Recurrent Early Pregnancy Loss

Early pregnancy loss is defined as the termination of pregnancy before 20 weeks' gestation or with a fetal weight of below 500 g. According to the definition set forth by the American Society for Reproductive Medicine, recurrent pregnancy loss is a disease distinct from infertility and is defined by the spontaneous loss of two or more pregnancies. ^[1]

Genetic causes

Most spontaneous miscarriages are caused by an abnormal (aneuploid) karyotype of the embryo. At least 50% of all first-trimester spontaneous abortions (SABs) are cytogenetically abnormal.

Diagnosis

• Perform karyotype of parents with family or personal history of genetic abnormalities

• Perform karyotype of the abortus in recurrent cases

Management

For couples who have had an SAB due to a suspected genetic cause, the standard of care is to offer genetic counseling.

Although preimplantation genetic screening (PGS) of a removed blastomere for aneuploidy would theoretically increase the likelihood of embryonic implantation, reports in the literature have been conflicting with regard to the efficacy of this technique.

However, couples in whom pregnancy loss can be attributed to a balanced translocation may benefit from specific genetic testing by preimplantation genetic diagnosis (PGD).

Immunologic causes

Tests for antiphospholipid antibodies (APLAs), signaling the presence of the autoimmune disease antiphospholipid antibody syndrome (APS), have reportedly been positive in 10-20% of women with early pregnancy losses.

Three classes of clinically significant APL antibodies have been identified: anticardiolipin (aCL), lupus anticoagulant (LAC), and anti-β2 glycoprotein I antibodies.

Diagnosis

Diagnosis of APS requires the presence of at least 1 of the clinical criteria and at least 1 of the laboratory criteria. The clinical criteria include the following:

• Vascular thrombosis

• 3 or more consecutive unexplained miscarriages

• At least 1 unexplained death of a morphologically normal fetus at or after 10 weeks' gestation

• At least 1 premature birth of a morphologically normal neonate at or before 34 weeks' gestation, associated with severe preeclampsia or severe placental insufficiency

The laboratory criteria include the following:

• 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

• Prolonged phospholipid-dependent coagulation on screening tests

• Inability to correct the prolonged screening test with normal platelet-poor plasma

• Successful correction of the prolonged screening test with excess phospholipids

• Exclusion of other coagulopathies as clinically indicated and heparin

Management

Treatment options for APS include the following:

• Subcutaneous heparin

• Low-dose aspirin

• Prednisone

• Immunoglobulins

• Combinations of these therapies

Anatomic causes

Anatomic uterine defects can cause obstetric complications, including recurrent pregnancy loss, preterm labor and delivery, and malpresentation.

Diagnosis

Imaging studies in the diagnosis of uterine defects include the following:

• Hysteroscopy

• Hysterosalpingography (HSG)

• Sonohysterograms

• Vaginal ultrasonography

Management

Data from uncontrolled, retrospective reviews have suggested that resection of the uterine septum increases delivery rates, although a prospective, controlled trial did not show that surgical correction of uterine abnormalities benefits pregnancy outcomes.

Infectious causes

Infection is considered a rare cause of recurrent miscarriage. Most patients with a history of recurrent miscarriage do not benefit from an extensive infection workup.

Environmental causes

Approximately 10% of human malformations result from environmental causes. Clinicians should encourage life-style changes and counseling for preventable exposures to reduce the risk of environmentally related pregnancy loss.

Endocrine causes

Diabetes

Women with poorly controlled diabetes are at a significantly increased risk of miscarriage and fetal malformation. However, screening for occult diabetes in asymptomatic women is not necessary unless the patient presents with an elevated random glucose level or exhibits other clinical signs of diabetes mellitus or if there is an unexplained loss in the second trimester.

Thyroid dysfunction

Although the presence of antithyroid antibodies may represent a generalized autoimmune abnormality, which could be a contributing factor in miscarriages, screening for thyroid disease is not useful unless the patient is symptomatic.

Luteal phase defects

The criterion standard for the diagnosis of a luteal phase defect (LPD) is the finding that the histologic characteristics of a luteal phase endometrial biopsy are more than 2 days behind the findings expected in a normal cycle. However, the physician must be selective in deciding who should be screened for such defects, since there is no definitive treatment to make a difference in pregnancy outcomes in patients with an LPD.

Hematologic causes

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 pregnancy loss.

Management

Aspirin and heparin therapy may be administered for proven diagnoses of thrombophilic disorders.

Early pregnancy loss is a frustrating and heart-wrenching experience for both the patient and the physician. Early pregnancy loss is unfortunately the most common complication of human gestation, occurring in as many as 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% result in spontaneous abortions (SABs) or ectopic pregnancies. 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 a new window)

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

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. ^[2]

The likelihood for an SAB increases with each successive miscarriage. 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%, which is comparable to the risk in those who had 2 SABs. This data prompted a controversy regarding the timing of diagnostic evaluation, with many specialists preferring to begin after 2 losses rather than 3.

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

  • Aneuploidy

  • Somatic

  • Sex chromosome

  • Mendelian disorders

  • Multifactorial disorders

  • Parental chromosomal abnormalities (translocations)

  • Chromosomal inversions

• Immunologic causes

  • Autoimmune causes

  • Alloimmune causes

• Anatomic causes

  • Uterine müllerian anomaly

    • Uterine septum (the anomaly most commonly 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

  • Caffeine

• 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.

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

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 types of chromosomal abnormalities: (1) the recurrence of a numerical abnormality (aneuploidy) in the embryo, which is usually not inherited or (2) a structural abnormality derived from 1 parent.

Aneuploidy

Cytogenetically abnormal embryos are usually aneuploid because of sporadic events, such as meiotic nondisjunction, or polyploid from fertilization abnormalities.

Autosomal trisomy

Autosomal trisomy is involved in 50% of the cytogenetically abnormal abortuses in the first trimester. It may arise de novo because of meiotic nondisjunction during gametogenesis in parents with a normal karyotype. Autosomal trisomy results from maternal meiosis I errors (either complete trisomies or monosomies).

Specific trisomies

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) survive to term.

Autosomal monosomies

Autosomal monosomies are rarely, if ever, observed.

Monosomy X (Turner syndrome)

Turner syndrome is frequently observed and is the most common chromosomal abnormality observed in SABs. Turner syndrome accounts for 20-25% of cytogenetically abnormal abortuses.

Triploidy and tetraploidy

Triploidy and tetraploidy are related to abnormal fertilization and are not compatible with life. Triploidy is found in 16% of abortions, with fertilization of a normal haploid ovum by 2 sperm (dispermy) as the primary pathogenic mechanism. 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 chromosomal abnormalities occur in approximately 3% of cytogenetically abnormal abortuses.

• These abnormalities are thought to be most commonly inherited from the mother.

• Structural chromosomal problems found in men often lead to low sperm concentrations, male infertility, and, therefore, a reduced likelihood of pregnancy and miscarriage.

Translocations are the most common types of structural abnormalities and can be balanced or unbalanced. Slightly more than one half of unbalanced rearrangements result from abnormal segregation of Robertsonian translocations (when 2 acrocentric chromosomes fuse near the centromere region with loss of the short arms), and the rest arise de novo during gametogenesis.

In reciprocal translocations, there is an exchange of material between nonhomologous chromosomes. The offspring created from parental gametes with the abnormality may have normal or 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.

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

Genetic Abnormalities/Mendelian Disorders

Certain genetic mutations, such as the autosomal dominant disorder leading to myotonic dystrophy, may predispose a patient to infertility or even miscarriage. The cause of the abortion in this disease is unknown, but it may be related to abnormal gene interactions combined with disordered uterine function and implantation defects.

Other presumed autosomal dominant disorders associated with SAB include lethal skeletal dysplasias, such as 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 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. ^[3] 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. ^[4] Therefore, couples with recurrent miscarriage should undergo karyotype evaluation by means of amniocentesis or chorionic villus sampling during a subsequent pregnancy.

Because karyotype analysis does not help in detecting abnormalities caused by single gene mutations or mutations at several loci (small structural deletions and rearrangements), different techniques, such as fluorescence in situ hybridization (FISH), are being used to complement standard cytogenetics. If a parental chromosome abnormality is found, this should be the starting point for familial testing, and proper family counseling is recommended. If an increased risk for future pregnancies is identified, all alternatives should be discussed, including foregoing any attempts at further conception, adopting, trying to conceive again with early prenatal testing, using donor gametes, or performing preimplantation genetic diagnosis (PGD).

The concept of preimplantation genetic screening (PGS) has been recently introduced. This involves using FISH to screen the removed blastomere for aneuploidy in older women and in those with recurrent SABs.

PGS and FISH can be used to accurately detect common aneuploidies accounting for 70% of aneuploidic first trimester losses (chromosomes 13, 15, 16, 17, 18, 21, X, and Y), but these methods are criticized for their inability to detect all chromosomal abnormalities. Theoretically, selection of chromosomally normal embryos for uterine transfer increases the likelihood for implantation, but the reports in the literature have been conflicting in regards to the efficacy of PGS in this setting.

In 2006, a retrospective analysis by Munne et al of women older than 40 years showed a decrease in the SAB rates from 40% to 22% in the group that underwent PGD. ^[5] However, efficacy of PGS in decreasing SAB rates was challenged in other studies.

A randomized trial of 408 women of advanced maternal age undergoing a total of 836 cycles concluded that the ongoing pregnancy rate, as well as live birth rate, were significantly lower in the women assigned to the PGS group compared with those without PGS. ^[6] The authors theorized the possibility that biopsy of a blastomere on day 3 hampers the potential of an embryo to successfully implant. Another reason for their result could be the flaws inherent in the FISH procedure, such as inability to detect aneuploidy in all chromosomes or examining mosaic cells.

Based on the practice guidelines published in Fertility and Sterility in 2007, available evidence does not support the use of PGS to increase live birth rates in women of advanced maternal age. ^[7]

Also, available evidence does not currently support the use of PGS for patients with recurrent pregnancy loss because it does not improve ongoing pregnancy or live birth rates and does not decrease miscarriage rates in such women. However, couples in whom pregnancy loss can be attributed to a balanced translocation may benefit from specific genetic testing by PGD.

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.

Autoimmune Abnormalities

Recurrent pregnancy loss is associated with several autoimmune diseases. One such disease is antiphospholipid antibody syndrome (APS), also known as lupus anticoagulant syndrome and Hugh syndrome. This disorder is characterized by the presence of APL antibodies, which are frequently linked to pregnancy losses in the pre-embryonic (< 6 wk), embryonic (6-9 wk), and fetal (≥10 wk gestation) time periods. 10-20% of women with early losses are positive for the anti-phospholipid antibodies, and an unusually high proportion of pregnancy losses occur in the fetal period compared to unselected population.(NEJM 2002)

Three classes of clinically significant APL antibodies have been identified: anticardiolipin (aCL), lupus anticoagulant (LAC), and anti-β₂ glycoprotein I antibodies. In addition, biologically false-positive serologic test results for syphilis may have similar clinical significance.

APS is diagnosed when medical, obstetric, and appropriate laboratory findings are present. Diagnosis of APS requires the presence of at least 1 of the clinical criteria and at least 1 of the laboratory criteria:

• Clinical criteria

  • Vascular thrombosis

  • Pregnancy morbidity

    • 3 or more unexplained consecutive miscarriages with anatomic, genetic, and hormonal causes excluded

    • 1 or more unexplained death(s) of a morphologically normal fetus at or after the 10 weeks' gestation

    • 1 or more premature birth(s) of a morphologically normal neonate at or before 34 weeks' 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. Notably, the presence of the antibodies alone in the absence of other clinical symptoms does not define the syndrome.

Patients with the combination of high antiphospholipid antibody (APLA) titers and the IgG isotype have a prognosis worse than those with the combination of low titers and the IgM isotype. However, the type of APLA (aCL, LAC, or anti–beta-2 glycoprotein I) does not influence the prognosis.

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 systemic lupus erythematosus (SLE).

Systemic lupus erythematosus  ^{[8, 9]}

Systemic lupus erythematosus (SLE) is by far the most common disease associated with APS. Patients with SLE have a 12-30% prevalence for ACL antibodies, and 15-34% for LAC antibodies. SLE, as associated with antiphospholipid antibodies, has been linked to increased rates of miscarriage and late pregnancy loss since 1954. Patients with SLE have a median miscarriage rate of 10%, which is similar to the general population. However, the 8% median rate of late pregnancy loss among these patients is considerably higher than in their healthy counterparts.

The higher late pregnancy loss rate is related to increased incidence of fetal death in the second and third trimesters in patients with SLE, and most of these are associated with the presence of APLAs. ^[8]

Three factors are predictive of adverse obstetric outcome in patients with SLE.

• Disease before conception

• Onset of SLE during pregnancy

• Underlying renal disease

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

• Obstetric conditions associated with APLAs

  • Preeclampsia ^[10]

  • 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

Antinuclear antibodies

Antinuclear antibodies (ANAs) have also 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.

Antithyroid antibodies

Unlike ANA, antithyroid antibodies are known as independent markers for an increased risk of miscarriage. In 1990, Stagnaro-Green et al 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. ^[11] 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.

Therapy

Vascular thrombosis associated with 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 may help to explain the action 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.

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 APS.

Treatment options include the following:

• Subcutaneous heparin

• Low-dose aspirin

• Prednisone

• Immunoglobulins

• Combinations of these therapies

Additionally, 1 study of pregnancy loss in a mouse model showed that treatment with ciprofloxacin decreases pregnancy loss by modulating IL-3 expression in splenocyte. IL-3 is hypothesized to act as a placental growth hormone that can compensate for damaged placental tissue. No clinical reports in human have been published on the use of ciprofloxacin.

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 plus subcutaneous heparin) was found to be 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. ^[12]

Intravenous immunoglobulin (IVIG) therapy has been thought to be effective, decreasing fetal losses and also decreasing the incidence of preeclampsia and fetal growth restriction in several small studies. However, other placebo-controlled trials failed to demonstrate a difference in the treatment group with respect to reproductive outcomes. To date, no large randomized placebo-controlled trials have been conducted to show a benefit with using IVIG therapy.

A recent systematic review of 8 randomized controlled trials evaluating IVIG for treatment of spontaneous recurrent miscarriage in a total of 442 women concluded that although IVIG did not significantly increase the odds ratio of achieving a live birth when compared with placebo overall, women with secondary recurrent miscarriage were more likely to have a live birth following IVIG use. ^[13] IVIG treatment is expensive and should not be used as first-line therapy in all patients with recurrent pregnancy loss until further data on its effectiveness are available.

Alloimmune Abnormalities

Miscarriage may occur when the maternal immune response to antigens of placental or fetal tissues is abnormal. Human leukocyte antigen (HLA) sharing ^[14] 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 uterine defects are known to cause obstetric complications, including recurrent pregnancy loss, preterm labor and delivery, and malpresentation, although many women with such defects may have uncomplicated pregnancies. Most commonly, the complications result from impaired vascularization and fetal growth restriction.

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 performed at the time of delivery, uterine anomalies are found in approximately 3% of women. However, uterine abnormalities are present in approximately 27% of women with a history of pregnancy loss.

Uterine müllerian anomalies

The most common uterine defects include septate, unicornuate, bicornuate, and didelphic uteri. Of these, the unicornuate uterus is least common, but can result in malpresentation and fetal growth restriction. The highest rate of reproductive losses are found in bicornuate uteri (47%) compared with unicornuate uteri (17%), but both are frequently associated with second trimester loss and preterm delivery. 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

Accurate diagnosis of mullerian anomalies is essential. Imaging studies of choice include hysteroscopy, hysterosalpingography (HSG), sonohysterograms, 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).

The theory that microbial infections can cause miscarriage has been presented in the literature as early as 1917 when DeForest et al observed recurrent abortions in women exposed to farm animals with brucellosis. Numerous organisms have been implicated in sporadic causes of miscarriage, but common microbial causes of RPL have not been confirmed. In fact, infection is viewed as a rare cause of recurrent miscarriage. 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.

For related information, see the following Medscape Reference articles.

• Listeria Monocytogenes

• Chlamydial Genitourinary Infections

• Ureaplasma Infection

• Mycoplasma Infections

• Bacterial Vaginosis

• Cytomegalovirus

• Pediatric Rubella

• Herpes Simplex

• HIV Disease

• Parvovirus B19 Infection

• Toxoplasmosis

• Treponematosis (Endemic Syphilis)

• Lyme Disease

• Malaria

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)

Isotretinoin is a retinoic acid used to treat severe acne and is associated with SAB.

Anesthetic gases

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. ^[15] However, the studies that did show an increased incidence of miscarriage and congenital anomalies had many flaws. A meta-analysis from 1997 pooled data from 19 reports and concluded that in the prescavenging era, the relative risk of spontaneous abortion from exposure to anesthetic gas was 1.9. Since then, most operating rooms use ventilation systems to minimize occupational exposure to the gases. ^[16]

Tobacco

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 reduce placental and fetal circulation through its vasoactive actions. Carbon monoxide depletes both fetal and maternal oxygen supply, and lead is a known neurotoxin. Despite the many harmful effects to a woman’s health, maternal smoking appears to only slightly increase the risk of SABs.

Alcohol

Maternal exposure to excess alcohol has been reported to be associated with an increased risk for SAB.

Coffee consumption

Coffee consumption has been the subject of much debate since the 1980s. Studies have demonstrated conflicting results, some finding that moderate coffee consumption (< 350 mg/d) is not related to the risk of SABs ^[17] , whereas others claim that the risk of SAB increases even at this level of exposure ^[18] .

In 2008, a large cohort study of 1063 patients by Weng et al demonstrated that caffeine consumption had a dose-dependent increase in the risk of miscarriage at all levels of consumption. Patients with caffeine intake of less than 200 mg/d were 1.42 times more likely to have an early miscarriage, whereas in those with intake of 200 mg/d or greater, the risk increased to 2.23 times compared with patients with no caffeine use. In addition, the magnitude of the association appeared to be stronger among women without a history of miscarriage than that among women with such a history. ^[19]

Ovulation, implantation, and the early stages of pregnancy depend on an intact 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 poorly controlled diabetes, as evidenced by high glycosylated HgA1c levels in the first trimester, are at a significantly increased risk of both miscarriage and fetal malformation. The SAB rate increases 2-3 fold in these women compared with the general population. Screening for occult diabetes in asymptomatic women is not necessary unless the patient presents with an elevated random glucose level or exhibits other clinical signs of diabetes mellitus or if there is an unexplained loss in the second trimester.

Thyroid dysfunction

No direct evidence suggests that thyroid disease is associated with recurrent miscarriages. However, the presence of antithyroid antibodies (2 thyroid antigens: thyroglobulin and thyroid peroxidase) may represent a generalized autoimmune abnormality, which could be a contributing factor in miscarriages. Screening for thyroid disease is not useful unless the patient is symptomatic.

Low progesterone levels

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

Luteal support remains critical until approximately 7 weeks' 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 7 weeks, miscarriage results. If progesterone is given to these patients, the pregnancy is salvaged. Recent experience with RU486 (an antiprogestin) has shown that this treatment 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 defined as inadequate endometrial maturation resulting from a qualitative or quantitative disorder in corpus luteal function. Methods used to diagnose luteal phase defects (LPDs) include records of basal body temperature, evaluation of progesterone concentrations, and histologic dating of endometrial biopsy specimens.

The criterion standard in diagnosis of LPD is the histological characteristics of a luteal phase endometrial biopsy being more than 2 days behind the findings expected in a normal cycle. However, substantial inter- and intra-observer discrepancies occur even when the standard histologic criterion is applied, which has lead to the controversy surrounding this disorder. Furthermore, although LPD has been reported in 23-60% of women with recurrent miscarriage, as many as 31% of normally fertile women have an LPD according to the results from serial endometrial biopsy procedures. However, since no reliable method is available to diagnose this disorder, controversy exists regarding both the definition and the diagnosis itself. An additional factor that accounts for many of the discrepancies in the literature is the frequent use of the patient's subsequent menses as a reference point for determining when she had ovulated, which assumes a normal 28-day cycle.

In 1 of the few prospective studies on this subject, endometrial biopsy was performed in women with 3 or more consecutive miscarriages. The pathologist then accurately dated the biopsy samples using LH assays to pinpoint the time of ovulation. LPD was believed to be the cause in 17% of these recurrent miscarriages. The authors also examined luteal-phase serum progesterone levels, and noted that they were normal in the women with LPD. Thus, luteal phase deficiency was 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 finding is corroborated by other studies, showing that as many as 50% of women with histologically defined LPD have normal serum progesterone levels.

The physician must be selective in deciding who should be screened for LPD, since there is no definitive treatment to make a difference in pregnancy outcomes. Only 1 randomized trial has shown that treatment with progesterone supplementation has a beneficial effect on pregnancy outcomes ^[20] , while most other studies failed to demonstrate that any type of support (eg, progesterone, human chorionic gonadotropin) results in a significant difference. For example, a study by Coomarasamy et al randomly assigned 836 women with recurrent miscarriages to receive treatment with progesterone or a placebo to investigate whether the live birth rate would increase in the group that was treated with progesterone. The study did not find a significant increase as the rate of live births was 65.8% (262 of 398 women) in the progesterone group and 63.3% (271 of 428 women) in the placebo group. ^{[21, 22]}

So although it is known that postimplantation failure or an early nonviable pregnancy are associated with low serum progesterone levels, there is no evidence that progesterone supplementation in patients with LPD would restore the normal hormonal profile. Therefore, one approach is to screen only 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.

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, which 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 in this process 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 changes and pregnancy

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.

Normal pregnancy-associated hypercoaguable state

In normal pregnancy, there is an increase in the levels of procoagulant factors, such as factors VII, VIII, X, and fibrinogen, as early as 12 weeks' gestation. However, this thrombogenicity is not balanced by an increase in naturally occurring anticoagulants (ie, antithrombin III, proteins C and S). In fact, protein S levels decrease by 40-50%, while antithrombin III and protein C levels remain constant.

Fibrinolytic activity is also decreased, with progressively increasing levels of plasminogen activator inhibitor-1 (PAI-1), produced by endothelial cells, and plasminogen activator inhibitor-2 (PAI-2), produced by the trophoblast, during pregnancy. The effects of PAI-1 and PAI-2 are localized to the invasive trophoblast, which is seemingly regulated to some extent by the balance between plasminogen activators and inactivators.

Platelet activation and increased production of thromboxane, as well as decreased sensitivity to the antiaggregation effects of prostacyclin, increases the prothrombic state of pregnancy. Vasorelaxation and the resulting stasis of the venous blood flow further favors coagulation.

Urokinase plasminogen activator (uPA), which is active around the time of implantation, triggers the localized production of plasmin, which in turn catalyzes the destruction of the extracellular matrix, thus 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, acting to limit deposition of fibrin in the intervillous spaces.

Changes associated with abnormal pregnancy

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

Abnormal gestations are associated with production of certain factors (eg, cytokines) that may convert a thromboresistant endothelium to one that is more thrombogenic. Abnormal gestations have abnormal fibrin distribution in chorionic villi that make allogenic contact with maternal tissue. Endothelial cells in these areas appear to be deficient in the thrombin-thrombomodulin anticoagulant pathway, making the area more prone to clot formation. Defective trophoblast invasion of the spiral arteries has been found when placental-bed biopsies are performed on women after a miscarriage and on those patients with preeclampsia or intrauterine growth restriction.

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 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 or not they were aCL positive, had a defect in their fibrinolytic pathway. ^[23]

Evidence also suggests that just before a miscarriage, defects are present in hemostatic variables. In 1991, Tulppala and coworkers 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' gestation, as compared with women without such a history. ^[24] 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.

In 2005, a review of the literature from the previous 10 years revealed that only 3 types of thrombophilia may be related to recurrent pregnancy loss: elevated homocysteine levels, factor V Leiden or APC resistance (associated with second trimester loss), and antiphospholipid antibodies (associated with second trimester loss). ^[25]

Most studies report that 5-20% of women with recurrent pregnancy loss have positive test results for antiphospholipid antibodies. ^[26] In a cohort of 76 women with antiphospholipid antibodies, 50% of pregnancy losses occurred after the first trimester compared with 10% in women without antiphospholipid antibodies.

Activated protein C resistance (Factor V Leiden)

Factor V is a coagulation factor that is normally cleaved and inactivated by activated protein C (APC). Patients with a single point mutation in the gene coding for factor V produce a mutated factor V (called Factor V Leiden) that is resistant to inactivation by APC, resulting in increased thrombin production and a hypercoagulable state. This mutated gene is inherited as an autosomal dominant trait and is the most common cause of thrombosis and familial thrombophilia, with a prevalence of 3-5% in the general population. In patients with a history of venous thrombosis, the prevalence rate is as high as 40%.

In normal pregnancies, APC resistance naturally decreases. However, women with APC resistance before pregnancy tend to have an even greater degree of resistance.

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 antibodies. 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%).

The best way to detect APC resistance is both coagulation-based assay and DNA testing to detect the actual mutation.

Coagulation inhibitors

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

Specific coagulation factor deficiencies

The deficiency of factor XII (Hageman) is associated with both systemic and placental thrombosis, leading to recurrent miscarriage in as many as 22% of patients evaluated in 1 study. Overall, however, the data on deficiency of this factor 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 with a history of elevated homocysteine levels had recurrent pregnancy loss. The gene for the inherited form is transmitted in an autosomal recessive form. The most common acquired form is due to folate deficiency. In these patients, folic acid replacement helps achieve normal homocysteine levels within a few days.

Therapy for coagulation disorders

Aspirin

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, stimulate production of IL-3, an essential factor for implantation and placental growth.

Heparin

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. Low molecular weight heparin (ie, Lovenox) has not been studied in pregnancy loss, but has been found to be as effective as heparin in other applications.

The primary adverse effects heparin therapy are osteopenia and thrombocytopenia. Osteopenia occurs when heparin is used at therapeutic doses for prolonged intervals, and is reversed when heparin is discontinued. Thrombocytopenia, on the other hand, may appear within a few weeks of starting even a low prophylactic dose of heparin, so platelet levels should be checked routinely in patients using heparin.

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 performed based on a suspected cause because of lacking 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 karyotype of parents with family or personal history of genetic abnormalities.

  • Perform karyotype 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 are diagnosed with APS.

• Anatomic causes

  • Imaging may include HSG, hysteroscopy, ultrasonography, and/or MRI.

  • Surgical correction may be required.

• 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 may be given for proven diagnoses.