Recurrent Pregnancy Loss

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:

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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.

Management of an Early Unlocated Pregnancy

Today we’re bringing back Dr. Erin Cleary one more time before she transitions to her new role as an MFM fellow at the Ohio State University! Dr. Cleary today talks with us on early pregnancy of unknown location - a common problem in the office or the emergency department/triage.

Women presenting to the ED with first trimester bleeding, pain, or both, have had a demonstrated prevalence rate of ectopic pregnancy up to 18% in some studies. Ruptured ectopic is a leading cause of pregnancy-related mortality in the first trimester, accounting for 2.7% of pregnancy-related deaths overall in 2011-2013. Proper identification and management of early, unlocated pregnancy is life-saving!

Dr. Cleary was kind enough to put together her high points from this episode for our blog post today:

H&P:

• Any patient with an unlocated pregnancy should be considered to have a potential ectopic pregnancy.

  • Women with prior ectopic, regardless of method of treatment, are at risk for ectopic in a subsequent pregnancy (three- to eightfold higher compared with other pregnant women).

  • If pregnancy is present while IUD is in place, risk of ectopic is 1 in 2 pregnancies for the levonorgestrel IUD and 1 in 16 pregnancies for the copper IUD.

  • Women with a history of PID have an approximately threefold increased risk of ectopic pregnancy

• Pelvic exam. THIS MUST BE DONE.

Beta-HCG

• The threshold for a positive qualitative β-hcg test is 20-50 milli-int units, depending on test. For quantitative serum tests, the threshold is 5-10 milli-int units, and 1-2 milli-int units, for ultrasensitive tests.

• The β-hcg concentration doubles every 29 to 53 hours during the first 30 days after implantation of a viable, intrauterine pregnancy.

• When ectopic pregnancy is on the differential, a qualitative test is not sufficient. A serum quantitative value is essential to:

  • 1. Interpret imaging (“discriminatory zone”)

  • 2. Have a baseline in the event the β-hcg must be trended

The Discriminatory Zone

• Definition: A concept that there is a quantitative β-hcg level above which the landmarks of a normal intrauterine pregnancy (yolk sac and embryo) should be visible on ultrasound.

  • Therefore, the absence of a gestational sac when β-hcg level is above the DZ is strongly suggestive of nonviable pregnancy, with 50-70% being ectopic.

• Pelvic ultrasound is the gold standard first line imaging modality in early pregnancy and for evaluation of suspected ectopic pregnancy

• Imaging results will fall into 1 of 5 main categories

  • IUP with normal adnexa. Normal pregnancy!

  • IUP with abnormal adnexa. Although rare, must evaluate for heterotopic pregnancy, or presence of both an intra and extra-uterine pregnancy.

  • No IUP, extra-uterine mass with YS/FP. Confirms ectopic pregnancy.

  • No IUP, adnexal mass without YS/FP. Suspicious for ectopic pregnancy

  • No IUP, normal adnexa. Differential includes normal but early IUP, failed IUP, or unidentified ectopic.

• A patient with a confirmed ectopic requires evaluation and counseling by an OBGYN to evaluate candidacy for medical or surgical evaluation.

Management:

• Expectant management: serial quantitative β-hcg level assessment ~q 48 hours, only for stable patients.

  • Scenario A: The β-hcg level rises appropriately (doubles approximately every 2 days).

  • Scenario B: The β-hcg level falls precipitously.

  • Scenario C: The β-hcg level neither rises appropriately nor drops precipitously. Now we should be MORE concerned about ectopic pregnancy, but abnormal IUP is also on the differential.

• Repeat pelvic imaging is very helpful

• Every patient who is stable and an appropriate candidate to trend β-hcg levels will eventually declare herself, with either a located IUP, a failed IUP/SAB, or a confirmed or presumed ectopic pregnancy.

We will cover ectopics for surgical and medical management in a future episode, so stay tuned!