Recurrent Pregnancy Loss

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Today we discuss a fortunately uncommon problem, but a difficult one to workup appropriately. Recurrent pregnancy loss is defined the American Society of Reproductive Medicine (ASRM) as two or more failed clinical pregnancies; though ideally a threshold of three or more is utilized for research purposes. It is estimated that less than 5% of women will experience 2 consecutive miscarriages, and less than 1% will experience three or more consecutive miscarriages. That said, the live birth rates are still excellent overall for women experiencing recurrent miscarriages:

ASRM

Let’s review the most common causes of RPL.

Unexplained: About 50-75% of couples with RPL have no explanation, but the below should be evaluated and ruled out.

Cytogenetic: These are abnormalities in chromosome number or structure. This accounts for at least 50% of early pregnancy loss!

  • Aneuploidy: risk of aneuploidy increases with increasing number of miscarriages.

  • Chromosomal rearrangements: 3-5% of couples with RPL have a major chromosomal rearrangement (vs. 0.7% in general population).

Cytogetnetic abnormalities can be evaluated by karyotyping to review for balanced reciprocal translocations. Preimplantation genetic screening can be used if other genetic causes are identified.

Antiphospholipid syndrome (APLS): 5-15% of patients with RPL may have APLS. The diagnosis of APLS is challenging to make, and requires the following criteria:

One of two clinical criteria:

  1. Vascular thrombosis 

  2. Pregnancy morbidity, defined as:

    1. One or more unexplained deaths of morphologically normal fetus after 10 weeks of gestation by ultrasound or direct examination of fetus.

    2. One or more premature births of morphologically normal neonate before 34 weeks because eclampsia or severe pre-eclampsia or recognized features of placental insufficiency.

    3. Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation with maternal anatomic or hormonal abnormlaities and paternal and maternal chromosomal causes excluded.

And one of the following laboratory criteria 

  1. Lupus anticoagulant present in plasma on 2 or more occasions at least 12 weeks apart or 

  2. Anticardiolipin antibody IgG or IgM isotype in serum or plasma present in medium or high titer on 2 or more occasions at least 12 weeks apart, or  

  3. Anti-B2 glycoprotein-I antibody of IgG and/or IgM isotype in serum or plasma (in titer >99th%ile), present on two or more occasions at least 12 weeks apart 

If your patient is found to have APLAS, treatment is with heparin and aspirin.

Anatomic:

  • Uterine: congenital uterine anomalies are present in 10-15% of women with RPL, vs 7% of the general population. Additionally uterine leiomyoma, polyps, or adhesions can also be at play. Saline sonohysterogram or hysterosalpingogram can be used to evaluate the cavity.

Hormonal or metabolic 

  • Poorly controlled DM - associated with early and late pregnancy loss; several studies have linked high hemoglobin A1c values early in pregnancy (>8%) to increased frequency of miscarriages and congenital malformation.

  • PCOS - mechanism unknown, but miscarriage rate is as high as 20-40%.

  • Thyroid antibodies and disease - some studies have reported an increased rate of fetal loss in women with high serum thyroid antibody concentrations; also related to unexplained infertility and implantation failure.

  • Hyperprolactinemia - may be associated with RPL through alterations in the HPO axis.

  • Thrombophilia - association between hereditary thrombophilia and fetal loss have been suggested, but prospective cohort studies have failed to confirm this 

Psychologic 

  • There was a nonrandomized trial that looked at cohorts of couples with 3 or more consecutive pregnancy losses and no other identifiable etiology. These were divided into “standard care” vs “tender-loving care” or TLC group, consisting of psychologic support with weekly medical and ultrasonographic exams and instructions to avoid heavy work, travel, and sex. There was a 36% livebirth rate in the control group and 85% in the TLC group! 

Personal habits: There is no clear association between RPL and obesity, smoky, alcohol use, and caffeine consumption. That said, these may have some dose-dependent effect.