Abortamento de repetição - Epidemiologia,
etiologia, diagnóstico e conduta
Aust N Z J Obstet Gynaecol. 2006 Aug;46(4):316-22.
The epidemiology of recurrent miscarriage: a descriptive study of 1214
prepregnant women with recurrent miscarriage.
Yang CJ, Stone P, Stewart AW.
School of Medicine, The University of Auckland, Auckland, New Zealand.
AIMS: To describe the characteristics of the prepregnant population attending the Recurrent Miscarriage Clinic (RMC) at
the National Women's Hospital (NWH), Auckland, between 1986 and 2003, and to compare them with the overall
obstetric booking population of the hospital. METHODS: The identifying details of 1214 prepregnant women attending
the RMC were obtained. Both hospital and RMC records, which were kept separately, were retrospectively reviewed for
demographic information and results of diagnostic investigations. Data from Auckland residents who attended the clinic
were compared with data from all Auckland women booking or delivering at NWH. RESULTS: RMC attendees were older
than the general NWH population, but had similar parity. Clinic attendees had a higher incidence of personal and family
history of antepartum haemorrhage, fetal abnormalities, stillbirths and neonatal deaths than reported rates for the general
population. Chromosomal anomalies were detected in 86 women, reproductive tract anomalies were found in 142
women, and polycystic ovarian syndrome was detected in 49 women. The majority (52.7%) of women had no identifiable
cause for recurrent miscarriage detected. CONCLUSIONS: These data support the concept of women with recurrent
miscarriage being at high risk for adverse obstetric outcomes including fetal abnormalities, stillbirths and neonatal
deaths, even when the pregnancies are ongoing. We conclude that recurrent miscarriage is different from subfertility, and
provide information of use in planning care for such women.
PMID: 16866793 [PubMed - indexed for MEDLINE]
Lancet. 2006 Aug 12;368(9535):601-11.
Recurrent miscarriage.
Rai R, Regan L.
Department of Obstetrics and Gynaecology, St Mary's Campus, Imperial College London, Mint Wing, South Wharf Road,
London W2 1PG, UK.
Many human conceptions are genetically abnormal and end in miscarriage, which is the commonest complication of
pregnancy. Recurrent miscarriage, the loss of three or more consecutive pregnancies, affects 1% of couples trying to
conceive. It is associated with psychological morbidity, and has often proven to be frustrating for both patient and
clinician. A third of women attending specialist clinics are clinically depressed, and one in five have levels of anxiety that
are similar to those in psychiatric outpatient populations. Many conventional beliefs about the cause and treatment of
women with recurrent miscarriage have not withstood scrutiny, but progress has been made. Research has emphasised
the importance of recurrent miscarriage in the range of reproductive failure linking subfertility and late pregnancy
complications and has allowed us to reject practice based on anecdotal evidence in favour of evidence-based
management.
PMID: 16905025 [PubMed - indexed for MEDLINE]
Reprod Biomed Online. 2009 Sep;19(3):296-7.
How do you solve the problem of recurrent miscarriage?
Tzioras S, Polyzos NP, Economides DL.
Department of Obstetrics and Gynecology, Royal Free Hospital, London, UK. spyrostz@hotmail.com
Recurrent miscarriage is the loss of two or more consecutive pregnancies and affects 1% of couples trying to conceive. It
has proven to be frustrating for both patient and clinician. The majority of investigations and treatments offered remain
controversial. However, practice must be evidence based and unproven investigations and treatments should be
abandoned. Psychological support is of paramount importance since a significant number of women attending RM clinics
have high levels of anxiety or are clinically depressed. Setting up a RM clinic is important to provide a dedicated service
to couples with RM so as to avoid unnecessary and potentially harmful treatments, and also to recruit patients in trials
that will delineate causes and efficacy of treatments.
PMID: 19778472 [PubMed - in process]
Gynecol Obstet Invest. 2008;66(4):257-67. Epub 2008 Aug 1.
Multifactorial etiology of recurrent miscarriage and its scientific and clinical
implications.
Christiansen OB, Steffensen R, Nielsen HS, Varming K.
Fertility Clinic 4071, Rigshospitalet, Copenhagen, Denmark. obchr@post5.tele.dk
A considerable proportion of recurrent miscarriage (RM) cases are caused by recurrent chromosomally abnormal
conceptions. However, in younger patients and patients with multiple miscarriages, maternal causes seem to dominate.
No single biomarker with a high predictive value of maternally caused RM has been identified. Non-genetic biomarkers in
RM may not reflect conditions in the pregnant uterus and we rarely know whether they are causes or consequences of
miscarriage. Studies of genetic biomarkers are probably the best way to reveal the pathophysiological mechanisms
behind RM. Epidemiological and genetic studies suggest that RM due to maternal causes has a multifactorial
background. The risk of RM in each patient is probably determined by the interaction of many genetic variants and
environmental factors but only few of these have so far been identified. The genetic biomarkers for RM can probably be
classified into three groups: (1) variants associated with excessive inflammatory responses and autoimmunity; (2)
variants of importance for insulin and androgen sensitivity and turn-over, and (3) variants associated with thrombophilia.
Identification of these markers will require whole genome association studies comprising thousands of individuals.
Acknowledgement of the multifactorial background for RM has important implications for the management of patients in
clinical practice. (c) 2008 S. Karger AG, Basel.
PMID: 18679035 [PubMed - indexed for MEDLINE]
Am J Reprod Immunol. 2005 Apr;53(4):159-65.
Embryo aneuploidy screening for unexplained recurrent miscarriage: a
minireview.
Rubio C, Pehlivan T, Rodrigo L, Simón C, Remohí J, Pellicer A.
Instituto Valenciano de Infertilidad (IVI), University of Valencia, Spain.
PROBLEM: The aim of this study was to investigate the incidence of chromosomal abnormalities in unexplained
recurrent miscarriage (RM) patients and assess the role of pre-implantation genetic diagnosis (PGD) in preventing
subsequent pregnancy loss and improving pregnancy outcome. METHOD OF STUDY: Pre-implantation genetic
diagnosis was performed in 241 RM cycles and in 35 cycles in patients undergoing PGD for sex-linked diseases (control
group). Chromosomes 13, 16, 18, 21, 22, X and Y were analysed by fluorescence in situ hybridization. RESULTS: The
implantation and pregnancy rates in RM patients were 26.4 and 36.5% versus 20.6 and 29.0% in the control group,
respectively. The percentage of abnormal embryos was significantly increased in RM patients compared with controls.
CONCLUSIONS: Recurrent miscarriage is associated with a higher incidence of chromosomally abnormal embryos. In
vitro fertilization (IVF) plus PGD is an important step in the management of these couples. Copyright 2005 Blackwell
Munksgaard.
PMID: 15760376 [PubMed - indexed for MEDLINE]
J Obstet Gynaecol Res. 2009 Aug;35(4):609-22.
Recurrent pregnancy loss: a disease of inflammation and coagulation.
Kwak-Kim J, Yang KM, Gilman-Sachs A.
Departments of Obstetrics and Gynecology, Rosalind Franklin University of Medicine and Science/The Chicago Medical
School, North Chicago, IL, USA. Joanne.kwak-kim@rosalindfranklin.edu
Recurrent pregnancy loss (RPL) is one of the most common obstetrical complications. Multiple etiologies, such as
endocrine, anatomic, genetic, hematological and immunological causes have been reported for this devastating disease.
However, over half of the cases remain unexplained. Thrombotic/inflammatory processes are often observed at the
maternal-fetal interface as the final pathological assault in many cases of RPL, including those of unexplained etiologies.
In the present paper, cellular immune responses (T, natural killer [NK], natural killer-T [NKT], regulatory T [Treg] cells and
their cytokines) and autoimmune abnormalities of women with RPL are reviewed. In addition, metabolic diseases and
hematological conditions which often lead to thrombotic/inflammatory conditions are discussed in association with RPL.
Finally, current therapeutic options for RPL are reviewed.
PMID: 19751318 [PubMed - indexed for MEDLINE]
Curr Opin Obstet Gynecol. 1999 Oct;11(5):435-9.
Recurrent pregnancy loss: an update.
Kutteh WH.
Department of Obstetrics and Gynecology, The University of Tennessee, Memphis 38163-2116, USA.
wkutteh@utmem.1.utmem.edu
This review highlights recent studies that investigate causes and treatments for recurrent pregnancy loss. Generally the
causes of recurrent pregnancy loss are classified as genetic, endocrinologic, anatomic, immunologic, microbiologic, and
environmental. The majority of recent work has focused on potential autoimmune and alloimmune causes; however,
controversy still exists over appropriate testing and treatment. Reports have investigated the potential associations
between autoimmune factors (antithyroid antibodies and antiphospholipid antibodies) and alloimmune factors (natural
killer cells, cytotoxic T cells, and embryotoxic factors) and recurrent pregnancy loss. Increasingly, clinical reports are
suggesting intravenous immunoglobulin as a potential treatment for these immunologic problems. Several lines of
investigation have suggested certain hypercoagulable states as causative of recurrent pregnancy loss. New studies
relating recurrent pregnancy loss to endocrinologic aberrations (hyperprolactinemia and hyperandrogenism) as well as
social/environmental factors (stress, caffeine use, tobacco use, human immunodeficiency virus, and history of induced
abortion) have been made. A summary of proposed evaluation and treatment options is presented.
PMID: 10526918 [PubMed - indexed for MEDLINE]
Am J Reprod Immunol. 2009 Jul;62(1):9-24.
Anti-phospholipid antibodies and other immunological causes of recurrent foetal
loss--a review of literature of various therapeutic protocols.
Shetty S, Ghosh K.
National Institute of Immunohaematology (ICMR), KEM Hospital, Parel, Mumbai 400012, India.
PROBLEM: An immune-based aetiology is one of the several accepted causes for recurrent foetal loss (RFL). However,
most of the immunological theories have not fulfilled the criteria for causality. This is a review of the various
immunological causes of RFL and the outcome of different treatment protocols. METHOD OF STUDY: Both auto- and
alloimmune maternal immunological abnormalities have been proposed to account for foetal loss. Among the
autoimmune factors, anti-phospholipid antibodies (APAs) have been demonstrated to be the strongest risk factors for
foetal loss, the prevalence of which is as high as 40% in women with RFL. Other autoimmune antibodies implicated in
RFL are anti-nuclear antibodies (ANAs), anti-thyroid antibodies and anti-endothelial cell antibodies. The alloimmune
factors implicated in pregnancy loss of unknown aetiology include abnormal natural killer (NK) cell activity, alteration in T
helper 1 (Th1) and T helper 2 (Th2) ratios, presence of alloimmune antibodies like anti-paternal cytotoxic antibodies, antiidiotypic antibodies, mixed lymphocyte reaction blocking antibodies and abnormal expression of HLA-G molecules.
Management of patients with RFL is mainly based on immunomodulatory (prednisolone, intravenous immunoglobulins,
plasma exchange, paternal lymphocyte therapy), anti-aggregation (aspirin) or anti-coagulation (unfractionated or low
molecular weight heparin) agents. RESULTS: Low-molecular-weight heparin with low-dose aspirin has been found to be
the most effective treatment for women with APAs and RFL. Differences in dosage, timing of treatment, inclusion criteria,
outcome assessment parameters etc. are some of the factors which have resulted in discrepancies in various reports.
CONCLUSION: Identification of the immunological mechanisms involved in pregnancy loss and the action of different
therapeutic reagents is important so that effective therapies can be designed and investigated.
PMID: 19527228 [PubMed - indexed for MEDLINE]
Best Pract Res Clin Obstet Gynaecol. 2008 Apr;22(2):375-89. Epub 2007 Oct 29.
Progesterone for recurrent miscarriage: truth and deceptions.
Walch KT, Huber JC.
Department of Obstetrics and Gynaecology, Division of Gynaecological Endocrinology and Reproductive Medicine,
Medical University of Vienna, Waehringer Guertel 18-20, A - 1090 Vienna, Austria. katharina.walch@meduniwien.ac.at
Recurrent miscarriage is known to affect 0.5-2% of pregnant women, and the standard investigative protocol fails to
identify a specific cause in 50% of cases. Progesterone, a key hormone in pregnancy maintenance, has been used to
support early pregnancy for decades. A growing body of considerable evidence indicates that in addition to women with
luteal phase defects, women with idiopathic recurrent miscarriage may benefit from progestogen treatment, as
progesterone has been shown to be an essential immunomodulatory agent in early pregnancy. It plays a critical role in
the expression, modulation and inhibition of various growth factors, cytokines, cell adhesion molecules and decidual
proteins. Some studies have revealed a remarkable improvement in pregnancy outcome after progestogen
supplementation in women suffering from recurrent miscarriage. As most studies on this topic are of unsufficient
statistical power, further research on the efficacy of progestogen treatment in affected women is required.
PMID: 17964858 [PubMed - indexed for MEDLINE]
Clin Lab. 2007;53(5-6):309-14.
Recurrent pregnancy loss and thrombophilia.
Di Micco P, D'uva M, Strina I, De Placido G, Di Fiore R, Quaranta S, Castaldo G.
Internal Medicine Division, Buonconsiglio Fatebenefratelli Hospital of Naples, Naples, Italy. pdimicco@libero.it
In the last decades we found many data concerning the association between a hypercoagulable state and its causes and
adverse pregnancy outcome, in particular recurrent pregnancy loss (RPL). Although first studies were focused only on
the association between thrombophilia and RPL, subsequent studies underlined also a potential role of antithrombotic
treatment to prevent vascular complication such as venous thromboembolism (VTE) during pregnancy. Now, emerging
data seem to be available also on the role of active thromboprophylaxis with heparin and pregnancy outcome. This
review will be focused on the recent knowledge between thrombophilia, hypercoagulable state, RPL, VTE and future
perspectives.
PMID: 17605406 [PubMed - indexed for MEDLINE]
Semin Hematol. 2007 Apr;44(2):93-7.
Pregnancy failure and heritable thrombophilia.
Middeldorp S.
Department of Clinical Epidemiology, and Vascular Medicine Unit, Leiden University Medical Center, Leiden, The
Netherlands. s.middeldorp@lumc.nl
Heritable thrombophilia is associated with an increased risk for pregnancy failure, defined as sporadic and recurrent
miscarriage, late fetal loss, and other vascular pregnancy complications such as preeclampsia and intrauterine growth
retardation. The pathogenesis is likely to include effects on trophoblast differentiation and not solely hypercoagulability.
This is in line with the observation that most recurrent miscarriages occur early. Therapeutic options include aspirin as
well as low-molecular-weight heparin. However, in women with heritable thrombophilia and unexplained recurrent
pregnancy loss, evidence is not available as published trials have not used an adequate comparator (no treatment or
placebo). Currently, randomized controlled trials with no treatment or placebo are being carried out and results should be
awaited before implementing a potentially harmful intervention in pregnant women with heritable thrombophilia and a
history of pregnancy failure. Both infertility and pregnancy failure are extremely distressing for couples with the desire to
have children. Pregnancy failure comprises (recurrent) early miscarriage, as well as late pregnancy loss. The role of
heritable thrombophilia in pregnancy failure is reviewed, with a focus on recurrent miscarriage, in terms of epidemiology,
etiology, and potential therapeutic implications.
PMID: 17433901 [PubMed - indexed for MEDLINE]
Clin Obstet Gynecol. 2007 Mar;50(1):132-45.
Evaluation and management of recurrent early pregnancy loss.
Stephenson M, Kutteh W.
Section of Reproductive Endocrinology and Infertility, University of Chicago, Chicago, Illinois, USA.
mstephen@babies.bsd.uchicago.edu
Recurrent pregnancy loss affects up to 5% of couples trying to establish a family. Evaluation classically begins after 3
consecutive miscarriages of less than 10 weeks of gestation but may be warranted earlier if a prior miscarriage was
found to be euploid, or if there is concomitant infertility and/or advancing maternal age. The evaluation begins with an
extensive history and physical, followed by a diagnostic screening protocol. Management must be evidence-based;
unproven treatments should be avoided. If no factor is identified, many couples will still eventually have a successful
pregnancy outcome with supportive therapy alone.
PMID: 17304030 [PubMed - indexed for MEDLINE]
Gynecol Obstet Fertil. 2006 Oct;34(10):927-37. Epub 2006 Sep 20.
[Early recurrent spontaneous abortion: How to take care in 2006?]
[Article in French]
Lejeune V.
Service de gynécologie-obstétrique, centre hospitalier général, allée Marie-Clarac, 32000 Auch, France. v.lejeune@chauch.sante32.com
More than 1% of the couples whishing children suffer from recurrent miscarriage, but investigations and treatment are
not consensual. Most patients have several risk factors, and a minimum investigation of known factors has to be
undertaken: karyotyping of the couple, hysteroscopy for searching uterine anatomic anomalies, evaluation for
thrombophilias (anticardiolipin antibodies, lupus anticoagulant, protein C activity, Proteine S activity, factor V Leiden and
factor II mutations, activated protein C resistance), antinuclear antibodies. Systemic diseases (like lupus) and endocrine
abnormalities (like thyroid diseases and diabetes mellitus) have to be detected by clinical examination and questioning.
No endocrine investigation is recommended, unless irregular menstruations or sterility. Research in recurrent pregnancy
loss are conducted in new associated factors, such as skewed-X-chromosome inactivation, maternal HLA types,
modifications in specific immune molecules and cells regulation. Therapeutic proposals are preimplantation genetic
diagnosis in case of abnormal karyotiping, hysteroscopic surgery for septate uterus, aspirin plus heparin in
antiphospholipid-positive patients, and aspirin plus corticosteroids in systemic lupus. Heparin seems to improve
obstetrical prognosis for patients with congenital or acquired thrombophilias, but there are only few studies carried out on
the subject. This new therapeutic approach should incite the patients with a negative medical appraisal to be referred to
specialized consultations in order to include them in eventual clinical tests. Finally, empathic listening and psychological
support are necessary in a pathology with multiple etiological factors.
PMID: 16987688 [PubMed - indexed for MEDLINE]
Obstet Gynecol Clin North Am. 2006 Sep;33(3):429-42.
Thrombophilia and recurrent pregnancy loss.
Carp HJ.
Department of Obstetrics and Gynecology, Sheba Medical Center, Tel Hashomer, 52621 Israel, Tel Aviv University,
Ramat Aviv, 69978, Israel. carp@netvision.net.il
Many unanswered questions regarding thrombophilia and recurrent pregnancy loss exist. For example, does a true
association exist? Are thrombotic mechanisms relevant? Is a second messenger necessary to cause the manifestation of
thrombosis? At present it seems that thrombophilia are associated with and may even cause some cases of pregnancy
loss. The role of treatment remains to be determined. Although the aim of physicians working in this field is entirely
laudable, to allow childless couples to have children, it is necessary to have good evidence of effect before treatment is
given to all patients. A serious ethical dilemma remains, however, namely should treatment that may be effective be
denied to patients who have prior pregnancy losses? Denial of treatment is extremely distressing for the patient and the
physician. The author's own practice is to offer treatment after a full explanation, particularly because treatment is
generally prescribed in the antiphospholipid syndrome and justified in hereditary thrombophilias according to the report of
Carp and colleagues, showing a 25% improvement in live birth rates in treated patients. When treatment fails, however,
the embryo should be karyotyped to exclude chromosomal aberrations.
PMID: 16962919 [PubMed - indexed for MEDLINE]
J Reprod Med. 2006 Apr;51(4):303-10.
Management of recurrent early pregnancy loss.
Stephenson MD.
Section of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Chicago,
5841 South Maryland Avenue (MC 2050), Chicago, IL 60637, USA. mstephen@babies.bsd.uchicago.edu
Recurrent pregnancy loss is a devastating health problem that affects many couples who are trying to establish a family.
Evaluation depends on a number of factors, including the pattern of pregnancy loss, underlying medical disease and lifestyle issues. A detailed obstetric history, including gestational age at the time of death, ultrasound, pathology and
cytogenetic results, is key in the evaluation and management of recurrent pregnancy loss. This complex reproductive
disorder requires a multidisciplinary approach since genetic, endocrinologic, anatomic, immunologic, infectious,
thrombophilic and iatrogenic factors may require evaluation and management. Monitoring of subsequent pregnancies
requires close supportive care.
PMID: 16737026 [PubMed - indexed for MEDLINE]
Semin Reprod Med. 2006 Feb;24(1):54-66.
Thrombophilias and recurrent pregnancy loss.
Kutteh WH, Triplett DA.
University of Tennessee, Memphis, Memphis, Tennessee 38120-2363, USA. wkutteh@utmem.edu
Thrombophilia by definition represents acquired and/or genetic conditions that predispose patients to both venous and
arterial thromboembolic events. Thrombosis is the most common cause of death worldwide. On the arterial side,
myocardial infarction and stroke result in significant morbidity and mortality. Venous thromboembolic events most
commonly involve the deep veins of the lower extremity with potential complications of pulmonary emboli. Pregnancy is a
hypercoagulable state, and thromboembolism is the leading cause of antepartum and postpartum maternal mortality.
With the description by Dahlback in 1993 of a condition initially labeled activated protein C resistance, significant
advances have rapidly followed. Activated protein C resistance was linked to an underlying point mutation resulting in
coagulation factor V (factor V Leiden). Recent attention has focused on certain inherited thrombophilic factors that may
predispose to arterial and/or venous thromboses and their possible association with pregnancy complications, including
early pregnancy loss. These include a group of mostly autosomal dominant, inherited gene mutations leading to a
hypercoagulable state, such as factor V Leiden G1691A, factor II or prothrombin G20210A, and hyperhomocysteinemia
associated with methylenetetrahydrofolate reductase C677T mutation. In addition, deficiencies in protein S, protein C,
and antithrombin can lead to a hypercoagulable state. Although some studies of recurrent pregnancy loss patients with a
positive test for an inherited thrombophilia are conflicting, a case-control study of untreated recurrent miscarriage
patients who were heterozygous for the factor V Leiden mutation revealed a lower success rate than the controls who
had a history of idiopathic recurrent miscarriage. With the identification of genetic risk factors, there has been synergistic
amplification of thrombotic risk when one has an abnormal gene (e.g., factor V Leiden) plus environmental issues (e.g.,
pregnancy). Current understanding indicates that a combination of risk factors, including multiple inherited thrombophilic
defects associated with secondary hypercoagulable states, have a particularly strong association with adverse
pregnancy outcome.
PMID: 16418978 [PubMed - indexed for MEDLINE]
Semin Reprod Med. 2006 Feb;24(1):33-9.
Endocrinology of recurrent pregnancy loss.
Arredondo F, Noble LS.
Division of Reproductive Endocrinology and Infertility, Case Western Reserve University, Cleveland, Ohio, USA.
Following implantation, the maintenance of the pregnancy is dependent on a multitude of endocrinological events that
will eventually aid in the successful growth and development of the fetus. Although the great majority of pregnant women
have no pre-existing endocrine abnormalities, a small number of women can have certain endocrine alterations that
could potentially lead to recurrent pregnancy losses. It is estimated that approximately 8 to 12% of all pregnancy losses
are the result of endocrine factors. During the preimplantation period, the uterus undergoes important developmental
changes stimulated by estrogen, and more importantly, progesterone. Progesterone is essential for the successful
implantation and maintenance of pregnancy. Therefore, disorders related to inadequate progesterone secretion by the
corpus luteum are likely to affect the outcome of the pregnancy. Luteal phase deficiency, hyperprolactinemia, and
polycystic ovarian syndrome are some examples. Several other endocrinological abnormalities such as thyroid disease,
hypoparathyroidism, uncontrolled diabetes, and decreased ovarian reserve have been implicated as etiologic factors for
recurrent pregnancy loss.
PMID: 16418976 [PubMed - indexed for MEDLINE]
Semin Reprod Med. 2006 Feb;24(1):25-32.
Anatomic factors in recurrent pregnancy loss.
Devi Wold AS, Pham N, Arici A.
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Yale University School
of Medicine, New Haven, Connecticut, USA.
Anatomic uterine defects are present in 15% of women evaluated for three or more consecutive spontaneous abortions.
These anatomic abnormalities can be classified as congenital or acquired. In addition to pregnancy loss, uterine
malformations appear to predispose women to other reproductive difficulties including infertility, preterm labor, and
abnormal presentation. These poor reproductive outcomes resulting from uterine septum, intrauterine adhesions, polyps,
and fibroids are amenable to surgical correction. Therefore, it is essential to make an accurate diagnosis to offer an
adequate treatment. In this article, we review the common congenital and acquired uterine anomalies associated with
recurrent pregnancy losses, and discuss contemporary diagnosis and treatment options.
PMID: 16418975 [PubMed - indexed for MEDLINE]
Semin Reprod Med. 2006 Feb;24(1):17-24.
Genetics of recurrent pregnancy loss.
Sierra S, Stephenson M.
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynaecology, University of British
Columbia, Vancouver, British Columbia, Canada.
Recurrent pregnancy loss (RPL) is a devastating reproductive problem affecting approximately 5% of couples trying to
conceive. Genetic factors appear to be highly associated with reproductive loss. In this article, genetic factors are
reviewed in terms of random numerical chromosome errors in miscarriage specimens and carriers of structural
chromosome rearrangements that may result in unbalanced chromosome errors in pregnancies. Recently, research has
generated interest in genetic markers for recurrent loss such as skewed X-chromosome inactivation and human
leukocyte antigen-G polymorphisms. Assisted reproductive technologies (specifically, preimplantation genetic diagnosis)
have been offered to couples with recurrent pregnancy loss; however, more data need to be evaluated before routine
use can be advocated. Management of genetic factors in RPL should include therapy based on the highest level of
evidence, genetic counseling, and close monitoring of subsequent pregnancies.
PMID: 16418974 [PubMed - indexed for MEDLINE]
Arch Gynecol Obstet. 2005 Jul;272(2):95-108. Epub 2005 May 19.
An update in recurrent spontaneous abortion.
Pandey MK, Rani R, Agrawal S.
Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center, MLC 7021 TCH RF 5503 3333 Burnet
Avenue, Cincinnati, OH, 45229-3039, USA. Manoj.Pandey@cchc.org
Recurrent spontaneous abortion (RSA) is defined as three or more consecutive pregnancy losses prior to the 20th week
of gestation. The etiology of recurrent spontaneous abortion is often unclear and may be multifactorial, with much
controversy regarding diagnosis and treatment. Reasonably accepted etiologic causes include, genetics, anatomical,
endocrine, placental anomalies, hormonal problems, infection, smoking and alcohol consumption, exposure to
environmental factors, psychological trauma and stressful life event, certain coagulation and immunoregulatory protein
defects. Detection of an abnormality in any of these areas may result into specific therapeutic measures, with varying
degrees of success. However, the majority of cases of RSA remains unexplained and is found to be associated with
certain autoimmune (APA, ANA, ACA, ATA, AECA) and alloimmune (APCA, Ab2, MLR-Bf) antibodies that may play
major role in the immunologic failure of pregnancy and may lead to abortion. Alteration in the expression of HLA-G
molecules, T-helper-1 (Th-1) pattern of cytokines and natural killer (NK) cells activity may also induce abortion. Various
forms of treatment like antithrombotic therapies such as aspirin and heparin, intravenous immunoglobulin (IVIg) therapy,
immunotherapy with paternal lymphocytes and vitamin D3 therapy are effective mode of treatment for unexplained cause
of fetal loss in women with RSA.
PMID: 15906053 [PubMed - indexed for MEDLINE]
Fertil Steril. 2005 Apr;83(4):821-39.
Evidence-based investigations and treatments of recurrent pregnancy loss.
Christiansen OB, Nybo Andersen AM, Bosch E, Daya S, Delves PJ, Hviid TV, Kutteh WH, Laird SM, Li TC, van der Ven
K.
Fertility Clinic 4071, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. obc@pregnancyloss.dk
Comment in:

Fertil Steril. 2005 Sep;84(3):813; author reply 813-4.

Fertil Steril. 2006 Mar;85(3):812-3.
OBJECTIVE: To give an overview of currently used investigations and treatments offered to women with recurrent
pregnancy loss (RPL) and, from an evidence-based point of view, to evaluate the usefulness of these interventions.
DESIGN: Ten experts on epidemiologic, genetic, anatomic, endocrinologic, thrombophilic, immunologic, and
immunogenetic aspects of RPL discussed methodologic problems threatening the validity of research in RPL during and
after an international workshop on the evidence-based management of RPL. CONCLUSION(S): Most RPL patients have
several risk factors for miscarriage, and an extensive investigation for all major factors should always be undertaken.
There is an urgent need for agreement concerning the thresholds for detecting what is normal and abnormal, irrespective
of whether laboratory tests or uterine abnormalities are concerned. A series of lifestyle factors should be reported in
future studies of RPL because they might modify the effect of laboratory or anatomic risk factors. More and larger
randomized controlled trials, including trials of surgical procedures, are urgently needed, and to achieve this objective
multiple centers have to collaborate. Current meta-analyses evaluating the efficacy of treatments of RPL are generally
pooling very heterogeneous patient populations and treatments. It is recommended that future meta-analyses look at
subsets of patients and treatment protocols that are more combinable.
PMID: 15820784 [PubMed - indexed for MEDLINE]
Best Pract Res Clin Obstet Gynaecol. 2005 Feb;19(1):85-101.
Evidence-based care of recurrent miscarriage.
Porter TF, Scott JR.
Department of Obstetrics and Gynecology, University of Utah Health Sciences Center, Maternal-Fetal Medicine, LDS
Hospital, 8th Avenue and C Street, Salt Lake City, Utah 84143, USA. ldtporte@ihc.com
Between 0.5 and 1.0% of couples experience recurrent pregnancy loss (RPL), which is defined as three or more
consecutive miscarriages. Losses are classified as pre-embryonic (<5 weeks), embryonic (5-10 weeks) or fetal (>10
weeks). Genetic abnormalities are responsible for RPL in 2-4% of these couples. Inadequate progesterone production
has been proposed a cause of RPL and progesterone is given to prevent miscarriage, despite a lack of supportive
evidence. The factor V Leiden and prothrombin G20210A mutations are common inherited thrombophilias also
associated with RPL. Antenatal thromboprophylaxis is sometimes recommended although no data exist regarding
efficacy. Antiphospholipid syndrome is known to cause RPL and antenatal thromboprophylaxis reduces the risk of
miscarriage. Uterine abnormalities might also result in RPL. About 50% of cases of RPL have no identifiable cause.
Alloimmune incompatibility has been proposed as a cause for RPL in these women. The concept of alloimmune-related
RPL has not been scientifically validated.
PMID: 15749068 [PubMed - indexed for MEDLINE]
Eur J Obstet Gynecol Reprod Biol. 2005 Feb 1;118(2):143-53.
Thrombophilias and recurrent pregnancy loss: a critical appraisal of the
literature.
Krabbendam I, Franx A, Bots ML, Fijnheer R, Bruinse HW.
Department of Perinatology and Gynaecology, University Medical Centre Utrecht, 3508 AB Utrecht, The Netherlands.
Thrombophilias are suggested to play a role in recurrent miscarriage. The aim of this study was to evaluate the literature
of the past 10 years regarding the association between thrombophilias and recurrent miscarriage. We concluded that
there is a large variety in applied study methodology. Therefore, we defined criteria for an adequate study on the
relationship of thrombophilias on recurrent pregnancy loss: (i) no exclusion criteria for patients or at least the same
criteria for patients and controls; (ii) a clear definition of the gestational age at previous losses; (iii) a well-described
control group; (iv) clear description of the test methods and moment of testing; and (v) a clear description of the (non)
significant differences or odds ratio between cases and controls. Eleven out of 69 studies fulfilled these criteria. Their
results show significant higher serum homocysteine levels among women with a history of recurrent miscarriage. No
relation was found between recurrent miscarriage and the methylenetetrahydrofolate reductase C667T mutation. No
relation was observed for the levels of antithrombin, protein C and protein S. Seven studies on the association of factor V
Leiden (FVL) and/or pathologic activated protein C ratio (pAPCR) showed that FVL may play a role in second trimester
losses, as do antiphospholipid antibodies. Studies on the prothrombin gene mutation yielded conflicting results.
Consequently, large prospective studies according to the aforementioned criteria are needed to establish if there is a
relationship between thrombophilias and recurrent miscarriage at all. At present, there is only justification for testing for
homocysteine levels, antiphospholipid antibodies and FVL in women with a history of recurrent miscarriage.
PMID: 15653194 [PubMed - indexed for MEDLINE]
J Reprod Immunol. 2004 Jun;62(1-2):41-52.
Active or passive immunization in unexplained recurrent miscarriage.
Christiansen OB, Nielsen HS, Pedersen B.
Fertility Clinic 4071, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. obc@pregnancyloss.dk
Controversy exists as to whether active immunotherapy with allogeneic lymphocyte transfusions (ALT) or passive
immunotherapy with intravenous immunoglobulin (IvIg) improve the chance of live birth in women with unexplained
recurrent miscarriages (RM). Meta-analyses of the placebo-controlled trials carried out as Cochrane reviews have
concluded than none of the different forms of immunotherapy has proved effective in the total RM population. However,
the included trials have generally been small and very heterogenous with respect to the clinical histories of patients and
the immunization protocols. Thus, other meta-analyses which have looked at the efficacy in subgroups of RM patients
have reported that ALT and IvIg may be effective in women with primary RM and secondary RM, respectively. In RM
clinics in Denmark, ALT with donor lymphocytes or IvIg immunotherapy have been tested in several placebo-controlled
trials since 1986 in which greater doses than used in other trials have been administered, and both treatments are now
used for routine therapy. Our results have convinced us that using the correct immunization protocols on the right
subsets of RM patients is effective, but we admit that new placebo-controlled trials focusing on subsets of RM patients
are now urgently needed. Furthermore, treated patients should be extensively monitored for changes in a series of
immune parameters that may predict pregnancy success and be of importance for our understanding of the mechanisms
of action of immunotherapy in RM.
PMID: 15288180 [PubMed - indexed for MEDLINE]
Curr Opin Obstet Gynecol. 1997 Aug;9(4):279-82.
Antiphospholipid antibodies, infertility and recurrent miscarriage.
Rai R, Regan L.
Department of Obstetrics and Gynaecology, Imperial College School of Medicine at St Mary's, London, UK.
Antiphospholipid antibodies are found in 15% of women with recurrent miscarriage. These women have only a 10% live
birth rate in subsequent pregnancies in which no pharmacological treatment is given. Pregnancy loss is often attributable
to uteroplacental insufficiency subsequent to placental thrombosis. Treatment with low dose aspirin improves the live
birth rate amongst women with antiphospholipid antibodies to 40% but this is further and significantly increased to 70%
when they are treated with aspirin together with low-dose heparin.
PMID: 9263721 [PubMed - indexed for MEDLINE]
Curr Opin Obstet Gynecol. 1996 Dec;8(6):449-53.
Recurrent second trimester miscarriage.
Flint S, Gibb DM.
Department of Obstetrics and Gynaecology, King's College Hospital, London, UK.
Understanding the aetiology of a second trimester miscarriage allows the obstetrician to assess the recurrence risk in the
next pregnancy and guides future management. Causes include anatomical abnormalities, cervical incompetence,
genital tract infection, multiple pregnancy, auto-immune factors, vaginal bleeding, and fetal abnormalities. Transvaginal
ultrasound of the cervix in pregnancy may have a role in the diagnosis of cervical incompetence. There is an association
between genital tract infection and second trimester miscarriage, but the value of antibiotics in the prevention of
miscarriage is still to be defined.
PMID: 8979017 [PubMed - indexed for MEDLINE]