Second-trimester maternal serum alpha-fetoprotein (MSAFP) iselevated in women with adverse pregnancy outcome associated with inherited thrombophilias

Obstetric complications, such as severe pre-eclampsia, fetal growth restriction, abruptio placentae, or stillbirth are associated with abnormally elevated second-trimester maternal serum alpha-fetoprotein (MSAFP) and β subunit of human chorionic gonadotrophin (βhCG). This has been attributed to placental abnormalities. Women with thrombophilias have been shown to have abnormalities of the placenta resulting in adverse pregnancy outcome in these patients. The purpose of the present study was to evaluate whether women with pregnancy complications and inherited thrombophilias have abnormally elevated second-trimester MSAFP or βhCG. Sixty-two women with pregnancy complications were tested for inherited thrombophilias several months after delivery. The thrombophilia group included 29 women with pregnancy complications and an inherited thrombophilia and the control group included 33 other patients without thrombophilia. Patients in the thrombophilia group had a higher median MoM MSAFP compared to the controls (1.337 vs 1.086, p=0.0516). The incidence of abnormally elevated MSAFP (>2.5 MoM) was also significantly higher in the thrombophilia group compared to controls (21% vs 3%, p=0.04). Neither the median MoM βhCG nor the incidence of abnormally elevated βhCG were significantly different between the groups. We conclude that second trimester MSAFP, but not βhCG, is abnormally elevated in patients with thrombophilia and obstetric complications. Copyright © 2001 John Wiley & Sons, Ltd.     

First-trimester maternal serum alpha-fetoprotein as a marker for fetal chromosomal disorders

We evaluated first-trimester maternal serum alpha-fetoprotein (MS-AFP) as a marker for fetal chromosomal disorders. The multicentre study was performed under the auspices of the Dutch Working Party on Prenatal Diagnosis. MS-AFP was measured in 2404 normal pregnancies and 72 chromosomally abnormal pregnancies. The median multiple of the normal median (MOM) in 32 Down's syndrome pregnancies was 0·83 with a 95 per cent confidence interval ranging from 0·60 to 1·04. The difference between the distributions of first-trimester MS-AFP in normal and Down's syndrome pregnancies was statistically significant (t-test: t = 2·34, P<0·05). Thirty-one per cent of the Down's syndrome pregnancies were found below the tenth percentile. We found no difference between normal pregnancies and pregnancies with other chromosomal disorders (eight cases with trisomy 18, MOM = 1·26; seven cases with sex chromosome abnormalities, MOM = 1·07; 22 cases with a chromosomal mosaic pattern in chorionic villi, MOM = 1·08). We conclude that first-trimester MS-AFP can discriminate between normal and Down's syndrome pregnancies, but is not an effective marker. First-trimester MS-AFP has no value as a marker for other fetal chromosomal disorders.     

Second trimester two-step trisomy 18 screening using maternal serum markers

Trisomy 21 maternal serum marker screening has led to screening for other anomalies, including trisomy 18. Trisomy 18 is generally prenatally diagnosed because of major morphological defects. However, in up to 30% of cases ultrasound signs are unclear, and in most cases diagnosis is performed late in pregnancy. Of the different maternal serum markers, PAPP-A is now considered as the best for trisomy 18 screening. However, pregnancy-associated plasma protein A (PAPP-A) is of value in first trimester screening for trisomy 21, but not in the second trimester. We therefore propose a two-step screening strategy. Based on 45 trisomy 18 cases, we confirm the values of alpha-fetoprotein (AFP) (median 0.61 MoM), free β-human chorionic gonadotrophin (β-hCG) (median 0.24 MoM) and of PAPP-A (median 0.08 MoM). In the first step, a 0.5 MoM cut-off for AFP or for free β-hCG resulted in detection of 37/45 trisomy 18 cases (82%) with a 10% false-positive rate. The second step consisted of the measurement of PAPP-A for all these false-positive cases. Using a PAPP-A cut-off of 0.5 MoM, all the 37 trisomy 18 cases were detected, but now with a 0.1–0.2% false-positive rate. Amniocentesis was only offered to these few patients. This two-step second trimester screening will be of value for patients who have not been included in first trimester screening based on nuchal translucency (NT) measurement combined with the first trimester markers, PAPP-A and free β-hCG. Copyright © 2002 John Wiley & Sons, Ltd.     

First-trimester maternal serum unconjugated oestriol and alpha-fetoprotein in fetal Down's syndrome

Maternal sera (MS) taken from 1396 women prior to chorionic villus sampling at 9–12 menstrual weeks were assayed for unconjugated oestriol (uE3) and alpha-fetoprotein (AFP). Median levels increased by 41 and 26 per cent per week respectively in normal pregnancies. There were 32 pregnancies with a chromosome abnormality. The median MS uE3 and AFP were 0.73 and 0.75 multiples of the median (MoM) respectively in the ten cases of Down's syndrome (DS) but not decreased in the other abnormalities. These results suggest that both uE3 and AFP may be useful in identifying DS in the first trimester. Additional prospective studies are needed to confirm these findings.     

Very low versus undetectable maternal serum alpha-fetoprotein values and fetal death

Very low maternal serum alpha-fetoprotein (MSAFP) levels (<10 ng/mL) are known to be associated with non-viable pregnancies, including conditions such as fetal death, molar pregnancies, and non-pregnancies. There has not been agreement, however, as to whether very low MSAFP levels indicate already existing fetal deaths or are actually predictive. We analysed 230 pregnancies with MSAFP levels <10 ng/mL from among 15 807 women (1.5 per cent) screened consecutively during a three-year period and identified 26 non-viable pregnancies, 22 of which were diagnosed sonographically as part of the screening process (17 missed abortions, 3 blighted ova, 2 non-pregnancies). Furthermore, 20 of these 22 pregnancies were associated with essentially undetectable MSAFP levels (<5 ng/mL). Our data indicate that pregnancies with MSAFP values <5 ng/mL are the group most strongly associated with fetal non-viability and that very low MSAFP values are not strongly predictive for fetal death.     

First trimester maternal serum placenta growth factor (PIGF)concentrations in pregnancies with fetal trisomy 21 or trisomy 18

Placenta growth factor (PIGF), an angiogenic factor belonging to the vascular endothelial growth factor family, pregnancy-associated plasma protein A (PAPP-A) and free β-human chorionic gonadotrophin (β-hCG) were measured in maternal serum from 45 pregnancies with trisomy 21, 45 with trisomy 18 and 493 normal controls at 10–13 completed weeks of gestation. In the normal pregnancies maternal serum PIGF levels increased exponentially with gestation. The median multiple of the median (MoM) PIGF concentration in the trisomy 21 group (1.26 MoM) was significantly higher (p<0.0001) than in the control group (1.00 MoM). In the trisomy 18 group the median PIGF was lower (0.889 MoM) but this did not quite reach significance (p=0.064). The corresponding median MoM values for PAPP-A were 1.00 MoM for the controls, 0.49 MoM for trisomy 21 and 0.16 MoM for trisomy 18. The median MoM values for free β-hCG were 1.00 MoM for the controls, 2.05 MoM for trisomy 21 and 0.38 MoM for trisomy 18. In the control group there was a small but significant correlation of PIGF with free β-hCG (r=+0.1024) and PAPP-A (r=+0.2288). In the trisomy 18 group there was a significant association between PIGF and free β-hCG (r=+0.2629) but not with PAPP-A (r=+0.0038). In the trisomy 21 group there was a small but significant association with PAPP-A (r=+0.1028) but not with free β-hCG (r=+0.0339). The separation of affected and unaffected pregnancies in maternal serum PIGF is small, and therefore it is unlikely that measurement of PIGF would improve screening for these abnormalities provided by the combination of fetal nuchal translucency and maternal serum PAPP-A and free β-hCG. Copyright © 2001 John Wiley & Sons, Ltd.     

Simpson—Golabi—Behmel syndrome: Disproportionate fetal overgrowth and elevated maternal serum alpha-fetoprotein

Simpson—Golabi—Behmel (SGB) syndrome is an X-linked condition with pre- and postnatal overgrowth, characteristic facies, and visceral and skeletal anomalies. We report an affected male who presented at 16 weeks' gestation with elevated maternal serum α-fetoprotein (MSAFP). Fetal measurements at 20 and 31 weeks' gestation were disproportionate, with marked macrosomia but a low head to abdominal circumference ratio and normal femur length. Fetal overgrowth with elevated MSAFP may prove to be useful markers for the prenatal diagnosis of SGB syndrome.     

Raised maternal serum alpha-fetoprotein in the absence of fetal abnormality-placental findings. A quantitative morphometric study

Ten placentae from pregnancies proceeding to term from mothers who on routine screening at 16–18 weeks gestation were found to have a raised serum AFP but no increase in amniotic fluid AFP and no fetal abnormality, were studied using morphometric techniques. The results were compared with 20 placentae from normal term pregnancies where the maternal serum AFP level was not elevated. The mean total placental volume, volume of parenchyma and villous surface area were increased in the placentae associated with a raised maternal serum AFP. More of these placentae were infarcted and the fetal-placental weight ratio was significantly lower. The hypothesis that elevation of maternal serum AFP level is related to the increase in placental size is addressed.