MSAFP
MSAFP
Abstract & Commentary
Synopsis: Pregnant women with extreme MSAFP values in the second trimester have an increased risk of fetal and infant deaths.
Source: Krause TG, et al. Obstet Gynecol. 2001;97(2):
277-282.
Krause and colleagues reviewed data from 77,149 pregnancies screened with maternal serum alpha feto-protein (MSAFP). Armed with a powerful Danish national database, Krause et al were able to obtain comprehensive follow-up with regard to spontaneous abortion, fetal demise, infant death, delivery timing, and birth weight. Since MSAFP elevation could well have represented a sign of fetal demise or imminent demise at the time of sampling, Krause et al plotted spontaneous abortions according to weeks post-sampling and found, not surprisingly, a high rate of abortion soon after the patients’ bloods were drawn. However, after 3 weeks the rate plateaued. For this reason, Krause et al focused particularly on fetal death after 3 weeks as a more clinically relevant variable against which to compare high (> 2.5 MoM) and low (< 0.25 MoM) levels of MSAFP. Krause et al arbitrarily chose 28 weeks as a cutoff below which fetal death was labeled as an "abortion."
These results indicated that having an MSAFP above 2.5 MoM predisposed patients to a higher risk of preterm delivery (PTD) (relative risk [RR], 4.8; 95% confidence interval [CI], 4.1-5.5%), small-for-gestational age (SGA) (RR, 2.8; CI, 2.4-3.2%), low birth weight (LBW) (RR, 5.8; CI 9.7-16.1%), spontaneous abortion (SAB) (RR, 12.5; CI 9.7-16.1%), and infant death (RR, 1.9; CI 1.2-2.8%). Patients with MSAFP values below 0.25 MoM had a RR of PTD of 2.2; CI 1.3-3.8%, and a SAB RR of 15.2; CI 9.3-24.8%. The RR of stillbirth (after 28 weeks) was 4.0 with a low MSAFP and 2.9 for high MSAFP, but neither achieved statistical significance after adjusting for LBW.
Comment by John C. Hobbins, MD
MSAFP screening for fetal neural tube defects (NTD) came into being in the 1970s. A decade later, estriol (E3) and human chorionic gonadotropin (HCG) were added to the screening armamentarium to identify pregnancies at high risk for fetal Down syndrome (DS). In the later 1980s and early 1990s, reports began to emerge suggesting higher rates of adverse outcome (unrelated to fetal anomalies) in patients having elevations of MSAFP and HCG in the second trimester. The outcome that seemed to generate the most attention was a higher rate of stillbirth. Because of this, many patients with elevated MSAFPs, having made it through the anxiety-provoking amniocentesis and/or ultrasound testing to rule out NTD or ventral wall defects, were then subjected to a regimen of once or twice weekly nonstress testing (or biophysical profiles) after 28-30 weeks of gestation.
When our antenatal testing center became flooded with these patients (representing 5% of our pregnant population), I reviewed the literature looking for instances where high MSAFP was associated with stillbirth in the absence of fetal growth restriction (SGA), and could find few cases where the stillborn fetus was appropriately grown. In the above Danish study, only 10 of the 282 nonanomalous stillbirths in the study were in patients whose MSAFP was > 2.5 MoM. The RR of stillbirth in this category was 2.9, but, after adjusting for LBW, the RR was not statistically significant (0.9). Unfortunately, Krause et al did not account for how many of the LBW stillbirths in the high-MSAFP category were SGA, but from other studies one could assume that a large proportion was.
The study tells us that patients with extremely low-MSAFP levels (0.025 MoM) are at greater risk for preterm birth, low birth weight, and spontaneous abortion. Although a few reports in the literature have shown similar results, low MSAFP has gotten far less attention than high MSAFP, and interestingly, elevated HCG, which may be an even better predictor of adverse outcome than high or low MSAFP, has barely raised a ripple of interest.
It is not completely clear why elevations of MSAFP and HCG portend trouble. However, it is likely the placenta is the culprit responsible for the adverse outcomes. Since AFP is produced almost exclusively by the fetus, whatever is in the maternal circulation (in microgram amounts compared with milligram amounts in the fetus) gets there across the placenta. Usually the placenta grudgingly allows AFP across, but when it acts as an inefficient excluder of AFP in the second trimester, it undoubtedly is giving a warning that it may be a poor supplier of oxygen and nutrients in the third trimester. On the other hand, HCG is a product of the placenta and elevations of HCG represent either greater production or release of the substance from placental cells. In vitro studies have shown that the placenta releases HCG under the influence of hypoxia.
The big question is what to do when components of a triple screen suggest a higher rate of adverse outcome? Although our record so far for preventing preterm birth is dismal, with "raised antennas" we might possibly do better. Certainly spontaneous abortion would be difficult to prevent, and infant death often results from factors that cannot be controlled, even when caregivers are forewarned. Perhaps because of this, many have concentrated on preventing stillbirth (through timely delivery) as a way to have a positive impact. However, doing serial nonstress tests on every patient with an abnormal triple screen is an inefficient way to identify fetuses most apt to be snatched from death’s jaws. A better way would be to narrow down the group to be watched by performing 1 ultrasound after 30 weeks on those with worrisome triple screens and identifying those that have small-for-dates fetuses. By performing umbilical artery Dopplers in those fetuses with estimated fetal weights below the 10th percentile (or abdominal circumferences below the 5th percentile) one could more precisely identify the truly compromised fetus that would benefit from timely delivery.
By concentrating on the undergrown fetus one could prevent fetal death in those most likely to be stillborn and, perhaps, through improvement in uterine blood flow by lateral recumbent positioning and by optimizing the timing of delivery through comprehensive fetal Doppler testing, we could also improve overall neurological outcome.
Not only would this "coned down" version of fetal surveillance most efficiently prevent most stillbirths in patients with elevated MSAFP, but it would be more cost effective. About 5% of all patients will have an MSAFP above 2.5 MoM. Weekly NSTs or biophysical profiles starting at 30 weeks would result in an average of 8 to 10 tests per pregnancy (that might not provide the clues to a fetal death 5 to 6 days later). Doubling up on the testing (biweekly) would result in 16 to 20 investigations per patient. On the other hand, 1 third-trimester ultrasound should identify most, if not all, of the SGA fetuses in the at-risk group. Using the Danish RR of 2.8 in high MSAFP, one would expect an incidence of SGA of 28%, at most, leaving the remaining 72% to have a test-free remainder of their pregnancies. The SGA pregnancies would then be followed with serial Doppler evaluations, which, by providing early evidence of fetal compromise as shown in many studies, including 2 meta-analyses, is far more efficient in optimizing perinatal survival than NSTs. And from a public health standpoint, the cost savings would be prodigious.
Suggested Reading
1. Waller DK. Obstet Gynecol. 1996;88:816-822.
2. Divon M. Am J Obstet Gynecol. 1996;174:10-14.
3. Benn PA, et al. Obstet Gynecol. 1996;87(2):217-222.
4. Marsal K. Baillieres Clin Obstet Gynaecol. 1988;2:
125-144.
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