In-depth analysis of recurrent miscarriage in surrogate mothers and precise intervention strategies
Recurrent miscarriage in surrogate mothers (RSA) refers to 2 or more consecutive spontaneous miscarriages before 28 weeks of gestation in surrogate mothers, excluding biochemical pregnancies.The incidence of RSA is as high as 25%-30% in women over 35 years of age, while it is only 1%-3% in the general population. The following is a systematic analysis of the etiologic mechanisms, diagnostic pathways and treatment breakthroughs.
Genetic factors: the invisible killer of chromosomal abnormalities
Chromosomal abnormalities in couples (4%-6% of cases)
Balanced translocation: two chromosome segments are interchanged (e.g. 46,XX,t(2;5)(q21;q23)), and the probability of chromosomally normal embryo is only 1/18, and the clinic often screens for balanced embryos through pre-implantation genetic testing (PGT-SR), with the rate of live births increased to 65%.
Roche translocation: fusion of proximal mitotic chromosomes (e.g., 45,XY,der(13;14)(q10;q10)), the probability of a healthy offspring in natural pregnancy is 1/6, and PGT-A combined with prenatal diagnosis is recommended.
Embryonic chromosomal aneuploidy (main cause of 60%-70% early miscarriages)
Oocyte meiosis error rate spikes at advanced age (≥35 years) and risk of trisomy 21 rises from 0.1% (20 years) to 3% (40 years). Solution:
PGT-A screening: selection of aneuploid embryos for transfer, miscarriage rate reduced from 40% to 10%;
Egg/sperm donation: live birth rate up to 70% in repeated aneuploidy miscarriages.
II. Anatomical abnormalities: fatal defects in the uterine environment
Congenital malformations
Uterine longitudinal septum: low septal vascular density (resistance to flow index RI > 0.8), pregnancy rate rises from 15% to 75% after hysterectomy;
Bicornuate uterus: miscarriage rate 40%, laparoscopic plasty combined with orthopedic uterine stent improves outcome.
Acquired lesions
Uterine adhesions (Asherman’s syndrome): 12% incidence after miscarriage, 60% live birth rate with restoration of endometrial thickness ≥7 mm by hysteroscopic cold knife dissection + estrogen cycling (estradiol valerate 6 mg/d);
Cervical insufficiency: for cervical length <25 mm at 18-22 weeks of gestation, cervical cerclage increases the rate of full-term labor from 20% to 85%. III. Endocrine imbalance: fine tuning of the hormonal network Luteal insufficiency (LPD) Progesterone 15 ng/mL. Abnormal thyroid function Subclinical hypothyroidism (TSH >2.5 mIU/L): levothyroxine (LT4) adjusts TSH to 1.0-2.5 mIU/L and reduces miscarriage rate from 35% to 12%;
Positive thyroid antibodies (TPOAb >60 IU/mL): 2-fold increased risk of miscarriage even with normal thyroid function, requiring LT4 prophylaxis.
Insulin resistance and diabetes
Pre-pregnancy glycated hemoglobin (HbA1c) >6.5%: HbA1c decreased by 1.5% in 3 months and live birth rate increased to 58% with metformin (1500 mg/d) combined with lifestyle intervention.
IV. Immune disorders: maternal rejection of the fetus
Antiphospholipid syndrome (APS)
Diagnostic criteria: lupus anticoagulant (LA) positive/anti-cardiolipin antibody (aCL) >40 GPL/MPL/anti-beta2 glycoprotein I antibody >99th percentile + history of thrombosis/pathologic pregnancy.
Treatment regimen: initiation of low molecular heparin (enoxaparin 40 mg/d) + low dose aspirin (81 mg/d) in the first 3 months of pregnancy, live birth rate increased from 20% to 80%.
Other autoimmune diseases
Abnormal NK cell activity (>18%): immunomodulation with intravenous gammaglobulin (IVIG 0.4 g/kg per month) increased pregnancy success from 30% to 65%;
Sequestering antibody deficiency: lymphocyte immunotherapy (LIT) induces maternal immune tolerance and increases the clinical pregnancy rate to 70%.
V. Pre-thrombotic state: invisible obstruction of microcirculation
Hereditary susceptibility to thrombosis
Factor V Leiden mutation: 3-fold increased risk of miscarriage in heterozygotes, initiation of heparin anticoagulation (dalteparin sodium 5,000 IU/d) early in pregnancy increases the rate of full-term births from 45% to 82%;
Protein S deficiency: activity <40% at term, heparin dose needs to be adjusted to anti-Factor Xa activity of 0.2-0.6 IU/mL.
Acquired hypercoagulation
Antithrombin III (ATIII) 80% to reduce risk of placental infarction.
VI. Unexplained RSA: the hidden biological code
About 50% of patients with RSA have an unknown etiology, latest research spotlight:
Endometrial tolerance defects: clinical pregnancy rate increased from 32% to 68% by localizing the implantation window with endometrial tolerance assay (ERA) and personalizing the timing of embryo transfer;
Microbial imbalance at the mother-fetus interface: vaginal colonization with probiotics (Lactobacillus ≥10^5 CFU/g) improves the microenvironment and reduces the miscarriage rate by 40%;
Abnormal mitochondrial function: coenzyme Q10 (600 mg/d) enhances oocyte energy metabolism and increases the rate of high-quality embryos by 25%.
VII. Systematic diagnosis and treatment pathway
Level 1 assessment (basic screening):
Chromosomal karyotype, hysteroscopy, thyroid function, antiphospholipid antibody, coagulation complete set;
Secondary deepening (special tests):
Endometrial immunohistochemistry (CD56+ uNK cell count), thromboelastography (TEG), paternal HLA compatibility analysis;
Individualized intervention:
PGT, immunomodulation, anticoagulation, or surgical correction depending on the etiology, with a cumulative live birth rate of 75%-85% over 3 years.
Recurrent miscarriage in surrogate mothers requires multidisciplinary collaboration (reproductive medicine, hematology, immunology) for precise treatment. For recurrent failures, emerging technologies such as exosomal miRNA testing (AUC=0.89 for predicting pregnancy outcome) and single-cell embryo metabolomics will provide new directions for etiologic unraveling. Early comprehensive screening and targeted therapy is the key to break the miscarriage spell.
