Prenatal screening tests aim to detect categories of expectant women at
higher risk for having a baby with a birth defect. To detect early fetal
abnormalities, pregnant women undergo screening test during the first
(10 weeks 3 days through 13 weeks 6 days of gestation) and second trimester
(15 through 18 weeks of gestation). These tests combine maternal blood
screening with an ultrasound of the fetus that determines nuchal translucency
(fluid beneath the skin behind baby's neck) and the crown–rump
length (CRL), among other parameters, to measure risk for fetal abnormalities
such as Down syndrome (trisomy 21: T21) and trisomy 18.
These tests are the most accurate and the least invasive. When combined,
first and second-trimester screening can detect up to 88% of fetal abnormalities
with a 5% false positive rate (fetal abnormalities will be detected in
5 pregnancies out of 100 although the babies will be totally healthy).
- First-trimester: serum integrated screen
The first-trimester screening combines a measurement of nuchal translucency,
pregnancy-associated plasma protein A (PAPP-A) and the free beta subunit
of human chorionic gonadotropin (βhCG).
Following embryo implantation, a portion of placenta, the
syncytiotrophoblast, produces the hormone βhCG. It is the first pregnancy-associated
hormone detected in the blood during pregnancy, as soon as 11 days post
conception. Pregnancy-associated placental protein-A (PAPP-A) circulates
in maternal blood. Its maternal serum concentration in fetal trisomy 21
is decreased during the first trimester.
This is the method of choice to screen for Down syndrome (T21). The measurements
of free βhCG and PAPP-A are affected by maternal and pregnancy characteristics,
including maternal racial origin, weight, smoking status and method of
conception. These parameters are taken into account in the calculation
of risks for fetal abnormalities.
During pregnancy, various pathologies could over- or under estimate Down
syndrome risk by altering βhCG and PAPP-A levels.
- Systemic lupus erythematosus (SLE)
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease affecting
joints, skin, brain, heart and several other organs. A study involving
n=1150 singleton pregnancies that include 10 pregnancies with Systemic
Lupus Erythematosus (SLE) showed thatfree βhCG maternal serum levels are significantly elevated in SLE
pregnancies. These high free βhCG levels could be due to an altered renal function
in SLE patients (diminished renal excretion so higher βhCG serum
level). Alternatively, SLE causes placental vasculitis which induces local
hypoxia, factor known to enhance βhCG production; this could be a
compensatory mechanism to preserve pregnancy.
No differences have been reported in PAPP-A levels between SLE and control
pregnant populations.
- Insulin-dependent diabetes mellitus (IDDM) or type-1 diabetes
IDDM is a chronic condition where the pancreas is unable to secrete sufficient
amount of insulin, a hormone involved in the cellular production of energy
by glucose. A recent study including n=489 pregnancies with IDDM and n=83972
healthy pregnancies showed thatPAPP-A levels were significantly lower in IDDM pregnancies (15%) while free βhCG levels were not affected. These results have
been confirmed by other studies where PAPP-A levels were reduced up to 20%.
The PAPP-A levels reduction requires correction in the calculation of risks
for chromosomal defects to avoid an increase in the false positive rate.
- Second-trimester: quad marker screen
The second-trimester screening combines measurement of four serum markers:
alpha-fetoprotein (AFP), total human chorionic gonadotropin (hCG), unconjugated
estriol (uE3), and inhibin A.
- Antiphospholipid syndrome (aPL)
Antiphospholipid (aPL) syndrome is an immune disorder characterized by
the presence of abnormal blood clotting associated to aPL antibodies.
First recognized in patients with systemic lupus erythematosus (SLE),
this disorder may also occur alone. Pregnant women with aPL syndrome are
at high risk for recurrent spontaneous abortions (RSA), intra-uterine
growth retardation (IUGR), preterm delivery, preeclampsia and other vascular issues.
A low level of maternal serum
α-fetoprotein (AFP) is associated with chromosomal abnormalities particularly
trisomy 21
(T21) whereas high levels of maternal serum AFP carry an increased risk
of adverse pregnancy outcomes.
Several studies have reported
higher maternal serum AFP levels in SLE or aPL pregnant women compared to the control group
with no neural defects or fetal abnormalities. Placental injuries are very common in SLE and aPL syndrome and could
explain the high incidence of supranormal AFP levels.
An abnormal maternal serum AFP level is also associated with higher prednisone
dose and higher risk of preterm delivery.
Altogether, because AFP is involved in the calculation of the risk of
T21, these higher values led to
underestimate the risks for T21 that require a correction for its calculation.
- Insulin-dependent diabetes mellitus (IDDM) or type-1 diabetes
A meta-analysis study comparing the four second-trimester serum markers
between pregnant women with or without IDDM reported that median levels for
AFP and uE3 were statistically significantly lower in pregnant women with IDDM. The other markers were not significantly different between the two groups.
Therefore, AFP and uE3 levels should be adjusted in women with IDDM in
prenatal screening for Down syndrome.
Any disruption of the feto-maternal barrier (premature membrane rupture, placental injuries) result in
inflammation that is the principal cause of placental permeability (leakage). When placental integrity is damaged,
this could lead to an alteration of several maternal factor levels such as AFP.
At Braverman Reproductive Immunology, we see a large number of patients with inflammatory diseases who should
be aware that their
prenatal screening may be affected by their conditions and treatments.