What are the causes of spontaneous abortion in women of childbearing age, particularly those with a history of previous miscarriages, hormonal imbalances, or genetic disorders?

Causes of Spontaneous Abortion

Chromosomal and Genetic Abnormalities

Chromosomal abnormalities represent the most common cause of spontaneous abortion, particularly in first-trimester losses. 1, 2

• Fetal chromosomal abnormalities account for the majority of early pregnancy losses, with advanced maternal age (≥35 years) significantly increasing this risk through age-related aneuploidy 3
• Parental chromosomal abnormalities and known thrombophilias contribute to recurrent losses 1, 4
• Genetic testing through chorionic villus sampling or amniocentesis can identify these abnormalities, though the procedure itself carries a 0.25-0.50% miscarriage risk 3

Endocrine and Metabolic Disorders

Uncontrolled diabetes mellitus is a highly treatable cause of spontaneous abortion that requires preconception optimization. 5

• Elevated glucose levels during embryogenesis directly increase spontaneous abortion rates; achieving HbA1c <7% preconceptionally (ideally <6%) reduces this risk to levels comparable with non-diabetic pregnancies 5
• Thyroid dysfunction affects 5-10% of women with recurrent losses, particularly those with autoimmune conditions, making TSH testing essential 5
• Hormonal imbalances require optimization before conception to reduce pregnancy loss risk 5, 1

Anatomical Abnormalities

Uterine anatomical defects are frequently underdiagnosed causes of recurrent miscarriage. 6

• Hysterosalpingography reveals high incidence of anatomical abnormalities, predominantly uterus bicornis or uterus septus, which may require surgical or endoscopic correction 6
• Anatomical anomalies represent a significant proportion of recurrent spontaneous abortion cases and should be systematically evaluated 1, 2

Thrombotic and Coagulation Defects

Blood coagulation protein and platelet defects are common, treatable causes of recurrent fetal loss. 4

• Thrombotic defects can be managed with low-dose aspirin (81 mg/day) preconception followed by low-dose heparin (5000 units every 12 hours) postconception, achieving 100% success rates in some series 4
• Known thrombophilias increase risk of recurrent pregnancy loss and require specific evaluation 1

Environmental and Occupational Exposures

Lead exposure demonstrates a dose-dependent relationship with spontaneous abortion risk. 3

• Women with blood lead levels 5-9 µg/dL have an odds ratio of 2.3 for spontaneous abortion; this increases to 5.4 at 10-14 µg/dL and 12.2 at >15 µg/dL compared to <5 µg/dL (test for trend, p=0.03) 3
• Each 1 µg/dL increase in blood lead across the range of 1.4-29 µg/dL confers an OR of 1.13 (95% CI, 1.01-1.30) for spontaneous abortion before 21 weeks 3
• Occupational exposure to cytotoxic drugs (doxorubicin, cyclophosphamide, fluorouracilo, vincristine) carries an odds ratio of 2.30 for spontaneous abortion in exposed nurses 7
• Heavy metals, environmental pollution, and radiation exposure contribute to pregnancy loss risk 1

Epigenetic and Inflammatory Mechanisms

LINE-1 hypomethylation and dysregulated inflammation are emerging mechanisms in pregnancy loss. 8

• Women experiencing early pregnancy loss demonstrate significantly lower LINE-1 methylation (P<0.00001) and higher mean cytokine levels (IL6, IL10, IL17A, IL23; P<0.0001) compared to controls 8
• Inverse correlations exist between methylation and cytokine levels, suggesting epigenetic-inflammatory crosstalk in pregnancy maintenance 8
• MTHFR polymorphisms (rs1801133/rs1801131) show increased risk (OR=2.03; 1.2-3.47) while certain F13A1 variants (rs5985) appear protective (OR=0.24; 0.06-0.90) 8

Maternal Age and Lifestyle Factors

Advanced maternal age independently increases spontaneous abortion risk through multiple mechanisms. 3, 1

• Approximately 40% of pregnant women ≥35 years underwent prenatal diagnostic testing in 1990 due to age-related aneuploidy risk 3
• Female age affects pregnancy outcomes through chromosomal abnormalities and cumulative environmental exposures 1
• Smoking and alcohol consumption directly increase miscarriage risk and require complete abstinence 5, 1
• Both underweight and overweight/obesity status increase pregnancy complications including loss 5

Infectious and Immunologic Causes

Infections and autoimmune conditions contribute to pregnancy loss through distinct mechanisms. 1, 2

• Specific infections can trigger spontaneous abortion, though septic abortion represents a distinct clinical emergency requiring immediate intervention 2
• Autoimmune conditions including systemic lupus erythematosus and anticardiolipin syndrome are well-documented causes requiring exclusion 6

Critical Preconception Interventions

Achieving optimal metabolic control before conception is essential for reducing spontaneous abortion risk. 5

• Folic acid supplementation (minimum 400 mcg daily) started before conception prevents birth defects and reduces pregnancy loss 5
• Discontinue teratogenic medications (ACE inhibitors, statins) immediately when planning pregnancy 5
• Use effective contraception until all metabolic targets (glycemic control, thyroid optimization) are achieved 5
• Establish multidisciplinary care including endocrinology and maternal-fetal medicine for high-risk patients 5

Common Pitfalls

The most critical error is failing to pursue thorough evaluation after only one or two losses—many treatable causes (diabetes, thyroid dysfunction, anatomical defects, thrombophilias) will be missed without systematic investigation 5, 4. Additionally, overlooking environmental and occupational exposures, particularly lead and cytotoxic drugs, represents a missed opportunity for primary prevention 3, 7. Finally, delaying preconception optimization in women with diabetes or other metabolic disorders substantially increases pregnancy loss risk that could be mitigated with proper planning 5.