Reproductive Pearls: Recurrent Pregnancy Loss

Posted January 6, 2016 by Claire

Recurrent pregnancy loss (RPL) is distinct from infertility, and some confusion generally surrounds the appropriate work-up for these patients. Here, we try to provide a simple guide to help you evaluate your patients suffering from RPL.

Who to evaluate?

• Couples who have experienced 2 or more first trimester pregnancy losses.
• Classically, this excludes biochemical losses—evaluation is recommended for those with pregnancies reaching the 5-6th week gestation and/or recognized on ultrasound

What to evaluate?

The causes of RPL include anatomic, endocrine, autoimmune, genetic, and ovarian factors.

1. Anatomic: 3D ultrasound and/or sonohysterogram are used to evaluate for a uterine septum, other congenital uterine anomaly, or acquired anomalies such as uterine fibroids or adhesions.
2. Endocrine:
   1. Thyroid function should be tested with TSH and thyroid antibodies (TPO).
   2. Impaired glucose tolerance and diabetes should be ruled out with HgA1c testing in anyone who is overweight, has irregular cycles, has other risk factors, or has a strong family history of diabetes.
   3. Progesterone levels should be checked one week after ovulation to ensure adequate luteal function. (Day 21 if ovulation occurs on day 14; otherwise this should be timed one week after LH surge detected on ovulation predictor kit)
3. Autoimmune: Anticardiolipin antibodies (ACA), lupus anticoagulant (LAC) and anti beta-2-glycoprotein (B2GP) antibodies can be detrimental to placental implantation and should be tested in all patients with RPL. The tests are repeated 6-8 weeks later if a low-level positive is detected on the first screen.
4. Genetic: Karyotype abnormalities account for 5% of cases of RPL, and most commonly include reciprocal or Robertsonian translocations. Karyotype testing of both partners is recommended.
5. Ovarian: The most common cause for an individual miscarriage is aneuploidy—chromosomal abnormalities caused by ovarian aging. This can be assessed with day 3 labs (FSH and estradiol), and anti-mullerian hormone (AMH) testing.

Are other tests indicated?

• Karyotyping of the products of conception may provide useful information: if the fetus is identified as euploid (normal karyotype) this may indicate a maternal factor as listed above, whereas if it is aneuploidy (abnormal), then this is the presumed cause of the miscarriage.
  • Classic chromosome analysis requires cell culture and is limited by maternal contamination (an XX result may not represent the fetus but rather the mother).
  • Newer technologies, such as Anora Miscarriage testing are provided by Natera and involve DNA-based screening to prevent the need for cell culturing and cross-contamination.
• Testing for thrombophilia is indicated when there is a personal or family history of thrombosis. These tests include: FVL, Protein C and Protein S deficiency, Antithrombin III deficiency and Prothrombin gene mutation testing.
• Infectious testing has been explored (such as culturing cervical mucous for mycoplasma) but infection has not been identified as a cause of RPL.
• Internet searches commonly emphasize other auto-immune tests and their effects on implantation; for example: natural killer cells, HLA typing, or testing for other autoantibodies or cytokines. These tests and their treatments remain investigational and are not routinely performed. Additionally, positive anti-nuclear antibodies (ANA) have not been associated with RPL.

How to counsel patients?

Patients experiencing pregnancy loss have experienced overwhelming heartbreak and anxiety. These patients need resources, reassurance, and TLC. While in many cases the reasons for RPL are not understood, overall the prognosis for success in these patients is high: 70% will experience a live birth. This includes those with an abnormality identified on evaluation and those with “unexplained” RPL.

Summary of Evaluation and Treatment

Cause	Evaluation	Abnormality	Treatment
Anatomic	3D US, sonohysterogram	Uterine septum Adhesions Fibroid/ polyp	Hysteroscopic resection
Endocrine	TSH, TPO	TSH>2.5, +TPO	Synthroid
	HgA1c	HgA1c>5.7% HgA1c>6.0%	Metformin through first trimester Diabetes management
	Luteal progesterone	Progesterone <10	Progesterone 100-200mg q HS starting 3 days after ovulation Endometrin 100mg qd to BID Prometrium 200mg qHS
Auto-immune	ACA, LAC, B2GP	Moderate to high positive twice, 6-8 weeks apart	Lovenox or Heparin Low dose ASA daily
Genetic	Karyotype of both partners	Translocation	IVF with pre-implantation genetic diagnosis
Ovarian	Day 3 FSH, Estradiol AMH	FSH >10 E2 >50 AMH <1.0	IVF with pre-implantation genetic diagnosis