Isolated Abnormal Levels of Maternal Alpha Feto-Protein: Is it Significant? A Mini Review

Throughout the course of ante-natal obstetrical care, multiple screening approaches were designed to verify the appropriate development and growth of the fetus. So far, the cause-effect relationship hasn’t been fully understood between all the variables and the negative ante-natal and post-natal outcomes. Of these variables is the alpha-fetoprotein, a maternal serum marker that is measured usually at the beginning of the second trimester. Originally, Alpha-Fetoprotein (AFP) is a glycoprotein of fetal origin produced by the yolk sac, liver and gastrointestinal system in early pregnancy [1]. This protein has the ability to cross the feto-maternal barrier whether intact or due to an unknown damage resulting in detectable values in the maternal serum. After extensive research, maternal serum alpha feto-protein levels became a part of the triple (unconjugated estriol (uE3), hCG, and AFP levels) and quadruple (unconjugated estriol (uE3), hCG, AFP and inhibin A levels) ante-natal screening tests for the assessment of the fetal wellbeing. The different combinations of the mentioned markers and their most common associated abnormalities are presented in table 1. Elevated values more than2.0 or 2.5 MoM as the upper limit of normal usually warrant further investigations to rule out congenital malformations such as Neural Tube Defects (NTD) and gastro-intestinal abnormalities. However, the extensive investigations that are performed ante-nataly including the detailed ultrasounds might show a morphologically normal fetus. It should be highlighted that race and ethnicity, gestational age, multifetal gestation, maternal weight and diabetes status should be taken into consideration when interpreting the reported results as they have been shown to affect the maternal serum alpha fetoprotein levels. 

Table 1: Triple and Quadruple antenatal screening tests and the most common associated anomalies.

Studies done so far revealed a hypothetical link between unexplained isolated elevated levels of AFP (above 2.0 MoM) and adverse pregnancy outcomesnamely preterm premature rupture of membranes, preterm birth and low birth weight with an OR of 10.4, 3.5, 2.7 and 2.6 respectively [2-4]. Further evaluations revealed a possible association with life threatening situations such as pre-eclampsia and Intra-Uterine Fetal Demise (IUFD). In 2008, 295 pregnant women who had second trimester MSAFP screening were followed throughout pregnancy in order to document the post-natal outcomes. It was found that significantly higher MSAFP levels were associated with preterm labor, pre-eclampsia, oligo-hydraminios and low birth weight [5]. In 2017, another study showed that elevated MSAFP was associated with a 7.254 OR risk of having poor pregnancy outcomes, with an OR of 4.4 of IUFD [6,7]. It must be noted as well that lower than normal MSAFP levels can be associated with aneuploidies, miscarriages, and intra-uterine fetal demises [8]. However, according to a meta-analysis performed by Goto, et al. in a trial to detect the predictive potential of abnormal values of maternal serum markers and small for gestational age babies, the diagnostic accuracy of both MSAFP and human chorionic gonadotropin was found to be low. In other words, if the pregnant patient was found to have isolated abnormally elevated MSAFP or hCG during the screening tests, a direct link with Intra-Uterine Growth Restriction (IUGR) and Small for Gestational Age (SGA) can’t be assumed [9]. Therefore isolated abnormal MoM values should be interpreted cautiously. Pregnant patients who are found to have elevated MSAFP should be managed as high risk pregnancies and extensive workup should be done in order to assure a plausible ante- and post-natal outcome.