11/15/04 njm

**Q** Is routine antenatal surveillance indicated with an elevated
maternal serum alpha-fetoprotein (MSAFP)?

**A**. #1 No, it is not routinely recommended. #2 There may be a role in
certain high risk patients.

Basically, there are a series of associations with adverse outcomes, but
the associations are weak, and routine antenatal surveillance is not
indicated, as it does not improve outcome.

On the other hand, if there is a history of elevated MSAFP with certain
other complications, e.g., hypertension or congenital anomalies, then
antenatal surveillance may be indicated, though its benefit is unproven.
In the case of hypertension, antenatal surveillance is already
recommended.

**#1**

**Adverse pregnancy outcome** --- Women who are screen positive for Down
syndrome (low AFP and uE3, high hCG and inhibin A)
\[[22,23](http://www.uptodateonline.com/application/abstract.asp?TR=antenatl/13890&viewAbs=22~23&title=22,23)\],
neural tube defects (high AFP)
\[[22,24,25](http://www.uptodateonline.com/application/abstract.asp?TR=antenatl/13890&viewAbs=22~24~25&title=22,24,25)\],
or trisomy 18 (low AFP, uE3, and hCG)
\[[26](http://www.uptodateonline.com/application/abstract.asp?TR=antenatl/13890&viewAbs=26&title=26)\]
are also at risk for other adverse outcomes, such as fetal growth
restriction, preterm delivery, and fetal demise. Elevated MSAFP levels
as late as 28 weeks are predictive of preterm birth
\[[27](http://www.uptodateonline.com/application/abstract.asp?TR=antenatl/13890&viewAbs=27&title=27)\].
In addition, one retrospective case-control study observed that
nondiabetic women with unexplained very low MSAFP levels
(![](media/image1.png){width="8.333333333333333e-2in"
height="9.236111111111112e-2in"}0.25 MoMs, n = 178) were at increased
risk of delivering a macrosomic infant compared to normal controls (26
versus 13 percent)
\[[28](http://www.uptodateonline.com/application/abstract.asp?TR=antenatl/13890&viewAbs=28&title=28)\].

A low uE3 level (less than or equal to 0.2 ng/mL or 0.15 MoMs) has also
been associated with fetal steroid sulfatase deficiency and early fetal
death. In one series of 103 cases of unexplained low uE3, 41 fetal
demises occurred and 39 of these were at or before 20 weeks of gestation
\[[29](http://www.uptodateonline.com/application/abstract.asp?TR=antenatl/13890&viewAbs=29&title=29)\].
In almost all of these cases, there were additional maternal analyte
abnormalities. Elevated hCG levels are associated with multiple adverse
pregnancy outcomes
\[[25,30](http://www.uptodateonline.com/application/abstract.asp?TR=antenatl/13890&viewAbs=25~30&title=25,30)\].

However, these are weak associations; thus, it is not appropriate to
follow women for these complications based upon screening results alone.
Heightened pregnancy surveillance of women with an elevated MSAFP level
does not achieve earlier or improved detection of complications or
improve pregnancy outcome compared to routine management of such
pregnancies
\[[31](http://www.uptodateonline.com/application/abstract.asp?TR=antenatl/13890&viewAbs=31&title=31)\].
([See \"Etiology, prenatal diagnosis, and prevention of neural tube
defects\"](http://www.uptodateonline.com/application/topic.asp?file=antenatl/9177),
section on Other complications of pregnancy\").

An isolated low hCG concentration
(![](media/image1.png){width="8.333333333333333e-2in"
height="9.236111111111112e-2in"}0.5 MoMs) was not associated with
adverse pregnancy outcome in the only study that evaluated this finding
\[[32](http://www.uptodateonline.com/application/abstract.asp?TR=antenatl/13890&viewAbs=32&title=32)\].

**Pregnancy complications predicted by second trimester maternal serum
screening**

<http://www.uptodateonline.com/application/topic.asp?file=antenatl/13890&type=A&selectedTitle=4~12>

(Reference \# 31 below)

**\# 2**

**Association with other complications of pregnancy** --- An elevated
level of maternal serum alpha fetoprotein in the second trimester of
pregnancy that cannot be explained (eg, by a fetal anomaly, maternal
tumor) is associated with an increased risk of subsequent fetal death.
As an example, a case-control study of 612 women whose pregnancies ended
in fetal death and 2501 women who gave birth to live infants found that
women with an MSAFP level
![](media/image2.png){width="8.333333333333333e-2in"
height="9.236111111111112e-2in"}3.0 MoM had a 10-fold increase in risk
of fetal death as compared to women who had a normal level and the risk
remained high until term
\[[57](http://www.uptodateonline.com/application/abstract.asp?TR=antenatl/9177&viewAbs=57&title=57)\].
Elevated AFP levels were especially likely to be associated with fetal
death in pregnancies complicated by hypertension. In another series, a
high MSAFP value was associated with the following adverse outcomes:
neural tube defects (relative risk = 224), other major congenital
defects (relative risk = 4.7), fetal deaths (relative risk = 8.1),
neonatal death (relative risk = 4.7), low birth weight (relative risk =
4.0), newborn complications (relative risk = 3.6), oligohydramnios
(relative risk = 3.4), abruptio placentae (relative risk = 3.0), and
preeclampsia (relative risk = 2.3)
\[[52](http://www.uptodateonline.com/application/abstract.asp?TR=antenatl/9177&viewAbs=52&title=52)\].
([See \"Pregnancy complications predicted by second trimester maternal
serum
screening\"](http://www.uptodateonline.com/application/topic.asp?file=antenatl/13890)).

The mechanism for poor pregnancy outcome in these cases may relate to
defective placentation leading to higher than normal fetal to maternal
AFP transport. Increased fetal surveillance has been recommended in
these pregnancies, although the benefit of this intervention has not
been demonstrated in controlled trials.

Increased amniotic fluid AFP levels are not associated with an increased
risk of fetal death, in the absence of congenital anomalies
\[[57](http://www.uptodateonline.com/application/abstract.asp?TR=antenatl/9177&viewAbs=57&title=57)\].

**Etiology, prenatal diagnosis, and prevention of neural tube defects**

<http://www.uptodateonline.com/application/topic.asp?file=antenatl/9177>

(Reference #57 below)

**References:**

\# 31

TI - The association of abnormal alpha-fetoprotein and adverse pregnancy
outcome: does increased fetal surveillance affect pregnancy outcome?\
AU - Huerta-Enochian G; Katz V; Erfurth S\
SO - Am J Obstet Gynecol 2001 Jun;184(7):1549-53; discussion 1553-5.\
\
OBJECTIVE: Our purpose was to investigate whether adverse outcomes
associated with elevated maternal serum alpha-fetoprotein levels may be
prevented by intensive antenatal monitoring. STUDY DESIGN: Records of
patients with elevated maternal serum alpha-fetoprotein values of \> or
=2.0 multiples of the median between 1995 and 1999 were reviewed.
Pregnancy histories were analyzed to determine whether intensive
antenatal monitoring (twice-weekly nonstress tests and determinations of
the amniotic fluid index) would have detected the adverse outcomes when
routine obstetric care would have missed them. Women with elevations
explained by multiple gestations, structural abnormalities, or a fetal
death were excluded. RESULTS: The study enrolled 136 patients.
Twenty-three patients were excluded because of multiple gestations,
structural or chromosomal abnormalities, or fetal death or for lack of
available follow-up. Seventy-eight patients had no perinatal
complications, but 12 of these patients underwent heightened
surveillance. One of these patients was subjected to an induction of
labor. Thirty-five pregnancies had complications (21 with preterm labor,
7 with pregnancy-induced hypertension, 6 with growth restriction or
oligohydramnios, 1 with abruptio placentae, and 1 with vasa previa). Of
these 35 pregnancies, 22 were followed up with routine obstetric care
and 13 with heightened surveillance. Heightened surveillance did not
achieve earlier or improved detection in this group. These results
suggest that routine pregnancy management is an adequate strategy for
providing care to pregnant patients with unexplained elevated maternal
serum alpha-fetoprotein levels. Adverse outcomes were detected with
routine pregnancy management or were undetectable even with intensive
management. CONCLUSION: Increased risks of pregnancy-induced
hypertension, preterm delivery, intrauterine growth restriction,
intrauterine fetal death, oligohydramnios, and abruptio placentae are
associated with elevated maternal serum alpha-fetoprotein levels.
However, in our study, routine pregnancy management was an acceptable
method of detecting these adverse outcomes when they were detectable.

\# 57

TI - Second-trimester maternal serum alpha-fetoprotein levels and the
risk of subsequent fetal death.\
AU - Waller DK; Lustig LS; Cunningham GC; Golbus MS; Hook EB\
SO - N Engl J Med 1991 Jul 4;325(1):6-10.\
\
BACKGROUND. The finding of an elevated level of maternal serum
alpha-fetoprotein during the second trimester of pregnancy may indicate
that the fetus has died or is about to die. It is uncertain, however,
whether the finding is associated with an increased risk of fetal death
later in gestation independent of known causes of elevation, such as the
presence of neural-tube defects or multiple gestation. METHODS. To
address this question, we performed a case-control study of 612 women
whose pregnancies ended in fetal death and 2501 women who gave birth to
live infants, using reports from California vital statistics for 1987.
All the women had signleton pregnancies and alpha-fetoprotein screening
in the second trimester. RESULTS. Women with elevated levels of serum
alpha-fetoprotein in the second trimester of pregnancy had an increased
risk of fetal death, and the risk was increased until term. Women with
the highest levels of serum alpha-fetoprotein\--greater than or equal to
3.0 times the median value\--had a very high risk of fetal death (odds
ratio, 10.4; 95 percent confidence interval, 4.9 to 22.0) as compared
with women who had normal levels of alpha-fetoprotein. Maternal serum
alpha-fetoprotein levels that were 2.0 to 2.9 times the median were also
associated with an elevated risk of fetal death (odds ratio, 2.4; 95
percent confidence interval, 1.7 to 3.4). Elevated levels of
alpha-fetoprotein were especially likely to be associated with fetal
death in cases in which maternal hypertension or placental infarction
was also present. CONCLUSIONs. An unexplained elevated level of maternal
serum alpha-fetoprotein in the second trimester of pregnancy is
associated with an increased risk of subsequent fetal death, up to four
to five months after alpha-fetoprotein screening.