eMedicine Specialties > Obstetrics and Gynecology > General Gynecology

Early Pregnancy Loss

Author: John C Petrozza, MD, Instructor, Department of Obstetrics and Gynecology, Harvard Medical School; Consulting Staff and Chief, Division of Reproductive Medicine and IVF, Vincent Obstetrics and Gynecology, Massachusetts General Hospital
Coauthor(s): Gerard A Malanga, MD, Associate Professor, Department of Physical Medicine and Rehabilitation, University of Medicine and Dentistry at New Jersey, New Jersey Medical School; Director of Pain Management, Overlook Hospital; Director of Sports Medicine, Mountainside Hospital; Barbara O'Brien, MD, Staff Physician, Department of Obstetrics and Gynecology, New England Medical Center, Tufts University
Contributor Information and Disclosures

Updated: Aug 29, 2006

Introduction

For both the physician and the patient, early pregnancy loss is a frustrating and heart-wrenching experience. Early pregnancy loss is unfortunately the most common complication of human gestation, occurring in at least 75% of all women trying to conceive. Most of these losses are unrecognized and occur before or with the next expected menses. Of those that are recognized, 15-20% are spontaneous abortions (SABs) or ectopic pregnancies diagnosed after the pregnancy is clinically recognized. Approximately 5% of couples trying to conceive have 2 consecutive miscarriages, and approximately 1% of couples have 3 or more consecutive losses.

Early pregnancy loss is defined as the termination of pregnancy before 20 weeks' gestation or with a fetal weight of <500 g. Most investigators agree that both ectopic and molar pregnancies should not be included in the definition. Table 1 provides specific definitions.

Table 1: Terms Used to Describe Pregnancy Loss

Open table in new window

For excellent patient education resources, visit eMedicine's Pregnancy and Reproduction Center. Also, see eMedicine's patient education articles Miscarriage, Ectopic Pregnancy, Abortion, and Dilation and Curettage (D&C).

Incidence

The incidence of spontaneous miscarriage is10-15%, whereas the rate of recurrent miscarriage is 3-5%.

Most studies demonstrate a spontaneous miscarriage rate of 10-15%. However, the true rate of early pregnancy loss is close to 50% because of the high number of chemical pregnancies that are not recognized in the 2-4 weeks after conception. Most of these pregnancy failures are due to gamete failure (eg, sperm or oocyte dysfunction). In a classic study by Wilcox et al in 1988, 221 women were followed up during 707 total menstrual cycles. A total of 198 pregnancies were achieved. Of these, 43 (22%) were lost before the onset of menses, and another 20 (10%) were clinically recognized losses.

The likelihood for an SAB increases with each successive abortion. Data from various studies indicate that, after 1 SAB, the baseline risk of a couple having another SAB is approximately 15%. However, if 2 SABs occur, the subsequent risk increases to approximately 30%. The rate is higher for women who have not had at least 1 liveborn infant. Several groups have estimated that the risk of pregnancy loss after 3 successive abortions is 30-45%. Therefore, controversy exists regarding how many pregnancy losses should occur before a diagnostic evaluation is considered. One could argue that the diagnostic evaluation should be performed after 2 losses rather than 3 because diagnostic yields after 2 versus 3 miscarriages are identical.

Etiology

The etiology of early pregnancy loss is varied and often controversial. More than 1 etiologic factor is often present. The most common causes of recurrent miscarriages are as follows:

• Genetic causes
  • Mendelian disorders
  • Genetic translocations
  • Multifactorial disorders
  • Chromosomal inversions
  • Sex-chromosome aneuploidies
• Autoimmune causes
  • Immunologic causes
  • Alloimmune causes
• Anatomic causes
  • Uterine müllerian anomaly
    • Uterine septum (the anomaly most common associated with pregnancy loss)
    • Hemiuterus (unicornuate uterus)
    • Bicornuate uterus
  • Diethylstilbestrol-linked condition
  • Acquired defects (eg, Asherman syndrome)
  • Incompetent cervix
  • Leiomyomas
  • Uterine polyps
• Infectious causes
• Environmental causes
  • Smoking
  • Excessive alcohol consumption
• Endocrine factors
  • Diabetes mellitus
  • Antithyroid antibodies
  • Luteal-phase deficiency
• Hematologic disorders

The gestational age at the time of the SAB can provide clues about the cause. For instance, nearly 70% of SABs in the first 12 weeks are due to chromosomal anomalies. However, losses due to antiphospholipid syndrome (APS) and cervical incompetence tend to occur after the first trimester.

Genetic Causes

Most spontaneous miscarriages are caused by an abnormal (aneuploid) karyotype of the embryo. At least 50% of all first-trimester SABs are cytogenetically abnormal. (Note that this figure does not include abnormalities caused by single genetic disorders, such as Mendelian disorders or mutations at several loci. Examples are polygenic or multifactorial disorders that are not detected by evaluating karyotypes.)

The highest rate of cytogenetically abnormal concepti occurs earliest in gestation, with rates declining after the embryonic period (>30 mm crown-rump length). The rate of normal (euploid) and abnormal (aneuploid) abortuses increases with maternal age.

Recurrent miscarriage may result from 2 chromosomal abnormalities: (1) a structural abnormality derived from 1 parent or (2) the recurrence of a numerical abnormality, which is usually not inherited.

Aneuploidy

Cytogenetically abnormal embryos are usually aneuploid because of sporadic events, such as meiotic nondisjunction, or polyploid from fertilization abnormalities. One half the cytogenetically abnormal abortuses in the first trimester involve autosomal trisomy. Triploidy is found in 16% of abortions, with fertilization of a normal haploid ovum by 2 sperm (dispermy) as the primary pathogenic mechanism. Trisomies may arise de novo because of meiotic nondisjunction during gametogenesis in parents with a normal karyotype. For most trisomies, maternal meiosis I errors have been implicated. Abnormal meiotic segregation results in either complete trisomies or monosomies.

Trisomy 16, which accounts for 30% of all trisomies, is the most common. Viable trisomies have been observed for chromosomes 13, 16, and 21. Approximately one third of fetuses with Down syndrome (trisomy 21) fetuses survive to term. All chromosome trisomies except for trisomy 1 are reported in abortuses.

Of interest, trisomy 1 is reported in embryos obtained with in vitro fertilization (IVF). This finding logically suggests that trisomy 1 is most likely lethal at the preimplantation stage.

Autosomal monosomies are rarely, if ever, observed. In contrast, monosomy X (Turner syndrome) is frequently observed, and it is the most common chromosomal abnormality observed in SABs. Turner syndrome accounts for 20-25% of cytogenetically abnormal abortuses.

Other abnormalities include those related to abnormal fertilization (eg, tetraploidy, triploidy). These abnormalities are not compatible with life. Tetraploidy occurs in approximately 8% of chromosomally abnormal abortions, resulting from failure of an early cleavage division in an otherwise normal diploid zygote.

Parental chromosomal abnormalities

Structural rearrangements occur in approximately 3% of cytogenetically abnormal abortuses. Structural chromosomal abnormalities are thought to be most commonly inherited from the mother. Of note, structural chromosomal problems found in men often to lead to low sperm concentrations, male infertility, and, therefore, a reduced likelihood of pregnancy and miscarriage. The exception to this situation is the couple undergoing assisted reproductive technologies in which selected sperm can be injected into oocytes to force fertilization by using potentially genetically abnormal sperm.

Among structural rearrangements, translocations (most commonly reciprocal and Robertsonian) can be balanced or unbalanced. The incidence of translocations increases with the number of abortions. Slightly more than one half of unbalanced rearrangements result from abnormal segregation of Robertsonian translocations. Approximately one half of all unbalanced translocations arise de novo during gametogenesis. In reciprocal translocations, children created from these gametes have normal and carrier karyotypes. Adjacent segregation results in unbalanced distribution of the chromosomes involved in the translocation, leading to partial trisomy for 1 chromosome and partial monosomy for the other chromosome. The severity of the phenotype depends on the chromosomes involved and on the positions of their breakpoints. The risk is increased if the female partner carries the translocation.

Other structural rearrangements, such as inversions or ring chromosomes, are relatively rare. These chromosomal abnormalities can be associated with congenial malformations and mental retardation, as well as SAB.

Genetic abnormalities

Certain genetic mutations thought to be involved with implantation may predispose a patient to infertility or even miscarriage. An example of a single gene disorder associated with recurrent pregnancy loss is myotonic dystrophy, an autosomal dominant neuromuscular disorder with high penetrance. The cause of the abortion is unknown, but it may be related to abnormal gene interactions combined with disordered uterine function.

Other presumed autosomal dominant disorders include lethal skeletal dysplasias (eg, thanatophoric dysplasia and type II osteogenesis imperfecta).

Maternal disease associated with increased fetal wastage includes connective tissue disorders, such as Marfan syndrome, Ehlers-Danlos syndrome, homocystinuria, and pseudoxanthoma elasticum.

Hematologic abnormalities associated with recurrent pregnancy loss include dysfibrinogenemia, factor XIII deficiency, congenital hypofibrinogenemia and afibrinogenemia, and sickle cell anemia.

Women with sickle cell anemia are at increased risk for fetal loss, possibly because of placental-bed microinfarcts.

Management

For couples who have had an SAB due to a suspected genetic cause, the standard of care is to offer genetic counseling. Because advanced age increases the risk of an abnormal karyotype in a conceptus, amniocentesis is routinely offered for all pregnant women of advanced maternal age, which is defined as women older than 35 years. A woman's risk of having an aneuploid fetus is 1 per 80 when she is older than 35 years; this is far greater than the inherent risk of fetal loss after amniocentesis, which is 1 per 200.

A study by Warburton et al indicated that routine karyotype analysis after 1 miscarriage is not cost-effective or prognostic. However, after 2 SABs, analysis of the abortuses is useful. In 1990, Drugan et al examined 305 women with 2 or more miscarriages and found an increased risk for fetal aneuploidy in these couples with chorionic villus sampling or amniocentesis. Therefore, couples with recurrent miscarriage should undergo karyotype evaluation by means of amniocentesis or chorionic villus sampling during a subsequent pregnancy.

Because karyotype analysis do not help in detecting abnormalities caused by single gene mutations or mutations at several loci (small structural deletions and rearrangements), techniques are being used more frequently now than before to complement standard cytogenetics. These abnormalities can be identified with specialized methods, such as fluorescence in situ hybridization (FISH). If a parental chromosome abnormality is found, this should be the starting point for familial testing. If an inherited abnormality is found, proper family counseling is recommended. If an increased risk for future pregnancies is identified, each alternative should be discussed, including foregoing any attempts at further conception, adopting, trying to conceive again with early prenatal testing, using donate sperm or oocytes, or performing preimplantation diagnosis (PGD).

Couples who have had SABs can use assisted reproductive technology and PGD to improve their fertility. PGD entails IVF, removal of a blastomere (cell) from the developing embryo for genetic analysis, and implantation into the uterus of only those embryos that are genetically normal. However, cells in the early embryo may not genetically similar, and an apparently normal embryo may be abnormal. Fortunately, several methods are used in PGD to detect chromosomal translocation imbalance by means of FISH involving single cells

PGD and FISH can be used to detect common aneuploidies (eg, those involving chromosomes 13, 18, and 21) with high accuracy, but these methods are criticized for their inability to detect all chromosomal abnormalities. PGD is currently used to evaluate approximately 8 of the 24 types of chromosomes, ie, 13, 15, 16, 17, 18, 21, X and Y. Abnormalities of these chromosomes are responsible for most early pregnancy losses. These represent approximately 70% of known genetic aneuploidic causes for first-trimester losses. Results from PGD have notably decreased SABs because the selection of chromosomally normal embryos for uterine transfer increases the likelihood for implantation.

In 2006, Munne et al reported that the a 40% rate of SABs before PGD decreased to 22% with PGD in women over 40. However, PGD is recommended for women of all ages if the other findings from their workup for pregnancy loss are negative.

Reported disadvantages of PGD include misdiagnosis of chromosomal normality, possible lowering of implantation rates with embryonic biopsy, and poor suitability of tested embryos for cryopreservation.

Given that the delivery rate for IVF is only 35% even if normal embryos are transferred, PGD has improved outcomes of viable pregnancies for couples with chromosomal translocations.

Indications for PGD include age, recurrent pregnancy loss, multiple IVF failures.

Immunologic Causes

Autoimmune abnormalities

Associations and predictive factors

Recurrent pregnancy loss is associated with autoimmune diseases. In specific terms, systemic lupus erythematosus (SLE) has been implicated in increasing the rate of miscarriage and pregnancy loss, as associated with antiphospholipid antibodies (APLAs) since 1954. APS is an autoimmune disorder in which patients have elevated levels of APLAs and recurrent pregnancy loss, fetal death, and/or thrombosis.

Compared with the general population, the median rate of spontaneous miscarriage among patients with SLE is 10%. However, the 8% median rate of late pregnancy loss (ie, loss in the second and third trimesters) is considerably higher than that observed in the healthy general population. In 75% of patients with SLE, excess pregnancy loss seems to be isolated to fetal death in the second and third trimesters. Most, if not all, fetal deaths in these women are associated with the presence of APLAs.

Three other factors that are predictive are disease before conception, an onset of SLE during pregnancy, and underlying renal disease.

At least 3 APLA findings are well known to have important clinical relevance: lupus anticoagulant (LAC), anticardiolipin antibodies (aCLs), and a biologically false-positive serologic test result for syphilis. APS, also known as LAC syndrome and Hugh syndrome, is diagnosed when both obstetric or medical findings are clinically present and when specific levels of APLAs are present.

Other obstetric and medical conditions associated with APLAs are listed below.

• Obstetric conditions associated with APLAs
  • Preeclampsia
  • Intrauterine growth restriction
  • Abnormal fetal heart rate tracings
  • Preterm deliveries
  • Pregnancy wastage
• Medical conditions associated with APLAs
  • Arterial and venous thrombosis
  • Autoimmune thrombocytopenia
  • Autoimmune hemolytic anemia
  • Livedo reticularis
  • Chorea
  • Pulmonary hypertension
  • Chronic leg ulcers

Classification of APS

The International Consensus Workshop in 1998 proposed preliminary classification criteria for APS, as follows:

• Vascular thrombosis
• Pregnancy morbidity
  • 3 or more unexplained consecutive miscarriages with anatomic, genetic, or hormonal causes excluded
  • 1 or more unexplained deaths of a morphologically normal fetus at or after the 10th week of gestation
  • 1 or more premature births of a morphologically normal neonate at or before the 34th week of gestation associated with severe preeclampsia or severe placental insufficiency
• Laboratory criteria
  • aCL: Immunoglobulin G (IgG) and/or immunoglobulin M (IgM) isotype is present in medium or high titer on 2 or more occasions 6 or more weeks apart.
  • Demonstration of a prolonged phospholipid-dependent coagulation on screening tests (eg, activated partial thromboplastin time, kaolin clotting time, dilute Russell viper venom time, dilute prothrombin time, Textarin time)
  • Failure to correct the prolonged screening test result by mixing with normal platelet-poor plasma
  • Shortening or correction of the prolonged screening test result with the addition of excess phospholipids
  • Exclusion of other coagulopathies as clinically indicated (eg, factor VIII inhibitor) and heparin

These antibodies can be demonstrated with enzyme-linked immunosorbent assay (ELISA) or a coagulation result positive for LAC. Therefore, the presence of the antibodies alone in the absence of other clinical symptoms does not define the syndrome. APLAs are found in fewer than 2% of apparently healthy pregnant women, in fewer than 20% of apparently healthy women with recurrent fetal loss, and in more than 33% of women with SLE.

Therapy

Anticoagulant treatments, such as aspirin, heparin, intravenous immunoglobulin interleukin (IL)-3, and ciprofloxacin, are effective therapies. Ciprofloxacin is thought to work by means of IL-3, which is hypothesized to act as a placental growth hormone and which can compensate for damaged placental tissue.

The thrombosis of APLA is thought to be caused by an increase in the thromboxane-to-prostacyclin ratio. Thromboxane production by the placenta can lead to thrombosis at the uteroplacental interface, which helps rationalize the use of low-dose aspirin therapy during pregnancies in women with APLA. Some authors have proposed that the thrombosis is secondary to enhanced platelet aggregation, decreased activation of protein C, increased expression of tissue factor, and enhanced platelet-activating factor synthesis.

Patients with the combination of high antibody titers and the IgG isotype have a prognosis worse than those with the combination of low titers and the IgM isotype. In addition, no difference is noted regarding whether the APLA is aCL, LAC, or anti–beta-2 glycoprotein I.

Treatment data are difficult to analyze because most studies are not randomized and do not include appropriate controls. In addition, the serologic criteria for APLA, the clinical definitions of APS, and the dosing regimens for treatments vary greatly among studies. Treatment of patients with APS who have had previous fetal losses seems to improve pregnancy rates, but fetal loss may occur despite treatment. Overall, most studies report increased pregnancy survival in women undergoing treatment for APLA.

Treatment consists of subcutaneous heparin, low-dose aspirin, prednisone, immunoglobulins, or their combinations. Several well-controlled studies showed that subcutaneous heparin 5000 U given twice a day with low-dose aspirin 81 mg/d increases fetal survival rates from 50% to 80% among women who have had at least 2 losses and who have unequivocally positive results for APLA. Treatment started after pregnancy was confirmed and continued until the end of the pregnancy (just before delivery). This therapy (ie, low-dose aspirin, subcutaneous heparin) is equally effective and less toxic than prednisone 40 mg/d plus aspirin.

In 1992, Branch et al reviewed 82 consecutive pregnancies in 54 women with APS who were treated during the pregnancy with the following: (1) prednisone and low-dose aspirin; (2) heparin and low-dose aspirin; (3) prednisone, heparin, and low-dose aspirin; or (4) other combinations of these medications or immunoglobulins. The overall neonatal survival rate was 73%, excluding SABs, but fetal and neonatal treatment failures occurred in all treatment groups. Patients with successfully treated pregnancies had fewer previous fetal deaths than those with unsuccessfully treated pregnancies. In addition, outcomes did not significantly differ among the 4 treatment groups.

Intravenous immunoglobulin (IVIG) therapy has been effective, decreasing fetal losses and also decreasing the incidence of preeclampsia and fetal growth restriction. However, to date, no properly controlled studies have been conducted. IVIG treatment is expensive and should not be used as first-line therapy until further data on its effectiveness are available.

Antinuclear antibodies (ANAs) have been associated with recurrent pregnancy loss, even in patients without evidence of overt autoimmune disease. In most published studies, the ANA titers in women with recurrent miscarriages were only mildly elevated. However, these mild elevations are nonspecific and common in the general population (even in those with no history of pregnancy loss). Therefore, extrapolating this as a cause is difficult. Further studies are needed to prove or disprove ANA as a causal agent in recurrent miscarriages, and measuring ANAs is not recommended as part of an evaluation of recurrent miscarriage.

Unlike ANA, antithyroid antibodies are independent markers for an increased risk of miscarriage. Stagnaro-Green et al (1990) observed 500 consecutive women for thyroid-specific autoantibodies (specifically, antithyroglobulin and/or antithyroid peroxidase) in the first trimester of pregnancy. Women with a positive result for thyroid autoantibodies had a 17% rate of pregnancy loss compared with 8.4% for women without evidence of thyroid autoantibodies. None of the women with thyroid autoantibodies had clinically evident thyroid disease, and the increase in pregnancy loss was not due to changes in thyroid hormone levels or APLA. The pathophysiology involved in this phenomenon is unclear and probably represents a generalized autoimmune defect rather than a thyroid-induced abnormality. However, available data do not support the use of thyroid autoantibody testing in women with recurrent pregnancy loss.

Alloimmune abnormalities

When the maternal immune response to antigens of placental or fetal tissues is abnormal, SAB can result. Human leukocyte antigen (HLA) sharing has been reported as such an alloimmune response. HLA sharing is a condition in which the normal process that allows for the creation of maternal blocking antibodies in pregnancy is decreased. However, studies to date have proven no association between recurrent pregnancy loss and HLA.

Anatomic Causes

Anatomic uterine defects are known to cause obstetric complications, including recurrent pregnancy loss, preterm labor and delivery, and malpresentation. Therefore, a uterine malformation should be considered in any woman with recurrent pregnancy loss. However, not all women with abnormal uteri have obstetric complications. Impaired vascularization and fetal growth restriction due to uterine distortion are 2 commonly discussed reasons for pregnancy loss.

The incidence of uterine anomalies is estimated to be 1 per 200-600 women, depending on the method used for diagnosis. When manual exploration is preformed at the time of delivery, uterine anomalies are found in approximately 3% of women. However, in women with a history of pregnancy loss, uterine abnormalities are present in approximately 27%.

Uterine müllerian anomalies

The most common uterine defects include septate, bicornuate, and didelphic uteri. The unicornuate uterus is least common. Bicornuate and unicornuate uteri are frequently associated with second-trimester loss and preterm delivery. The highest rate of reproductive losses are found in bicornuate uteri (47%) compared with unicornuate uteri (17%). Malpresentation and fetal growth restriction are other complications that women with unicornuate uteri face. Women with unicornuate and didelphys uteri have the highest rate of abnormal deliveries, while women with uterine septa have a 26% risk of reproductive loss.

In addition to müllerian anomalies, other anatomic causes of recurrent pregnancy loss to consider for include diethylstilbestrol exposure related-anomalies, Asherman syndrome, incompetent cervix, leiomyomas, and uterine polyps.

Controversies exist among these listed uterine anatomic abnormalities as causes for pregnancy loss. They are suggested but not scientifically proven potential causes.

Management

Imaging studies of choice include hysteroscopy, hysterosalpingography (HSG), and vaginal ultrasonography. Findings may be confirmed with MRI. For instance, a banana-shaped cavity with a single fallopian tube is the most common finding in a unicornuate uterus. Prophylactic cervical cerclage should be considered in patients with a unicornuate uterus. Some authors support expectant management in these patients, with serial assessments of cervical lengths by using digital and ultrasonographic examinations.

Surgical correction of uterine anatomic abnormalities has not been shown to benefit pregnancy outcomes in a prospective controlled trial. However, data from uncontrolled retrospective reviews have suggested that resection of the uterine septum increases delivery rates (70-85% in 1 study).

Infectious Causes

The theory that microbial infections can cause miscarriage has been presented in the literature since as early as 1917, when DeForest et al observed recurrent abortions in humans exposed to farm animals with brucellosis. Although infection has been reported as a cause of pregnancy loss, few studies have been conducted, and results are inconsistent. Numerous organisms have been implicated in sporadic causes of miscarriage, but common microbial causes have not been confirmed. In fact, infection is viewed as a rare cause of recurrent miscarriage.

Organisms implicated with SAB include the following:

• Bacteria
  • Listeria monocytogenes
  • Chlamydia trachomatis
  • Ureaplasma urealyticum
  • Mycoplasma hominis
  • Bacteria causing vaginosis
• Viruses
  • Cytomegalovirus (CMV)
  • Rubella
  • Herpes simplex virus (HSV)
  • (HIV)
  • Parvovirus
• Parasites
  • Toxoplasma gondii
  • Plasmodium falciparum
• Spirochetes -Treponema pallidum

Different theories have been postulated to explain exactly how an infectious agent leads to miscarriage. These include the following:

• Toxic metabolic byproducts, endotoxin, exotoxin, or cytokines may have a direct effect on the uterus or the fetoplacental unit.
• Fetal infection may cause fetal death or severe malformation incompatible with fetal viability.
• Placental infection may result in placental insufficiency, with subsequent fetal death.
• Chronic infection of the endometrium from ascending spread of organisms (eg, M hominis, Chlamydia organisms, U urealyticum, HSV) from the lower genital tract may interfere with implantation.
• Amnionitis in the first trimester may play a role similar to chorioamnionitis in the third trimester, resulting in preterm labor (related to various common gram-positive and gram-negative bacteria, L monocytogenes).
• Induction of a genetically and anatomically altered embryo or fetus may occur because of viral infection (eg, rubella, parvovirus B19, CMV, chronic CMV, coxsackievirus B, varicella-zoster, HSV, syphilis, Lyme disease) during early gestation.

Any patient undergoing an infertility workup should be treated for any recognized vaginitis or cervicitis. In addition, chronic genital infection may be the most obvious initial manifestation of a general health problem. Chronic vulvovaginitis is associated with diabetes, other endocrinopathies, and, possibly, lupus erythematosus. In addition, gonorrhea and chlamydia should be eliminated before the infertility workup (eg, hysterosalpingograms) to avoid spreading the infection to the upper genital tract.

A recent review failed to show sufficient evidence for the notion that any type of infection can be identified as a causal factor for recurrent miscarriage. Most patients with a history of recurrent miscarriage do not benefit from an extensive infection workup. Exposure to a microbe that can establish chronic infection that can spread to the placenta in a patient who is immunocompromised is probably the most obvious risk situation in recurrent abortions.

Specific pathogens include Neisseria gonorrhoeae, which is associated with premature rupture of membranes and chorioamnionitis, and C trachomatis. Previous chlamydial infection is not associated with fetal loss in women with recurrent abortion. However, neonatal conjunctivitis and pneumonia are known sequelae.

Women who are in high-risk groups are the only patients who should be screened. Serologic studies have suggested an association between C trachomatis and recurrent abortion, and routine C trachomatis screening has been recommended for all patients undergoing an infertility workup. However, microbiologic testing for endocervical chlamydial infection during pregnancy has failed to confirm the association with recurrent abortion.

In 1992, Witkin and Ledger reviewed the relationship between high-titer IgG antibodies to C trachomatis and recurrent SAB. They found that high-titer IgG antibodies to C trachomatis were associated with recurrent SABs. They proposed the mechanism to be reactivation of a latent chlamydial infection, endometrial damage from past chlamydial infection, or an immune response to an epitope shared by a chlamydial and a fetal antigen.

Bacterial vaginosis is associated with preterm labor, intrauterine growth retardation, chorioamnionitis, and late miscarriage. However, no studies have been conducted to investigate its role in women with recurrent miscarriages. Most women are screened at their first prenatal visit and more frequently than this if they have a history of late miscarriages or preterm delivery.

Regarding genital mycoplasma M hominis and Ureaplasma species are isolated from the vagina in as many as 70% of pregnant women. Although these organisms are most frequently found in women with recurrent miscarriages, their elimination has not improved subsequent pregnancy outcome. Therefore, screening for Mycoplasma and Ureaplasma species is not recommended for the typical patient with a history of recurrent miscarriage.

L monocytogenes typically produces asymptomatic colonization of the maternal lower genital tract, though symptomatic maternal listeriosis characterized by bacteremia and influenza-like symptoms may occur.

Symptomatic listerial infection is typically described as a complication of the third trimester, resulting from ingestion of unpasteurized milk or cheese.

Asymptomatic genital Listeria colonization may result in high perinatal mortality and morbidity rates if the organism is spread to the fetus during labor and delivery. However, no evidence suggests that Listeria organisms play a role in patients with a history of recurrent pregnancy loss. Screening for Listeria during pregnancy or in routine cases of recurrent miscarriage is not recommended.

T pallidum is known to cause stillbirth and abortion in the second trimester. The timing of death is probably associated with the maturation of the fetal immune system at the 20th week of gestation. However, syphilis is unlikely to substantially contribute to the general problem of recurrent miscarriage.

Lyme disease (which is due to Borrelia burgdorferi) can result in stillbirth and fetal infection. Perform serologic testing if the patient relates a history suggestive of Lyme disease. However, Lyme disease is unlikely to substantially contribute to the general problem of recurrent abortion.

CMV is associated with random miscarriage but not recurrent miscarriage. In a large study, Stagno et al (1982) observed 3712 pregnant patients and documented 21 cases of primary maternal CMV infection during pregnancy. Only 11 of the 21 showed neonatal infection, and SABs did not occur in this group.

Primary HSV infection has been associated with SAB, and chronic HSV infection is a possible cause of recurrent abortion (especially in a patient who is immunocompromised). The risk rate for in utero HSV transmission from chronic maternal disease is low (approximately 0-3% of pregnancies). Therefore, the incidence of recurrent abortion secondary to chronic HSV infection is extremely low in the general population and does not warrant routine screening in patients with recurrent pregnancy loss.

Malaria due to P falciparum during pregnancy is associated with SAB, stillbirth, low birth weight, and prematurity. Screening is only important in those women who live where the disease is endemic or in symptomatic patients who have traveled to endemic countries.

Primary toxoplasmosis can lead to miscarriage and stillbirth. However, if the infection develops during the first trimester, the risk is less than 5%. In addition, repeated infections in subsequent pregnancies are unlikely, unless chronic infection develops in patients who are immunocompromised.

Studies have failed to show an increase in miscarriage rates for asymptomatic patients with HIV infection.

Environmental, Endocrine, and Hematologic Causes

Environmental causes

Environmental causes of human malformation account for approximately 10% of malformations, and fewer than 1% of all human malformations are related to exposures to prescription drugs, chemicals, or radiation. Isotretinoin (Accutane), a retinoic acid used to treat severe acne, is associated with SAB.

Recognizing these preventable exposures is important. For example, the relationship between exposure to trace concentrations of waste anesthetic gases in the operating room and the possible development of adverse health effects has been a concern for many years. However, the studies that showed an increased incidence of miscarriage and congenital anomalies had many flaws.

Maternal exposure to tobacco and its effect on reproductive outcomes has been the subject of many studies. Cigarette smoke contains hundreds of toxic compounds. Nicotine is thought to have vasoactive actions and is thought to reduce placental and fetal circulation. Carbon monoxide depletes both fetal and maternal oxygen supplies, and lead is a known neurotoxin. Maternal smoking appears to only slightly increase the risk of SABs.

Maternal exposures to excess alcohol and coffee consumption were reported to be associated with an increased risk for SAB.

Endocrine causes

Ovulation, implantation, and the early stages of pregnancy depend on an integral maternal endocrine regulatory system. Most attention was historically directed at maternal systemic endocrine disorders, luteal-phase abnormalities, and hormonal events that follow conception, particularly progesterone levels in early pregnancy.

Diabetes mellitus

Women with diabetes mellitus who have good metabolic control are no more likely to miscarry than women without diabetes. However, women with diabetes with high glycosylated A1c levels in the first trimester are at a significantly increased risk of both miscarriage and fetal malformation. Women with insulin-dependent diabetes with inadequate glucose control have a rate of SAB 2-3 times higher than that of the general population of women. Screening for occult diabetes in asymptomatic women is not necessary unless a random glucose value is elevated. For a patient with an unexplained loss in the second trimester or with clinical signs of diabetes mellitus, investigation is needed.

Thyroid dysfunction

No direct evidence suggests that thyroid disease is associated with recurrent miscarriages. However, the presence of antithyroid antibodies (to thyroid antigens thyroglobulin and thyroid peroxidase) may represent a generalized autoimmune abnormality rather than a specific thyroid dysfunction. Screening for thyroid disease is not useful unless the patient is symptomatic.

Low progesterone levels

Progesterone is the principal factor responsible for the conversion of a proliferative to a secretory endometrium, rendering the endometrium receptive for embryo implantation. In 1929, Allen and Corner published their classic results on physiologic properties of the corpus luteum. Since then, low progesterone levels have been assumed to be associated with miscarriage.

Luteal support remains critical until approximately the seventh week of gestation, at which time the placental trophoblast has acquired enough steroidogenic ability to support the pregnancy. In patients in whom the corpus luteum is removed before the seventh week, miscarriage results. If progesterone is given to these patients, the pregnancy is salvaged. Recent developments with RU486 (an antiprogestin) have shown that this can effectively terminate a pregnancy up to 56 days from the last menstrual period.

Luteal-phase defects

In 1943, Jones first discussed the concept of insufficient luteal progesterone resulting in either infertility or early pregnancy loss. This disorder was characterized by inadequate endometrial maturation resulting from a qualitative or quantitative disorder in corpus luteal function, which has been reported in 23-60% of women with recurrent miscarriage. However, no reliable method is available to diagnose this disorder, and controversy exists because of the inconsistencies in the methods of diagnosis.

Methods used to diagnose luteal-phase defects (LPDs) include records of basal body temperature records, evaluation of progesterone concentrations, and histologic dating of endometrial biopsy specimens.

The criterion standard has been endometrial biopsy performed in the luteal phase. This criterion uses the development of stromal and glandular cells to determine how many days after ovulation the patient was at the time of the biopsy. A delay of more than 2 days in maturation compared with when the patient exactly is on the basis of her surge in luteinizing hormone (LH) defined as LPD. However, substantial interobservational and intraobservational discrepancies occurs when the standard histologic criterion is applied.

Most studies use the patient's subsequent menses as a reference point, with the assumption that the patient has a normal 28-day cycle. This definition accounts for many of the discrepancies in the literature. As a consequence, as many as 31% of normally fertile women have an LPD according to the results from serial endometrial biopsy procedures.

In 1 of the few prospective studies in which women with 3 or more consecutive miscarriages were examined, LPD was believed to be the cause in 17%. The pathologist accurately dated the biopsy samples using LH assays to pinpoint the time of ovulation. In this study, luteal-phase serum progesterone levels were normal in the women with LPD. Luteal-phase deficiency is most likely the result of an abnormal response of the endometrium to progesterone rather than a subnormal production of progesterone by the corpus luteum. This is evident because as many as 50% of women with histologically defined LPD have normal serum progesterone levels.

In treating LPD, realizing that postimplantation failure or that an early nonviable pregnancy is associated with low serum progesterone levels is important. Only 1 randomized trial has shown that treatment with progesterone supplementation has a beneficial effect on pregnancy outcomes. Most studies have had opposite results, failing to show that any type of support (eg, progesterone, human chorionic gonadotropin) has beneficial results. Therefore, the physician must be selective in deciding who should be screened for LPD. One approach is to screen patients with either a history of recurrent miscarriages or recurrent failures with infertility therapy. In addition, the best accuracy is achieved if the same pathologist reviews the histologic findings and if the day of ovulation is based on LH levels rather than subsequent menses. The dose of progesterone should be adequate to stimulate luteinization of the endometrium with the fewest adverse effects.

Endocrine modulation of decidual immunity

The transformation of endometrium to decidua affects all cell types present in the uterine mucosa. These morphologic and functional changes facilitate implantation, but they also help control trophoblast migration and prevent overinvasion in maternal tissue. Attention focuses on the interaction between the extravillous trophoblast and the leukocyte populations infiltrating the uterine mucosa. Most of these cells are large granular lymphocytes (LGLs) and macrophages; few T and B cells are present. The LGL population is unusual, staining strongly for natural killer (NK) cell marker CD56, but the cells do not express the CD16 and CD3 NK markers. NK cells with this distinct phenotype are found in high numbers, primarily in the progesterone-primed endometrium of the uterus. The number of CD56 cells is low in the proliferative-phase endometrium, increases in the midluteal phase, and peaks in the late secretory phase, suggesting that recruitment of LGLs is under hormonal control.

Progesterone is essential because LGLs are not found before menarche, after menopause, or in conditions associated with unopposed estrogen (eg, endometrial hyperplasia, carcinoma). In women who have undergone oophorectomy, LGLs appear only after treatment with both estrogen and progesterone. The increase in the number of NK cells at the implantation site in the first trimester suggests their role in pregnancy maintenance. They preferentially kill target cells with little or no HLA expression. The extravillous trophoblast (which expresses modified forms of 1 HLA) is resistant to lysis by decidual NK cells under most circumstances, allowing the invasion needed for normal placentation. These CD56 cells probably differentiate in utero from precursor cells because serum levels are negligible.

The only cytokine that has been able to induce proliferation of these cells is IL-2. IL-2 also transforms NK cells into lymphokine-activated killer (LAK) cells, which can lyse first-trimester trophoblast cells in vitro. As expected, IL-2 has not been found in vivo at uterine implantation sites; otherwise, stimulation of decidual NK cells would cause widespread destruction of the trophoblast. Trophoblast HLA expression is increased by interferon, a phenomenon that may offer protection from LAK cell lysis. Therefore, an equilibrium exists between the level of HLA expression on the trophoblast and the amount of lymphokine activation of NK cells, leading to the concept of fine regulation of trophoblast invasion.

Hematologic defects

Many recurrent miscarriages are characterized by defective placentation and microthrombi in the placental vasculature. In addition, certain inherited disorders that predispose women to venous and/or arterial thrombus formation are associated with thrombophilic causes for pregnancy loss. Various components of the coagulation and fibrinolytic pathways are important in embryonic implantation, trophoblast invasion, and placentation. Because the association between APLA and recurrent miscarriage is now firmly established, interest has been garnered in the possible role of other hemostatic defects in pregnancy loss.

Pregnancy is a hypercoagulable state because of an increase in the levels of procoagulant factors, a decrease in the levels of naturally occurring anticoagulants, and a decrease in fibrinolysis.

Levels of factors VII, VIII, X, and fibrinogen increase during a normal pregnancy, as early as 12 weeks' gestation. This increase in factors is not balanced by an increase in anticoagulants (ie, antithrombin III, proteins C and S). In fact, protein S levels decrease by 40-50%. Antithrombin III and protein C levels remain constant. Fibrinolytic activity is also altered, with levels of plasminogen activator inhibitor-1 (PAI-1) and plasminogen activator inhibitor-2 (PAI-2) progressively increasing during pregnancy. PAI-1 is produced by endothelial cells and inhibits release of plasminogen activator. PAI-2 is produced by the trophoblast and helps regulate placental growth. Platelet activation increases and contributes to the prothrombic state of pregnancy, as reflected by an increase in platelet production of thromboxane and decreased platelet sensitivity to the antiaggregation effects of prostacyclin. The hemostatic changes in pregnancy favor coagulation.

Urokinase plasminogen (uPA) activator is active around the time of implantation. It triggers the localized production of plasmin, which catalyzes the destruction of the extracellular matrix, facilitating implantation. uPA is also found in the maternal venous sinuses and, therefore, plays a role in maintaining the patency of these channels. uPA receptors are also expressed on first-trimester human trophoblast cells, primarily those that are not actively invasive, which serves to facilitate generation of plasmin at the interface of these cells with maternal plasma, limiting deposition of fibrin in the intervillous spaces.

PAI-1 and PAI-2 have been localized to the invasive trophoblast. Therefore, trophoblast implantation and invasion are seemingly regulated to some extent by the balance between plasminogen activators and inactivators. Indeed, defective trophoblast invasion of the spiral arteries has been a common finding after placental-bed biopsies are performed on women who miscarry and on those patients with preeclampsia or intrauterine growth restriction.

In the normal placenta, important components of the hemostatic, fibrinolytic, and protein C anticoagulant (factor V Leiden) pathways are present and are responsible for the maintenance of hemostasis. Abnormal gestations are associated with an abnormal distribution of fibrin, and the production of certain factors (eg, cytokines) may convert a thromboresistant endothelium to one that is more thrombogenic. In support of this theory, fibrin deposition has been observed in chorionic villi that make allogenic contact with maternal tissue, which contains many factors and products of the hemostatic pathway. Endothelial cells in these areas appear to be deficient in the thrombin-thrombomodulin anticoagulant pathway; therefore, they are prone to clot formation. Normal villi have this pathway.

Compelling evidence suggests that women with a history of recurrent miscarriage are in a procoagulant state even when they are not pregnant.

A large study of 116 nonpregnant women with recurrent miscarriages who tested negative for LAC and aCLs showed that 64% had at least 1 abnormal fibrinolysis-related result, most commonly a high PAI-1 level. No abnormal defects were found in the control group, which consisted of 90 fertile women with no history of miscarriage.

In 1994, Patrassi and colleagues found that 67% of patients, regardless of whether they were aCL positive, had a defect in their fibrinolytic pathway.

Evidence also suggests that, just before a miscarriage, defects are present in hemostatic variables. Tulppala and coworkers (1991) revealed that women with a history of recurrent miscarriages have an abundance of thromboxane production at 4-6 weeks' gestation and a decrease in prostacyclin production at 8-11 weeks, as compared with women without such a history. This shift in the thromboxane-to-prostacyclin ratio can lead to vasospasms and platelet aggregation, causing microthrombi and placental necrosis. Levels of protein C and fibrinopeptide A seem to decrease just before a miscarriage occurs, suggesting activation of the coagulation cascade.

Activated protein C resistance

Resistance to the anticoagulant effects of activated protein C (APC) is inherited as an autosomal dominant trait and is the most important cause of thrombosis and familial thrombophilia. In more than 90% of patients, it is due to a single-point mutation (glutamine for arginine) at nucleotide position 1691 in the gene for factor V. This mutated gene is known as factor V Leiden. APC cleaves and inactivates coagulation factors Va and VIIIa in the presence of cofactor protein S. The mutated factor V is resistant to inactivation by APC, resulting in increased thrombin production and a hypercoagulable state. Its prevalence rate is 3-5%. In those with a previous venous thrombosis, the prevalence rate is as high as 40%.

In 1995, Rai and colleagues evaluated 120 women with a history of recurrent miscarriages. None of the women had a history of thrombosis, LAC, or aCL. The prevalence of APC resistance was higher in women who had a second-trimester miscarriage than in those with a first-trimester loss (20% vs 5.7%).

In normal pregnancies, APC resistance naturally decreases. However, women with APC resistance before pregnancy tend to have an even further decrease in resistance. The best way to detect APC resistance is both coagulation-based assay and DNA testing to detect the actual mutation. They complement each other because one is a genetic test and one is a functional test.

Coagulation inhibitors

Little data exist evaluating deficiencies of antithrombin III, protein S, or protein C and pregnancy loss.

Specific coagulation factor deficiencies

The deficiency is factor XII (Hageman) and is associated with both systemic and placental thrombosis. Factor XII deficiency has been reported to be associated with recurrent miscarriage in as many as 22% of patients evaluated. Again, the data are limited.

Abnormal homocysteine metabolism

Homocysteine is an amino acid formed during the conversion of methionine to cysteine. Hyperhomocystinemia, which may be congenital or acquired, is associated with thrombosis and premature vascular disease. This condition is also associated with pregnancy loss. In 1 study, 21% of women had recurrent pregnancy loss. The gene for the inherited form is transmitted in an autosomal recessive form. The most common acquired form is folate deficiency. In these patients, folic acid replacement helps achieve normal homocysteine levels within a few days.

Therapy for coagulation disorders

Low-dose aspirin 60-150 mg/d irreversibly inhibits the enzyme cyclooxygenase in platelets and macrophages. This effect leads to a shift in arachidonic acid metabolism toward the lipoxygenase pathway, resulting in inhibition of thromboxane synthesis without affecting prostacyclin production. It also stimulates leukotrienes, which, in turn, stimulates production of IL-3 that is essential for implantation and placental growth. Heparin inhibits blood coagulation by 2 mechanisms. At conventional doses, it increases the inhibitory action of antithrombin III on activated coagulation factors XII, XI, IX, X, and thrombin. At high doses, it catalyzes the inactivation of thrombin by heparin cofactor 2. Heparin does not cross the placenta; therefore, no risk to the fetus is present.

The primary adverse effects are osteopenia if heparin therapy is prolonged (usually therapeutic doses) and thrombocytopenia, which usually occurs within a few weeks of starting heparin (even at low prophylactic doses). Osteopenia is reversed when heparin is discontinued, and platelet levels should be checked routinely.

Summary of recommendations

Patients with early pregnancy loss and recurrent early pregnancy loss need education and support from their practitioner. Many controversies exist as to whether any intervention should be given on the basis of a suspected cause because of a lack of scientific proof of therapeutic efficacy in many areas. However, a few recommendations for evaluation and management based on current practices are listed below.

• Genetic causes
  • Perform karyotyping of parents with family or personal history of genetic abnormalities.
  • Perform karyotyping of the abortus in recurrent cases.
  • Provide genetic counseling for families with recurrent loss or familial history of genetic disease.
  • In patients with a high risk for recurrent, chromosomally abnormal conceptus, discuss the options of adoption, gamete donation, and PGD.
• Immunologic causes
  • Perform APLA testing if indicated.
  • If APLA levels are elevated, counseling with a hematologist and a specialist in maternal fetal medicine is recommended.
  • Aspirin and heparin therapy may be given to patients who test positive for APS.
• Anatomic causes
  • Imaging may include HSG, hysteroscopy, ultrasonography, and/or MRI.
  • Surgical correction may be needed.
• Infectious causes
  • Cervical cultures should be obtained during the evaluation of infertility.
  • Empiric antibiotics should be given before invasive testing, such as HSG.
• Environmental causes - Encourage life-style changes and counseling for preventable exposures.
• Endocrine factors - Perform thyroid-stimulating hormone (TSH) screening in symptomatic patients.
• Thrombophilic disorders - Aspirin and heparin therapy are given for proven diagnoses

Keywords

spontaneous abortion, SAB, ectopic pregnancy, molar pregnancy, miscarriage, chemical pregnancy loss, stillbirth, habitual abortion, recurrent abortion, spontaneous miscarriage, pregnancy failure, gamete failure, sperm dysfunction, oocyte dysfunction, trisomy 16, Down syndrome, Down's syndrome, Turner syndrome, Turner's syndrome, trisomy 21, tetraploidy, triploidy, chromosomal abnormalities, antiphospholipid syndrome, APS, antiphospholipid antibody, APLA, cervical incompetence, genetic translocation, robertsonian translocation, mullerian anomaly, mendelian translocation, myotonic dystrophy, lethal skeletal dysplasias, thanatophoric dysplasia, type II osteogenesis imperfecta, fetal wastage, connective tissue disorders, Marfan syndrome, Marfan's syndrome, Ehlers-Danlos syndrome, homocystinuria, pseudoxanthoma elasticum, sickle cell disease, sickle cell anemia, dysfibrinogenemia, factor XIII deficiency, congenital hypofibrinogenemia, congenital afibrinogenemia, systemic erythematosus, SLE, fetalloss,fetaldeath,LAC syndrome, lupus anticoagulant syndrome, Hugh syndrome, Hugh's syndrome

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