1.4 Prenatal Genetic Screening, Diagnostic Testing & Hereditary Risk

Genetic Screening vs. Diagnostic Testing

Per ACOG Practice Bulletin 226 and ACNM guidelines, all pregnant patients must be offered both prenatal aneuploidy screening and invasive diagnostic testing, regardless of maternal age. Midwives provide balanced, non-directive counseling respecting patient autonomy.

Aneuploidy Screening Modalities Comparison

Interpreting Serum Screening Patterns

• Trisomy 21 (Down Syndrome) on Quad Screen: The mnemonic "HI" indicates HCG and Inhibin A are Elevated, while MSAFP and unconjugated estriol (uE3) are Decreased.
• Trisomy 18 (Edwards Syndrome) on Quad Screen: All three serum analytes (MSAFP, hCG, uE3) are Decreased, with inhibin A low or normal.
• Isolated Elevated MSAFP (≥2.5 Multiples of the Median [MoM]): Associated with open neural tube defects (anencephaly, spina bifida), abdominal wall defects (gastroschisis, omphalocele), multifetal gestation, placental abruption, and fetal demise.
  • First Step: The most common cause of an aberrant MSAFP is inaccurate gestational dating. The midwife must immediately order a diagnostic ultrasound to confirm gestational age, evaluate fetal viability, exclude twins, and visualize the fetal spine and cranium.

Carrier Screening Guidelines

• Universal Carrier Screening: All pregnant individuals should be offered carrier screening for Cystic Fibrosis (CFTR gene) and Spinal Muscular Atrophy (SMA, SMN1 gene), along with a CBC to screen for hemoglobinopathies.
• Hemoglobinopathy Workup: If the red blood cell mean corpuscular volume (MCV) is <80 fL in the absence of iron deficiency, obtain a hemoglobin electrophoresis to detect sickle cell trait/disease, hemoglobin C, or beta-thalassemia. For alpha-thalassemia trait (common in Southeast Asian, Mediterranean, and African ancestries), normal electrophoresis requires alpha-globin gene deletion DNA testing.

Invasive Diagnostic Testing Procedures

Diagnostic testing provides definitive fetal karyotype or chromosomal microarray analysis (CMA).

1. Chorionic Villus Sampling (CVS):
   • Timing: 10 0/7 to 13 6/7 weeks.
   • Method: Transcervical or transabdominal aspiration of placental trophoblast tissue under continuous ultrasound guidance.
   • Advantages: First-trimester definitive genetic results; allows earlier, safer termination if chosen.
   • Disadvantages & Risks: Cannot assess for neural tube defects (does not sample amniotic fluid AFP); procedural pregnancy loss risk is approximately 0.1% to 0.2% (1 in 500 to 1,000) in experienced centers. If performed prior to 10 0/7 weeks, carries a documented risk of fetal transverse limb reduction defects.
2. Amniocentesis:
   • Timing: 15 0/7 to 20+ weeks.
   • Method: Transabdominal aspiration of 15–20 mL of amniotic fluid containing desquamated fetal amniocytes.
   • Advantages: Definitive genetic testing (karyotype/microarray) plus diagnostic assessment of Amniotic Fluid Alpha-Fetoprotein (AFAFP) and Acetylcholinesterase (AChE) to diagnose open neural tube defects.
   • Disadvantages & Risks: Procedure loss rate is approximately 0.1% (1 in 1,000). Transient vaginal spotting or amniotic fluid leakage occurs in 1–2%.
   • Midwifery Rule: Administer 300 mcg RhD immune globulin to all unsensitized Rh-negative patients immediately following CVS or amniocentesis.

Hereditary Cancer Risk Assessment

The same visit that covers aneuploidy and carrier screening is where hereditary cancer risk is captured, because the blueprint expects the midwife to screen for genetic carrier trait and hereditary cancer testing by personal and family history.

• Take a three-generation pedigree covering both maternal and paternal lineages: cancer type, age at diagnosis, bilateral or multifocal disease, and ancestry.
• Red flags for hereditary breast and ovarian cancer syndrome (BRCA1/BRCA2): breast cancer before age 50, triple-negative breast cancer before 60, ovarian, fallopian tube, or primary peritoneal cancer at any age, male breast cancer, pancreatic or metastatic prostate cancer, two or more primaries in one person, and Ashkenazi Jewish ancestry with any of these.
• Red flags for Lynch syndrome: colorectal or endometrial cancer before age 50, multiple Lynch-spectrum cancers (colorectal, endometrial, ovarian, gastric, urothelial), or a known family mutation.
• The USPSTF gives a B recommendation to assessing women with a personal, family, or ancestry-associated risk of BRCA1/2 mutations with a brief familial risk tool, and referring those who screen positive for genetic counseling and, if indicated, testing.
• Refer positives to a genetics professional rather than ordering a multigene panel directly; results drive surveillance, risk-reducing surgery, and cascade testing of relatives.