Introduction. Pregnancy
loss is a frustrating and challenging problem for couples and clinicians alike. Although medical textbooks specifically
target the recommended "work-up" towards those patients labeled as "recurrent" or "habitual
aborters", it is important, in this author's opinion, to consider certain specific aspects of evaluation after
any miscarriage. This is particularly true when other concomitant issues are present, such as primary or secondary
infertility, irregular menses, absent or irregular ovulation, a known history of uterine fibroids (myomata), and
a family history of miscarriage. Patient-driven concerns - such as advancing age, medical history, and a prior
history of pregnancy complications - certainly warrant a detailed consultation with a practitioner committed to
pregnancy loss evaluation.
Traditionally, reproductive health providers, such as obstetrician/gynecologists
and reproductive endocrinologists, have been trained to pursue a detailed evaluation in couples who have suffered
three or more miscarriages. More recently, many practitioners will initiate the same evaluation after two losses
when the maternal age is 35 or greater. When in doubt, this issue should be discussed directly with your physician.
How Common Is Miscarriage?
It is estimated that about 20-25% of all pregnancies end in miscarriage in the first trimester. Considering that
over four million babies are born in the United States every year, there are probably close to one million pregnancy
losses occurring every year in the U.S. The physical, emotional, and financial toll of pregnancy loss is large.
The relatively high frequency of miscarriage has led to the "rule" of many couples not telling family
or friends about their pregnancy initially. Miscarriage is often associated with guilt ("If I had only not
done. . . "), embarrassment ("There must be something wrong with me. . ."), and depressive states
("Why should I bother trying this again?"). The grief process and the period of grieving time that is
necessary varies dramatically but is often minimized by spouse, family, friends, and physicians.
The emotional issues surrounding pregnancy loss become magnified exponentially when
miscarriage occurs on a repetitive basis. Unfortunately, by statistical "bad luck" alone, 4-6% of all
women attempting pregnancy will experience at least two miscarriages, and about 1-2% will have three or more miscarriages.
When directing women towards an evaluation for recurrent pregnancy loss, and underlying contributing factor can
be identified 40-50% of the time. When a contributing factor is found and treated, the prognosis for successful
pregnancy outcome is typically about 80%. Even in couples where no underlying problem is found, the chances for
a successful pregnancy can typically be in the 50-70% range. When a couple has previously had a normal pregnancy
and delivery, the prognosis tends to be better.
Miscarriage and Genetics.
It is estimated that 50-60% of all first trimester pregnancy losses harbor a chromosomal abnormality, which leads
to abnormal growth and development of the pregnancy. The large majority of these abnormal pregnancies fail in the
first trimester, leading to clinical entities labeled as "blighted ovum", "fetal demise", "missed
abortion", and "empty sac". Often, ultrasound evaluation confirms the diagnosis of a loss, and attempts
to describe the abnormal features of the pregnancy. Occasionally, a genetically abnormal pregnancy will survive
into the second or third trimester (trisomy 21 - Down syndrome - is one example), leading to other issues for a
pregnant couple to consider.
In 1997, in order to diagnose a chromosomal disorder in pregnancy loss tissue,
it is necessary for the clinician to submit fresh tissue following a uterine curettage procedure (D & C or
D & E) to a cytogenetics lab. The lab will then culture cells that are believed to be pregnancy-derived and
perform a detailed chromosome assessment. This process takes 3-6 weeks but often provides a specific reason for
the loss. An abnormal chromosomal make-up generally occurs because of a specific problem with the egg or sperm
that contributed to the conception. Maternal age is generally believed to be a significant factor leading to potentially
abnormal egg development and genetic make-up of the pregnancy. Often, this is an important issue to discuss when
a couple seeks consultation. In some instances, either the maternal or paternal chromosomal make-up can predispose
a couples to chromosomally abnormal pregnancies. Typically, part of the evaluation should also include an assessment
of the parental chromosomes.
Many couples who come for consultation and evaluation have not had their prior
pregnancy loss tissue analyzed for potential chromosomal abnormalities. This can be frustrating to both the clinician
and the couple, particularly when considering other aspects of the evaluation for pregnancy loss. Also, cytogenetic
information obtained can often be misleading. For example, our research team (previously at the University of Pennsylvania)
found that about 30% of miscarriage specimens reported to be "normal" 46,XX (female) by the cytogenetics
lab were, in fact, incorrect diagnoses. We used more sophisticated DNA molecular approaches to ascertain these
findings, similar to techniques used by forensic investigators.
Although these same DNA analysis techniques could be applied on a more routine
basis, cost concerns come into play. However, it is this author's opinion that it is better to devote dollars to
more accurate and universal assessment of miscarriage tissues, rather than subjecting a patient to potentially
unnecessary diagnostic testing and treatments. Hopefully, as cytogenetic and DNA approaches merge, there will be
improved quality assurance of pregnancy loss genetic evaluation.
Importance of the Uterine Environment. A common aspect of the evaluation to uncover causes for miscarriage will typically involve inspection
of the macroenvironment and the microenvironment within the uterus. The lining of the uterus, known as the endometrium,
is an amazingly dynamic tissue, unlike any other part of the human body. In the first half of the menstrual cycle
(prior to ovulation), the endometrium has to be "primed" appropriately, primarily from estrogen derived
from ovarian follicle(s). Soon after ovulation, the endometrium undergoes an impressive sequence of microscopic
changes - primarily in response to progesterone - to allow for the "receptivity" of an implanting embryo.
If a pregnancy does not occur, progesterone levels fall and menses occur. If a pregnancy does occur, the endometrium
must develop further to provide ongoing attachment and nourishment for the developing pregnancy. Any process which
interferes with normal embryo-endometrium interaction can lead to pregnancy failure.
Evaluation of the macroenvironment within the uterine cavity is important for
uncovering structures that could interfere with an implanting or growing pregnancy. Acquired problems could include
polyps, fibroids, and adhesions, which even if small, could interfere with an otherwise normal pregnancy. Congenital
uterine problems include the septated uterus, a "horned" (bicornuate) uterus, or a T-shaped uterus (related
to in utero DES exposure). Diagnostic evaluation has typically utilized an X-ray approach in the past (hysterosalpingogram),
but newer imaging approaches employing ultrasound and/or MRI have been extremely helpful. It has been this author's
experience that ultrasound imaging with saline infusion (sonohysterography) is an extremely sensitive technique
for initially evaluating the uterine cavity. Recent publications by other investigators support this impression.
Treatment for acquired and congenital uterine problems typically employs a surgical approach. However, in many,
if not most instances, hysteroscopic surgical techniques can be employed. More complex cases of large uterine fibroids
or congenital uterine abnormalities may require an abdominal (laparotomy) approach.
Microscopic inspection of the endometrium appears to be an important aspect
of the evaluation. In collaboration with the Reproductive and Placental Pathology Unit at Yale University School
of Medicine, our team has identified a high rate of subtle and correctable abnormalities within the endometrium.
Evaluation of the endometrium requires a well-timed and well-processed biopsy of the endometrium. Endometrial biopsy
is a mildly uncomfortable office procedure (easy for a man to say) that should be performed in the latter part
of the luteal phase. Ideally, it should be timed in relation to the LH surge, with full interpretation depending
on the date of the LH surge and the date of the next menses. The biopsy should be evaluated by a pathologist with
a trained eye and experience with endometrial assessment. Direct communication with the pathologist is often helpful
in the assessment of the biopsy. If an abnormality is detected, specific hormonal-based treatments can be employed.
The issue of re-biopsy to verify the effectiveness of a chosen treatment, while appearing somewhat academic, is
commonly preferred by the patient. Often, the initially chosen treatment is proven not to be totally effective
based on re-assessment of the endometrium, and a modified hormonal regimen may be required.
What About "Luteal Phase Defects? Subtle abnormalities within the uterine lining could reflect aberrant hormone production by
the developing follicle or corpus luteum within the ovary. There is considerable debate regarding the best way
to diagnose a luteal phase abnormality. In general, it has been my practice to depend on the endometrial biopsy
as a way to gauge adequate hormone production by the ovary. However, there is a school of thought that relies upon
the measurement of serum progesterone levels during the luteal phase. Although there may be some validity to this
approach, it is difficult to assess effectiveness of therapy. It has also been my practice to discourage the use
of empiric progesterone supplementation without any prior diagnostic assessment of the luteal phase. Other empiric
regimens, such as the unmonitored use of clomiphene citrate, should also be discouraged.
The Quandary of the Immune System. As mammals, the human race has evolved to allow for the "foreign body" known as pregnancy
to implant, survive, and grow without immunologic rejection typical of other organ transplants or grafts. This
is true whether the egg leading to the pregnancy is genetically derived from the mother or from a donor. Thus,
it is believed that the uterus may provide an immunologically "privileged" site. However, extrauterine
locations (e.g. fallopian tube, ovary, and peritoneal cavity) can support implantation and pregnancy development
without evidence of immunologic rejection. Recent evidence suggests that trophoblasts, the placental cells responsible
for implantation and attachment, do not produce HLA transplant antigens typical of other tissues, thus possibly
explaining how a pregnancy escapes maternal immune rejection.
Until the issue of HLA antigen production in trophoblasts was examined, older
and more complex theories were proposed to attempt to explain the maternal acceptance or rejection of the pregnancy.
To this date, some Centers advocate complex and costly immunologic testing, along with the use of paternal or anonymous
lymphocyte immunization as ways to improve the immunologic "acceptance" of a pregnancy. The American
College of Obstetricians and Gynecologists regards lymphocyte immunization as an experimental technique that should
only be utilized within a research protocol. Retrospective data published in the American Journal of Reproductive
Immunology suggests that it is necessary to treat 11 women with recurrent miscarriages to possibly help one woman
via paternal lymphocyte immunization. Hopefully, the results of a double-blinded, prospective study sponsored by
the NIH at the University of Chicago will be forthcoming soon to help resolve this controversial area.
Another immunologically-mediated contributor to pregnancy loss that may be more
significant than originally thought is the anti-phospholipid antibody syndrome (APLA). This syndrome reflects a
subtle autoimmune condition that can lead to enhanced clot formation in certain microvessels with low flow or low
pressure. Although the exact mechanism of action for these antibodies is still being worked out, it is believed
that APLA can bind to phospholipids in the lining of blood vessels, platelets, and/or trophoblasts in the placenta,
leading to thrombosis. When thrombosis occurs in the early microvasculature of the implanting placenta and/or endometrium,
the pregnancy does not receive adequate nourishment, gas exchange, or blood flow. An otherwise normal pregnancy
can miscarry at any stage of pregnancy. Women with APLA are at higher risk in later pregnancy of pre-eclampsia,
fetal growth retardation, and fetal demise.
Diagnosis of APLA can be challenging, due to fluctuating titers of the antibodies,
a lack of agreement between laboratories concerning standardization of the assays, and debates among researchers
and clinicians concerning which antibodies to measure. Although multiple APLAs might eventually be considered pathologic
to pregnancies, anti-cardiolipin, anti-phosphotidylserine, and the 'lupus anticoagulant' are generally believed
to be culprits when identified in women with pregnancy losses.
Treatment for APLA syndrome generally requires daily baby aspirin prior to conception,
and the use of baby aspirin and heparin as soon as pregnancy is diagnosed. One recently published study demonstrated
an 80% success rate for treatment of APLA by this approach. The 20% failure rate is likely accounted for in large
part by genetically-abnormal losses. More aggressive treatment of APLA occasionally involves the use of human intravenous
immunoglobulin. This is an expensive therapy that has less clear-cut efficacy demonstrated. The use of empiric
intravenous immunoglobulin should generally be discouraged, and is not endorsed by the American College of Obstetricians
and Gynecologists.
Future Questions and Challenges. Most patients seeking consultation for pregnancy loss evaluation are in search of clear answers
and explanations. In the absence of a clear diagnosis, it is difficult, if not impossible, to propose a particular
treatment regimen. Important questions that remain to be answered include:
1) What new molecular DNA techniques
can be applied to the evaluation of pregnancy loss tissues? Can these techniques be applied to prior loss (archival)
specimens?
2) Will endometrial assessment
include molecular assessment along with histologic evaluation? What determines a normal, receptive endometrium?
3) What will be the role
of assisted reproductive technologies and pre-implantation genetic diagnoses in the management of recurrent pregnancy
loss?
4) Can the maternal age "factor"
be overcome by newer micromanipulation techniques during and following in vitro fertilization (IVF)?
5) Can better assays be developed
to characterize which patients are harboring pathologic anti-phospholipid antibodies? What other anti-thrombotic
regimens could be utilized?
As technical and diagnostic approaches to pregnancy loss continue to improve, it is hoped that all couples will
have the opportunity to explore a full range of evaluation and therapeutic options.
References and Further Reading
1. Bell KA, Van Deerlin PG, Feinberg RF: Tissue cytogenetic determinations of "normal 46,XX" karyotypes
in spontaneous abortions may frequently be misleading. Abstract O-087, Oral Presentation, 53rd Annual Meeting of
the American Society for Reproductive Medicine, Cincinnati, Ohio, October 18-22, 1997.
2. Coulam CB: Alternative treatment to lumphocyte immunization for treatment of recurrent spontaneous abortion:
Immunotherapy with intravenous immunoglobulin for treatment of recurrent pregnancy loss: American experience. Am
J Reprod Immunol 1994; 32: 286-89.
3. Coulam CB, Clark DA, Scott JR, Schlesselman JS: Worldwide collaborative observational study and meta-analysis
on allogenic leukocyte immunotherapy for recurrent spontaneous abortion. Am J Reprod Immunol 1994; 32: 55-72.
4. Cowchock S: Autoantibodies and pregnancy loss. N Engl J Med 1997; 337: 197-98.
5. Daly, DC, Maier D, Soto-Albors C: Hysteroscopic metroplasty: six years' experience. Obstet Gynecol 1989; 73:201-5.
6. Feinberg RF, Van Deerlin PG: Retrospective Analysis of Chromosomes (REACHTM): PCR-based strategies for analyzing
archival spontaneous abortion tissues. Abstract O-088, Oral Presentation, 53rd Annual Meeting of the American Society
for Reproductive Medicine, Cincinnati, Ohio, October 18-22, 1997.
7. Kutteh WH: Antiphospholipid antibody-associated recurrent pregnancy loss: Treatment with heparin and low-dose
aspirin is superior to low-dose aspirin alone. Am J Obstet Gynecol 1996; 174: 1584-89.
8. Lockwood CJ, Romero R, Feinberg RF, Clyne LP, Coster B, Hobbins JC: The prevalence and biological significance
of lupus anticoagulant and cardiolipin antibodies in a general obstetric population. Am J Obstet Gynecol 1989;
161: 369-73.
9. March CM, Israel, R: Hysteroscopic management of recurrent abortion caused by septate uterus. Am J Obstet Gynecol
1987; 156: 834-42.
10. Rand JH, Wu X-X, Andree HAM, Lockwood CJ, Guller S, Scher J, Harpel PC: Pregnancy loss in the antiphospholipid-antibody
syndrome - a possible thrombogenic mechanism. N Engl J Med 1997: 337: 154-160.
11. Stern JJ, Dorfmann AD, Gutierrez-Najar AJ, Cerrillo M, Coulam CB: Frequency of abnormal karyotypes among abortuses
from women with and without a history of recurrent spontaneous abortion. Fertil Steril 1996; 65: 250-53.
12. Yetman DL, Kutteh WH: Antiphospholipid antibody panels and recurrent pregnancy loss: prevalence of anticardiolipin
antibodies compared with other antiphospholipid antibodies. Fertil Steril 1996; 66: 540-46.
Additional Internet Resources:
http://www.info.med.yale.edu/obgyn/kliman
http://www.connix.com/~hygeia/
Dr. Feinberg would like to answer the numerous questions
he receives related to PCOS and fertility. However, the best medical advice you could obtain comes from your personal
physician who knows your medical history best. A list of Board-certified reproductive endocrinology and infertility
specialists throughout the country can be found at http://www.socrei.org
©Ronald F. Feinberg, MD, Ph.D.
This article formerly appeared as a RESOLVE MEDICAL SPOTLIGHT article
Reprinted with permission from Ronald F. Feinberg, MD, Ph.D
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