Second-Trimester Serum Screening Case File

Second-Trimester Serum Screening Case File

Eugene C. Toy, MD, Konrad P. Harms, MD, Keith O. Reeves, MD, Cristo Papasakelariou, MD, FACOG

Case 3

A 31-year-old G1 Caucasian female at 17 2/7 weeks’ gestation undergoes a second-trimester maternal serum quad screen. Her medical history is unremarkable. Her weight is 235 lb, however, and she reports having somewhat irregular menstrual periods. At her 16-week visit, she was counseled about maternal serum screening for fetal abnormalities and opted to undergo the blood draw for this. Her values are as follows:

AFP 3.1 MoM

uE3 1.4 MoM

hCG 0.9 MoM

Inhibin A 0.8 MoM

 

Based on these results, she is referred for genetic counseling and targeted sonography.

➤ What are some possible explanations for her elevated maternal serum alpha-fetoprotein (MSAFP)?

➤ Should this screening test be repeated?

ANSWERS TO CASE 3:

Second-Trimester Serum Screening

Summary: A 31-year-old G1 at 172/7 weeks’ gestation has an elevated MSAFP of 3.1 MoM.

➤ Some possible explanations for elevated MSAFP: Fetal open spina bifida, multiple gestations, anencephaly, erroneous gestational age, encephalocele, fetal death, ventral wall defect, miscellaneous metabolic/structural abnormalities.

➤ Repetition of screening test: No, because of the markedly elevated value.

ANALYSIS

Objectives

1. Describe the types of second-trimester serum testing for fetal aneuploidy.
2. Describe the role of serum testing for fetal neural tube defects.
3. Understand the diagnostic approach to abnormal second-trimester screening.

Considerations

In this patient, the MSAFP is 3.1 multiple of the median (MoM). Repeat testing of MSAFP levels will result in a reduction of the false-positive rate by nearly half. This is a result of regression toward the mean, a statistical property that states the more often a test is repeated, the more likely the result will represent the “true” value—meaning at or near “normal,” (assuming the fetus is structurally intact). From a practical standpoint, however, most centers do not advocate repeat testing if the initial value exceeds 3.0 MoM. This is because the repeat level is not likely to reach normal limits when the initial value is this elevated. Additionally, the likelihood of some type of pregnancy abnormality is inherently higher with increasing values of MSAFP (open spina bifida, ventral wall defect, twins). At the time of her ultrasound examination, the patient is found to be carrying a 17-week size fetus with open neural tube defect or myelomeningocele of the lumbosacral spine.

APPROACH TO

Second-Trimester Serum Screening

Elevated MSAFP

Is amniocentesis warranted if open spina bifida (OSB) is identified on sono? Rarely, spina bifida is associated with fetal aneuploidy. Some series report the incidence as high as around 15%, especially if additional anomalies are present. When isolated, the actual risk is probably around 1% to 2%. For this reason, karyotyping of the fetus is indicated. An abnormal karyotype would have significant impact on prognosis, and for this reason, patients may wish to know this information for decision making about continuing or terminating the pregnancy. Recurrence risk for this condition would be different if the fetal karyotype is normal, and the recommended tests in subsequent pregnancies would also be affected. Additionally, since an option of in utero treatment in the form of fetal surgery is being studied, a normal fetal karyotype should be confirmed. Measurement of amniotic fluid AFP has no correlation with degree of severity, size of lesion, or anticipated neurologic complications.

How should a couple found to have a fetus with an open spina bifida (OSB) be counseled about outcomes?

The long-term management of spina bifida in children (and adults) continues to evolve. At our center, consultation with a pediatric neurosurgeon is performed to give the prospective parents the latest information. Most newborns (80%-90%) will require ventriculoperitoneal shunting. The need for shunt revisions is based on development of shunt infection (around 5% in most institutions) or obstruction (0-6 per 10 patients-years) [1; level III]. Frequent shunt revision is associated with worse prognosis for neurologic function. For newborns with lumbosacral open spina bifida, most will require some combination of wheelchair assistance and/or crutches with braces. Mobility tends to deteriorate with age. Cognitive impairment is seen frequently, with reports of 15% incidence of mild mental retardation and 70% incidence of learning disability in children with low lesions (below L3). Higher lesions and larger lesions are associated with higher rates of these types of disabilities.

Is route of delivery important in prognosis for newborn?

There are conflicting and scant data about whether route of delivery impacts prognosis for the newborn with open spina bifida. There is no clear evidence that elective cesarean delivery has a direct benefit on outcome (2; level II-2). If the fetus is in a breech presentation, most would advocate for elective cesarean. Some centers report lower infection rates in the newborn’s CNS if delivered by elective C-section, but the long-term implications from this are unclear (1; level III). Others recommend C-section based on the following fetal criteria: (1) lesion protrudes more than 1 cm from surface of the back; (2) intact knee movement; and (3) absence of other severe, untreatable anomalies. With respect to timing and coordination of ancillary medical teams, a scheduled cesarean offers advantages, as these newborns typically need surgical closure relatively soon after delivery.

What risk factors for fetal neural tube defects does she have that are modifiable? (3; level III)

Weight (obese women about 2× higher risk)

Use of folate supplements (400 μg/d is recommended in low-risk women)

Teratogenic drugs and alcohol

Maternal diabetes (optimal glucose control preconceptionally)

Maternal fever

Genetic susceptibility (personal history or previous affected fetus) is not modifiable.

What form of prenatal testing is warranted in subsequent pregnancies?

Should the fetus in this current affected pregnancy have a normal chromosome complement, subsequent pregnancies need to be evaluated for recurrence of neural tube defects (NTD). Prior to conception, she should receive daily folic acid supplementation in the dose of 4 mg, typically given as 1 mg 4× each day (4; Level I). Early sonography is reasonable to exclude anencephaly. Amniocentesis would be indicated in subsequent pregnancies in the early second trimester, when visualization of a small spinal defect may not be readily accomplished. Testing for amniotic fluid acetylcholinesterase in subsequent pregnancies is routinely performed as well as AFP measurement.

What obstetrical implications are associated with an unexplained MSAFP?

Numerous retrospective series have delineated a relationship between unexplained elevated MSAFP and a variety of adverse outcomes. Higher rates of stillbirth, preterm labor, preeclampsia, and intrauterine growth restriction (IUGR) have all been reported from series of women with high MSAFP values (typically ≥ 2.5 MoM). However, use of midtrimester MSAFP to accurately predict complications is not feasible, given the poor sensitivity and specificity of this biomarker. Accordingly, no large-scale prospective trial of increased antepartum surveillance for these patients has demonstrated any added benefit in the early identification or prevention of such complications. Nonetheless, most clinicians choose to evaluate growth and fetal well-being in the third trimester as they would other high-risk pregnancies (5; Level III).

What does the evaluation consist of with an unexplained elevated MSAFP?

Once wrong dates, twins, and fetal anomalies that can be associated with an elevated MSAFP have been excluded by ultrasound, the option of amniocentesis should be presented. Measurements of amniotic fluid AFP (AFAFP) together with acetylcholinesterase (AChE) improve the accuracy of detecting

an open neural tube defect. AChE is derived predominantly from fetal neural tissue and is therefore more specific for central nervous lesions. However, targeted ultrasound in experienced hands can also be as sensitive and specific as AFAFP plus AChE and this information may be helpful to a patient when deciding on whether to proceed with invasive testing. The higher the MSAFP level the greater the risk of fetal abnormalities. Exceedingly high levels of MSAFP (> 5 or 6 MoM and AFAFP > 10 MoM) are associated with congenital nephrosis. This is an autosomal recessive disorder that leads to nephrotic syndrome. It is more common in the Finnish population, however, it can also occur in those of non-Finnish decent. Nephrotic syndrome in infancy can be lethal without treatment which may involve dialysis or renal transplant. Antenatal diagnosis can be strongly suspected in those with a very high MSAFP level, however, additional genetic testing for the most common mutations involving the nephrin (NPHS) gene may also be offered to improve the accuracy of antenatal diagnosis.

Comprehension Questions

3.1 A 25-year-old G1P0 at 19-weeks’ singleton by last menstrual period (LMP) consistent with 7-week crown to rump length (CRL) gestation is found to have an elevated MSAFP 3.1 MoM. An ultrasound is done confirming a singleton fetus without apparent anatomical abnormalities. What is the next step in management?

A. Offer amniocentesis for measurement of AFAFP and AChE.

B. Offer chorionic villus sampling.

C. Offer repeat serum alpha-fetoprotein in 2 weeks.

D. Explain to the patient that with a normal ultrasound, there are unlikely to be any complications to the pregnancy.

3.2 A 27-year-old woman G2P1 at 16 weeks’ gestation is noted to have a decreased MSAFP, with an increased risk of trisomy 18. Which of the following statements is most accurate?

A. A fetal ultrasound showing wrong dates is unlikely to show a

change in the trisomy 18 risk.

B. The serum hCG level is likely higher than expected.

C. The serum unconjugated estriol level is likely higher than expected.

D. The serum PAPP-A level is part of the calculation of the aneuploidy risk.

ANSWERS

3.1 A. Although amniocentesis should be offered in anyone with an unexplained elevated MSAFP, a targeted ultrasound in experienced hands can be just as sensitive and specific as AFAFP plus AChE in detecting open neural tube defects, thus avoiding the need to perform amniocentesis. Ultimately the decision to pursue invasive testing can be left to each individual patient and recommendation for further testing can be based on whether additional genetic testing for other conditions is warranted. Although there is no standard way of managing patients with an unexplained MSAFP level, it is not unreasonable to monitor fetal growth with periodic ultrasounds in the third trimester given the association with IUGR.

3.2 A. An increase in the fetal trisomy 18 risk is associated with a decrease in the serum analytes of hCG, AFP, and unconjugated estriol. Unlike Down syndrome, where the gestational age correction can alter the Down syndrome risk, with trisomy 18, wrong gestational age rarely leads to a normalization of the trisomy 18 risk. This difference is principally due to the direction of the hCG level with gestational age, which falls from 10 weeks gestation through 20 weeks gestation, and the fact that Down syndrome is associated with an elevated hCG.

Clinical Pearls

See US Preventive Services Task Force Study Quality levels of evidence in Case 1

➤ All women of reproductive age should consume healthy diets, including foods rich in folic acid. Because dietary sources are rarely adequate, periconceptional use of folic acid supplementation (400 μg daily in low-risk women) is recommended (Level I).

➤ Maternal serum screening for fetal neural tube defects (and other anomalies) should be offered to all pregnant women in the early second trimester (Level I).

➤ Further evaluation must be offered to all women found to have elevated levels of maternal serum alpha-fetoprotein (Level II-3).

➤ Women found to be carrying a fetus with a neural tube defect should receive appropriate counseling from specialists knowledgeable about treatment and prognosis for these conditions as part of the decision-making process about pregnancy management (Level III).

➤ Delivery options for fetuses with neural tube defects should be individualized depending on expected prognosis and specific characteristics of the lesion (Level III).

REFERENCES

1. Doherty D, Shurtleff DB. Pediatric perspective on prenatal counseling for myelomeningocele. Birth Defects Res (Pt A). 2006;76:645-653. Overview of key features of this malformation, focusing on prognosis and typical postnatal course (Level III). 

2. Lewis D, Tolosa JE, Kaufmann M, et al. Elective cesarean delivery and long-term motor function or ambulation status in infants with meningomyelocele. Obstet Gynecol. 2004;103:469-473. In this retrospective review of one center’s experience with long-term assessment of motor function in children born with spina bifida, there was no advantage to elective cesarean delivery in terms of preserving motor function or ambulation status (Level II-2). 

3. Mitchell LA. Epidemiology of neural tube defects. Amer J Med Genet (Pt C). 2005;135C:88-94. Review of risk factors and known etiologies of common neural tube defects, emphasizing preventable causes amenable to preconceptional and periconceptional interventions (Level III). 

4. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin study. Lancet. 1991;338:131-137. This large multicenter randomized controlled trial demonstrated a 72% reduction in recurrence of NTD when 4 mg folic acid are consumed daily prior to and during subsequent pregnancies (level I). 

5. Wilkins-Haug L. Unexplained elevated maternal serum alpha-fetoprotein: what is appropriate follow-up? Curr Opin Obstet Gynecol. 1998;10:469-474. In this review of studies examining outcomes of pregnancies associated with unexplained elevated MSAFP, it is clear that while these women are at higher risk, current means of antepartum surveillance fall short of achieving reductions in adverse outcomes (level III).

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