Technical Update No. 462: Abnormal maternal serum markers and adverse pregnancy outcomes

Objective

To review the current data on the association between abnormal first- or second-trimester aneuploidy screening serum markers and adverse pregnancy outcomes, as well as provide health care professionals with recommendations for managing patients with such abnormal serum marker results.

Target Population

Health care providers involved in antenatal care for pregnant individuals, including general practitioners, obstetricians, midwives, and maternal-fetal medicine specialists.

Benefits, Harms, and Costs

Implementation of the recommendations in this technical update should increase clinician competency in managing abnormal maternal serum markers results with respect to preventive interventions and antenatal surveillance.

∗Evidence

Published literature in English was retrieved through searches of PubMed or MEDLINE, CINAHL, and The Cochrane Library through to May 2024 using appropriate controlled vocabulary via MeSH terms (fetal growth retardation, small for gestational age, preeclampsia, preterm birth) and keywords (fetal growth restriction, growth retardation, IUGR, FGR, low birth weight, small for gestational age, Doppler, placenta, preeclampsia, hypertensive disorders of pregnancy, hCG, human chorionic gonadotropin, PAPP-A, pregnancy-associated plasma protein-A, inhibin-A, unconjugated estriol, PlGF, placental growth factor, AFP, alpha-fetoprotein, prenatal screening). Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, and observational studies. Grey literature was identified by searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies.

Validation Methods

The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretations).

Intended Audience

Obstetricians, family physicians, nurses, midwives, maternal-fetal medicine specialists, and other health care providers who provide perinatal care.

Tweetable Abstract

Technical update for the interpretation and management of abnormal serum markers

Summary Statements

• 1.
  Abnormal levels of placenta-derived proteins used in the first trimester (low PAPP-A, βhCG, or PlGF) or second trimester (low uE3, or high elevated hCG, AFP, or Inhibin-A) aneuploidy screening (also known ‘markers’) may be associated with placenta-mediated complications such as preeclampsia, fetal growth restriction, placental abruption, stillbirth, and preterm birth. (Strong)
• 2.
  The optimal management of patients with abnormal markers remains unclear and depends on the local availability of resources such as ultrasound and maternal serum markers. (Moderate)
• 3.
  The individual predictive capacity of these markers for placenta-mediated complications is low and falls below the stringency required for an effective screening test. (Strong)
• 4.
  First-trimester multimodal screening that combines maternal characteristics, biophysical markers (blood pressure and uterine artery Doppler when available), and serum markers (PlGF and/or PAPP-A) is the most accurate screening method for the prediction of preterm preeclampsia and using aspirin prophylaxis. (Strong)

Recommendations

• 1.
  Aneuploidy screening serum markers should not be used alone to screen for placenta-mediated complications unless they are considered within a broader multimodal screening strategy. (Good Practice Point, Moderate Quality)
• 2.
  In patients in which maternal serum markers are not available (e.g., those who performed non-invasive prenatal testing [NIPT], had a preimplantation genetic testing, or those who decline aneuploidy screening, etc.), first- or second-trimester serum markers should not be tested solely for the purpose of predicting placenta-mediated complications. (Good Practice Point, Moderate Quality)
• 3.
  A single abnormal first- -trimester marker, or a single mildly abnormal second-trimester marter, are not an indication for aspirin prophylaxis to prevent placenta-mediated complications. (Good Practice Point, Moderate Quality)

  • Mildly abnormal 1^st trimester markers: PAPP-A, PlGF<0.4 MoM; βhCG<0.35 MoM
  • Mildly abnormal 2^nd trimester markers: uE3≤0.5 MoM; Inhibin≥2.0 MoM; AFP>1.8 MoM, hCG≥2.0 MoM
• 4.
  Aspirin prophylaxis should be considered in cases where there is:

  • (i)
    First trimester serum markers: a combination of two abnormal serum markers, particularly low PAPP-A (<0.4 MoM) and low PlGF (<0.4 MoM);
  • (ii)
    Second trimester serum markers: the presence of one severely abnormal serum marker (Inhibin≥3.0 MoM; AFP ≥ 2.5 MoM, hCG≥4.0 MoM) or the combination of two mildly abnormal serum markers in the second trimester;
  • (iii)
    a positive first-trimester multimodal screening that includes maternal characteristics, biophysical markers (blood pressure and uterine artery Doppler when available), and serum markers (PlGF and/or PAPP-A). and should be ideally started by ≤16 weeks of gestation at bedtime until 36 weeks of gestation (Good Practice Point, Moderate Quality)
• 5.
  In the absence of first- or second-trimester serum screening, risk stratification during the second trimester using multimodel screening (which should include maternal PlGF test and/or uterine artery Doppler) may be considered to guide maternal and fetal surveillance. (Good Practice Point, Moderate Quality)
• 6.
  Patients identified as high risk for placenta-mediated complications should be educated about the signs and symptoms of preeclampsia. These patients should undergo close blood pressure monitoring and fetal growth should be assessed by ultrasound at least once between 30-34 weeks of gestation, including Doppler assessment. (Good Practice Point, Moderate Quality)