Immune conditions and treatment may affect prenatal screening tests

Posted By Dr. Braverman || 10-Feb-2015

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).

  1. 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.

  1. 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.

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