V717L mutation. JAMA 2002 Feb 27;287(8):1018-21 2. Verlinsky Y,
Rechitsky S, Schoolcraft W, Strom C, Kuliev A. Preimplantation
diagnosis for Fanconi?s anemia combined with HLA matching. JAMA 2001
Jun 27;285(24):3130-3 3. Warburton D, Kline J, Stein Z, Strobino B.
Cytogenetic abnormalities in spontaneous abortions of recognized
conceptions. In: Porter IH, Hatcher N, Willey (eds). Perinatal
Genetics. Academic Press, NY, 1986, pp 23-40. 4. Hill JA. Recurrent
Pregnancy Loss. In: Creasy and Resnick (eds). Maternal-Fetal Medicine,
4th edition. SB Saunders, NY 1998. 5. Guerneri S, Bettio D, Simoni
G, Brambat B, Lanzani A, Fraccoro M. Prevalence and distribution of
chromosome abnormalities in a sample of first-trimester internal
abortions. Hum Reprod 1987. 2: 735. 6. Fritz B, Hallermann C, Olert
J, Fuchs B, Bruns M, Aslan M, Schmidt S, Coerdt W, Muntefering H,
Rehder H. Cytogenetic analyses of culture failures by comparative
genomic hybridisation (CGH)-Re-evaluation of chromosome aberration
rates in early spontaneous abortions. Eur J Hum Genet 2001
Jul;9(7):539-47 7. Munné S, Magli C, Cohen J, Morton P, Sadowy S,
Gianaroli L, Tucker M, Márquez C, Sable D, Ferraretti AP, Massey JB,
Scott R. Positive outcome after preimplantation diagnosis of aneuploidy
in human embryos. Human Reprod 1999;14; :2191-2199. 8. Munné S, Lee
A, Rosenwaks Z, Grifo J, Cohen J. Diagnosis of major chromosome
aneuploidies in human preimplantation embryos. Hum Reprod
1993;8:2185-2191. 9. Gianaroli L, Magli MC, Ferraretti AP, Munné S.
Preimplantation diagnosis for aneuploidies in patients undergoing in
vitro fertilization with poor prognosis: identification of the
categories to which it should be proposed. Fertil.
Steril.1999;72:837-844. 10. Munné S, Magli C, Bahçe M, Fung J,
Legator M, Morrison L, Cohen J, Gianaroli L. Preimplantation diagnosis
of the aneuploidies most commonly found in spontaneous abortions and
live births: XY, 13, 14, 15, 16, 18, 21, 22. Prenat
Diagn.1998;18:1459-1466. 11. Jobanputra V, Sobrino A, Kinney A,
Kline J, Warburton D. Multiplex interphase FISH as a screen for common
aneuploidies in spontaneous abortions. Human Reprod 2002, 17:1166-1170. 12.
Gianaroli L, Magli MC, Ferraretti AP, Tabanelli C, Trombetta C,
Boudjema E. The role of preimplantation diagnosis for aneuploidy.
Reprod Biomedicine Online 2001. 13: 1656-1659. 13. Speroff L, Glass
RH, Kase NG. Recurrent early pregnancy losses. In: Clinical Gynecologic
Endocrinology and Infertility, 6th ed. Lippincott Williams &
Wilkins, Baltimore, MD, 1999. pp. 1043-1055. 14. Munné S, Scott R,
Sable D, Cohen J. First pregnancies after pre-conception diagnosis of
translocations of maternal origin. Fertil Steril 1998;69:675-681 15.
Munné S, Morrison L, Fung J, Márquez C, Weier U, Bahçe M, Sable D,
Grundfelt L, Schoolcraft B, Scott R, Cohen J. Spontaneous abortions are
reduced after pre-conception diagnosis of translocations. JARG
1998:290-296 16. Munné S, Cohen J, Sable D. Preimplantation genetic
diagnosis for advanced maternal age and other indications. Fert Steril
2002;78:2:234-236
Multiple Pregnancy
MULTIPLE BIRTHS: Risks and Rewards
By Serena H. Chen, M.D. Director of Ovum Donation and Associate Director Institute of Reproductive Medicine and Science Saint Barnabas Hospital, Livingston, NJ
INTRODUCTION Assisted
reproductive technologies (ART) have given tens of thousands of couples
throughout the world the opportunity to have children. Many infertile
couples had little hope of conceiving prior to the availability of
these advances in medical technology, which include controlled ovarian
hyperstimulation (COH) using fertility drugs, either with or without
intrauterine insemination; in vitro fertilization (IVF) and gamete
intrafallopian transfer (GIFT). However, there has been a price for
success. Along with the use of ART has come a dramatic increase in the
incidence of multiple gestations -- twins, and ?high order multiple
gestations? such as triplets, quadruplets and more. Currently, it is
estimated that 50% of twin pregnancies and 90% of triplet and greater
pregnancies are the result of ART. In many cases, couples are thrilled
at the prospect of more than one child: an instant family, their hopes
and dreams fulfilled, and then some. Indeed, twin pregnancies, with a
little extra attention from your regular obstetrician and pediatrician,
will usually do quite well. However, triplets and more must be
considered very high-risk pregnancies. This article will discuss
various techniques available to reduce the risks for multiple pregnancy.
SCOPE OF THE PROBLEM
According to the most recent statistics available from the federal
Centers for Disease Control and Prevention (CDC), 99,639 cycles of IVF
or one of its related procedures were carried out in 2000 in the United
States. A little over 25,228 of those cycles ended in a successful
pregnancy (25.3%), resulting in the birth of 35,025 babies. Of those
pregnancies, 35% were multiple gestations (30.7% twins, 4.3% triplets),
compared to 3% of live births in the general population. Depending upon
the mother?s age, the proportion of pregnancies that were twins ranged
from 15.2 to 31.9% and the proportion of pregnancies that were triplets
ranged from 2.6 to 8.5%; the younger the mother, the higher the chances
of multiples. The actual rate of multiple pregnancies is higher than
the delivery rate since some of these pregnancies end in miscarriage or
undergo multifetal pregnancy reduction. In the general, non-infertility
population, the expected proportion of triplet deliveries is
approximately 0.01%. The full CDC report can be found on the Internet
at: http://www.cdc.gov/nccdphp/drh/art.htm.
CONTROLLED OVARIAN HYPERSTIMULATION
Controlled ovarian hyperstimulation is the process of using fertility
drugs to induce more than one follicle (the sac around a single egg) to
develop, inducing multiple ovulation and increasing the pregnancy rate
compared to the natural cycle, where only a single egg is released.
Clomiphene citrate (Clomid or Serophene) can increase the rate of twins
from 1-2% to 5-10%. Triplet and higher order multiple pregnancies are
very rare with this drug. When pregnancy occurs using injectable
fertility drugs (gonadotropins such as Follistim, Gonal-f, Fertinex,
Humegon, Pergonal or Repronex) in combination with intercourse or
insemination, 15-20% of those pregnancies will be twin gestations and
5% triplets and above. The Iowa sextuplets were conceived with this
method. Careful monitoring with frequent blood hormonal levels and
transvaginal ultrasounds can reduce, but not eliminate the risks. When
more eggs are released, the pregnancy rate increases. Unfortunately,
the risk of multiple pregnancy increases too. If too many follicles
develop, or the hormone levels are too high, cancellation of the cycle
should be considered. The chance of pregnancy must be balanced against
the risks of high order multiple pregnancy.
COMPLICATIONS OF MULTIPLE PREGNANCY The
vast majority of complications and medical problems experienced by ART
children are due to the nature of multiple pregnancies and the fact
that women carrying multiples often deliver too early. The normal
length of gestation is 40 weeks. It is reduced to 36 weeks for twins,
33 weeks for triplets, and just 29 weeks for quadruplets. Complications
include an increased chance of miscarriage, birth defects, preterm
birth and lifelong mental or physical handicaps. Some studies show that
triplets have an up to 30% risk of neurodevelopmental abnormalities.
The death rate of infants less than 1 year old and born from twin
gestations is increased 4 times the rate for singletons, and death rate
for triplets is 10 times the risk for singletons. Maternal problems
include an increased risk of diabetes, hypertension, preeclampsia
(toxemia), prolonged bed rest and cesarean section. In general,
maternal and fetal complications are more severe the higher the number
of fetuses.
The increased complication rates for mother and
babies take a tremendous toll. The hospital cost of a triplet delivery
is estimated to be more than ten times the cost of delivering a
singleton pregnancy. Not only is the financial burden on the parents
magnified by the increased number of babies but often by previously
depleted funds due to the costs of extensive fertility treatments. This
financial stress, combined with the emotional stress and sleep
deprivation of new parenthood, can be overwhelming, even when the
babies are healthy. There are several organizations that recognize the
difficulties presented by multiple births and are dedicated to
providing information, fellowship and support to affected families:
Mothers of Twins (national) 1-(800)-243-2276; NOMTC, the National
Organization of Mothers of Twins Clubs 1-(877) 540-2200, web site:
http://www.nomotc.org/; Marvelous Multiples (Saint Barnabas)
1-(973)-322-5360; Mothers of Super Twins 1-(516)-859-1110; Triplet
Connection 1-(209)-474-0885; Mommies of Multiples 1-(973)-509-5276.
IN VITRO FERTILIZATION The
use of fertility drugs for hyperstimulation in conjunction with IVF or
GIFT offers a level of control that does not exist when the drugs are
coupled with insemination. The control results from decisions about the
number of eggs injected into the fallopian tube during a GIFT procedure
or the number of embryos transferred in an IVF procedure. The United
Kingdom, Canada, Singapore, Germany and Belgium have attempted to
reduce the incidence of multiple pregnancies by legislating the number
of embryos that may be created or transferred. In 1997, in response to
growing public concern about the consequences of high order multiple
births, the American Society for Reproductive Medicine (ASRM) published
guidelines on the appropriate number of embryos to transfer per cycle.
These guidelines were revised in November 1999.
HOW MANY EMBRYOS SHOULD BE TRANSFERRED?
In general, for women with the most favorable prognosis (women under 35
with very high quality embryos for transfer and excess embryos for
cryopreservation, or women using donated eggs), no more than two good
quality embryos should be transferred. In women with an above average
prognosis (less than 35 years old), no more than three good quality
embryos should be transferred. In women 35 to 40 years old, no more
than four good quality embryos should be returned. In women over 40,
the guideline is no more than five. However, while the ASRM recognizes
the serious risks of multiple gestations, they also recognize that
individual circumstances impact upon the appropriate number of embryos
to be transferred in a particular patient. These factors may include
embryo quality, previous IVF failure, the individual IVF program?s
success rate, and the couple?s feelings about multiple births and
multifetal pregnancy reduction. If the guidelines are not followed,
this decision should be based upon sound clinical data, not a desire to
achieve pregnancy at all costs.
MULTIFETAL PREGNANCY REDUCTION Another
attempt to limit the negative consequences of multiple births is
multifetal pregnancy reduction ? a selective abortion technique. This
procedure reduces the number of fetuses in an effort to increase the
likelihood that the pregnancy will continue. This procedure is most
commonly performed if there are four or more fetuses. A proportion of
triplet pregnancies may be reduced and rarely, in special clinical
circumstances, a twin pregnancy may be considered for reduction.
Since
the rate of miscarriage is higher in multiple pregnancies and the vast
majority of miscarriages occur before eight or nine weeks, the
procedure is usually carried out between nine and twelve weeks of
gestation (counting weeks after the last menstrual period, or seven to
ten weeks after the oocyte retrieval). In addition some multiple
pregnancies will reduce ?naturally? as a result of a phenomenon known
as ?the vanishing twin syndrome? which occurs in approximately 20% of
twin pregnancies in the first trimester. There are twice as many
triplet pregnancies as there are triplet live births due to a
combination of natural losses and multifetal reduction.
The
multifetal reduction procedure is performed on an outpatient basis
after sedation and antibiotics are given to the mother. Using
ultrasound visualization, the physician guides a needle through the
maternal abdomen or vagina and into the fetus, which may have been
selected for reduction because of an apparent abnormality. However, at
this early age, the detection of abnormalities is limited. It may be
reasonable to consider genetic testing via chorionic villus sampling
prior to the procedure, so that a genetically abnormal fetus can be
selectively reduced. The procedure, completed with an injection of
potassium chloride into the selected fetus, is successful if the
desired reduction occurs without harm to the remaining fetuses. The
rate of loss for the entire pregnancy from this procedure is
approximately 5 to 10% in the hands of an experienced physician.
However, one of the greatest difficulties of multifetal reduction is
making the often heart-wrenching but practical decision to go forward
with a procedure that could potentially end such a precious and
hard-won pregnancy.
BLASTOCYST TRANSFER Another technique
that may reduce the problem of high order multiple pregnancies is
blastocyst transfer. A blastocyst is a 5 to 6 day-old embryo at the
stage of development that occurs right before implantation into the
uterus. Recent developments in the laboratory have allowed
embryologists to grow blastocysts with a higher pregnancy potential
than younger embryos in some patients. The hope is that the pregnancy
potential of blastocysts will be so high that as few as one or two
embryos could be transferred while still maintaining a high chance for
success. One current disadvantage of blastocyst transfer is the greater
chance that the embryos will not survive five to six days, due to the
stress of being in the laboratory for an extended period of time. In
some cases, embryos that may have resulted in a pregnancy if
transferred to the body earlier may stop growing if left in the
laboratory for 5 to 6 days. In addition, this technology has not yet
been perfected and may not be appropriate for all patients. Before
considering this option, you should inquire about a particular
program?s specific success rates with blastocyst transfer, as well as
your doctor?s recommendation in your individual case.
IMPLANTATION RATE: THE KEY In
general, the best way to reduce multiple births is to transfer only
single embryos. In order to do that without dramatically lowering the
overall pregnancy rate, implantation rates need to be increased.
Implantation rate is the potential of a single embryo to result in a
pregnancy and is calculated by taking the total number of gestational
sacs divided by the total number of embryos replaced. Implantation rate
is always lower than the pregnancy rate because the vast majority of
IVF procedures involve the transfer of more than one embryo. The higher
the implantation rate, the lower the number of embryos needed to
achieve pregnancy, and the lower the multiple birth rate.
Improvements
in various techniques used in the laboratory have led to gradually
improving pregnancy rates across the country. Improved techniques of
embryo culture, assisted hatching and fragment removal are being used
more widely. As embryologists gain experience, implantation rates have
improved. Again, improvements in implantation rates will ultimately
allow physicians to replace fewer and fewer embryos, maintain or
improve the overall pregnancy rate and someday, eliminate the risk of
high order multiple pregnancy.
EMBRYO FREEZING Cryopreservation
or freezing of embryos is another technique that can be used to reduce
multiple births. Cryopreservation is widely available and can help
decrease the pressure to transfer large numbers of embryos by allowing
a couple to freeze extra embryos for use at a later date. The
disadvantages of cryopreservation are that some embryos will not
survive the freeze-thaw process and previously frozen embryos may have
less pregnancy potential than ?fresh? embryos. However, there does not
appear to be any increase in the rate of birth defects or miscarriages
in pregnancies conceived using frozen-thawed embryos. As this
technology continues to improve, with better freeze-thaw survival rates
and better pregnancy rates, it will become a more powerful tool to help
reduce multiple births.
PREIMPLANTATION GENETIC DIAGNOSIS (PGD) Preimplantation
genetic diagnosis (PGD), or the genetic analysis of embryos prior to
transfer into the body is an exciting new technology that could help
reduce multiple births. PGD can be used to look for chromosomal
aneuploidy (abnormal numbers of chromosomes) in the embryo. This
condition can lead to infertility, miscarriages and birth defects (an
extra chromosome 21 causes Down?s Syndrome). As a woman gets older, the
chance that her embryos are chromosomally normal drops dramatically. In
older women, the ability of the embryologist to select the embryos most
likely to result in a pregnancy decreases markedly. In addition, the
implantation rate of the embryos decreases. By using PGD to select the
chromosomally normal embryos, the implantation rate of the embryos that
are selected is increased. The higher the implantation rate, the lower
the number of embryos needed to achieve pregnancy and the lower the
multiple birth rate. At this time, PGD can analyze only a limited
number of chromosomes and only a few centers worldwide have significant
experience in this technique. However, it has already proven to be a
useful tool to improve pregnancy rates in older women, to lower the
miscarriage rates, and may ultimately allow us to offer all patients a
single embryo transfer, eliminating the multiple pregnancy problem
without sacrificing a high pregnancy rate.
CONCLUSION Despite
what many infertile couples think, it is possible to have too much of a
good thing. Multiple pregnancies involve reward and risk. High order
multiple pregnancy can result in serious complications for both the
mother and the babies. There are various techniques available to try
and minimize these risks. Couples should discuss these techniques with
their doctor to decide how or whether to use them in their individual
treatment plan. Copyright 2002 Serena H. Chen MD, all rights reserved.
