Elevated maternal serum alpha-fetoprotein, second-trimester oligohydramnios, and pregnancy outcome

Although the primary purpose of maternal serum alpha-fetoprotein (AFP) screening is to detect open neural tube defects, the technique is of value in the diagnosis of other fetal abnormalities. Six patients from the Alpha-Fetoprotein Screening Program, Perinatal Region IV, were found to have twice elevated maternal serum AFP levels associated with severe early second-trimester oligohydramnios. Five of the fetuses were found to have urinary tract abnormalities. The source of the elevated maternal serum AFP is not clear. Pregnancy prognosis appears poor. These cases should be thoroughly studied so that patients may be accurately informed of the recurrence risk.     

Elevated maternal serum alpha-fetoprotein levels and maternal risk factors. Their association with pregnancy complications.

Maternal serum alpha-fetoprotein (MS-AFP) screening programs identify a population of pregnant women with elevated MS-AFP values. When the levels are unassociated with a fetal anomaly, those women have a high incidence of pregnancy complications. Such patients were compared to a population with normal MS-AFP values to determine the incidence of historical risk factors and to ascertain if their presence affected the rate of pregnancy complications. A total of 358 patients were followed prospectively, 23 with elevated MS-AFP levels and 335 with normal levels (control group). Historical risk factors were more frequent in the patients with elevated MS-AFP levels. There was a fourfold increase in the rate of pregnancy complications when a patient had both risk factors and elevated MS-AFP levels as compared with elevated MS-AFP levels alone. In the control group, patients with known risk factors experienced twice the incidence of pregnancy complications as did patients with no risk factors. Using multiple logistic regression analysis, elevated MS-AFP levels were shown to be an independent variable in the risk assessment. The results of this study have wide application in the counseling and follow-up of patients identified by MS-AFP screening programs.     

Elevated maternal serum alpha-fetoprotein and mild fetal uropathy.

Sixty-one consecutive patients referred because of elevated maternal serum alpha-fetoprotein (MSAFP) levels and 80 referred for second-trimester ultrasound for other reasons were examined. Ultrasound examination of the genitourinary tract and assignment of phenotypic sex was done by ultrasonographers blinded to the MSAFP results. Among male fetuses with elevated MSAFP, 33% had pyelectasis compared with only 5% of controls. Among female fetuses, pyelectasis was seen in 16% of cases and no controls. Increased MSAFP not caused by an open neural tube defect may be seen in conjunction with mild benign uropathy in the second trimester.     

Prediction of fetal outcome by urinary estriol, maternal serum placental lactogen, and alpha-fetoprotein in diabetes and hepatosis of pregnancy.

Urinary estriol, serum placental lactogen (hPL), and alphafetoprotein (AFP) levels were investigated in singleton pregnancies of 75 diabetic women and 84 women with obstetric hepatosis. Fetal distress was demonstrated in 19 diabetic patients (25%) and in 18 cases of obstetric hepatosis (21%). Low urinary estriol correctly predicted fetal distress in 26% of the cases of diabetes and in 29% of the cases of hepatosis. False pathologic readings were found in 9% of pregnancies in either group. Diabetes was associated with higher than normal hPL levels with overlap of levels between cases with fetal distress and normal outcome. hPL levels were higher than normal and correctly predicted fetal distress in 2 of 18 cases of hepatosis (11%) with no false pathologic values. In diabetes, AFP predicted fetal distress in 2 of 4 cases in which a subsequent perinatal death occurred, and 1 additional case of fetal distress. False pathologic values were found in 4% of cases. Maternal AFP levels were normal in 2 cases of closed neural tube anomalies. In cases of hepatosis, AFP gave no information. In combination, estriol and AFP determinations gave correct information in 35% of diabetic pregnancies with pernatal morbidity or death. In hepatosis, estriol and hPL pointed out 33% of the cases of fetal distress.     

Elevated maternal serum alpha-fetoprotein concentration and fetal chromosomal abnormalities.

Amniocentesis was performed in 1038 patients with elevated maternal serum alpha-fetoprotein (MSAFP) concentrations. Patients were divided into two groups based upon the amniotic fluid AFP concentration. Group 1 (N = 964) had a normal amniotic fluid AFP concentration and group 2 (N = 74) had elevated amniotic fluid AFP. Fetal chromosomal results were reviewed from the study population, with the finding of eight major fetal chromosomal abnormalities. Of the eight fetal chromosomal abnormalities, five were associated with elevated amniotic fluid AFP and three were associated with normal amniotic fluid AFP. The sensitivity and specificity of elevated amniotic fluid AFP concentrations in screening for a fetal chromosomal abnormality were 62.5 and 93.3%, respectively. In women with elevated MSAFP but normal amniotic fluid AFP concentrations, the probability of a major fetal chromosomal abnormality is extremely small.     

Elevated maternal serum alpha-fetoprotein and amniotic fluid alpha-fetoprotein after multifetal pregnancy reduction.

Forty patients underwent fetal reduction at approximately 12 weeks' gestation for multiple pregnancy. Twenty-two had maternal serum alpha-fetoprotein (MSAFP) determinations and all but one was elevated, with a mean value of 9.41 multiples of the median (MOM). A total of 53 amniotic fluid specimens were evaluated for AFP; 25% were elevated above 2.0 MOM and one sample was positive for acetylcholinesterase. None of these elevations were associated with a neural tube defect, although two neural tube defects were detected by other means. Routine MSAFP is not recommended for patients with multifetal pregnancy reduction.     

Risk of fetal chromosomal anomalies in patients with elevated maternal serum alpha-fetoprotein.

When elevated maternal serum alpha-fetoprotein (MSAFP) results lead to diagnostic amniocentesis, a decision of whether to karyotype fetal cells must be made. We examined our experience with MSAFP screening in 71,563 unselected pregnancies in which karyotyping was performed when amniocentesis was done because of MSAFP elevations. A total of 727 women (1.0%) underwent amniocentesis because of elevated MSAFP values and among this group, seven chromosomal anomalies (incidence one in 104) were detected. Of the 727 women, 658 (91%) had normal amniotic fluid AFP. In this group, there were six (one in 109) chromosomally abnormal fetuses: three with triploidy, two with 47,XXX, and one with 46,XX,1q-. Among the 69 pregnancies with elevated amniotic fluid AFP, one fetal chromosomal anomaly (trisomy 13) was diagnosed. The incidence of all chromosomal anomalies observed in women undergoing amniocentesis because of elevated MSAFP is comparable to that reported in women 36 years of age undergoing testing because of advanced maternal age. We believe that chromosome analysis should be performed on amniotic fluid samples obtained because of elevated MSAFP unless there are compelling financial circumstances that preclude this. Even in such cases, cell cultures should be established until the amniotic fluid AFP result is available. Chromosome analysis is essential when the amniotic fluid AFP is elevated because of the known association between open fetal defects (spina bifida, omphalocele, and scalp defects) and trisomies 13 and 18.     

Detecting fetomaternal hemorrhage after first-trimester abortion with the Kleihauer-Betke test and rise in maternal serum alpha-fetoprotein

OBJECTIVE: To compare the incidence and detect the volume of fetomaternal hemorrhage (FMH) during first-trimester abortion with the Kleihauer-Betke test (KBT) and rise in maternal serum alpha-fetoprotein (AFP). STUDY DESIGN: Blood samples were drawn immediately before and after first-trimester termination of pregnancy in 48 women. AFP was estimated using an enzyme-linked immunosorbent assay technique. Fetal cells were counted using the acid elution technique described by Kleihauer. Volume of FMH with both techniques was calculated using standard formulae. Significant FMH was reported when there was a > 40% rise in AFP or > 0.25 mL bleed detected by KBT. RESULTS: Of the 48 cases studied, 18 (37.5%) showed no indication of FMH by either AFP or KBT. In 30 (62.5%) cases there was evidence of FMH; in 7 (14.6%) this was shown by both AFP and KBT. Another 10 (21%) showed significant changes in AFP concentration only, and 13 (27%) showed abnormal KBT results with stable AFP levels. The incidence of detectable FMH after first-trimester abortion in this series was 35% when assessed by AFP and 42% when assessed by KBT (P > .05). The mean volume of FMH detected by KBT was 0.5+/-0.05 mL and by AFP was 0.01+/-0.02 mL. CONCLUSION: This study showed that AFP and KBT are equally sensitive methods of detecting the incidence of FMH in first-trimester abortion, but concordance between the 2 tests is poor. The volume of FMH detected by KBT and FMH is also significantly different.     

Correlation of ultrasound and pathologic findings of placental anomalies in pregnancies with elevated maternal serum alpha-fetoprotein.

Twenty pregnancies with elevated maternal serum alpha-fetoprotein (MSAFP), a normal fetus and unusual or abnormal placental/cord sonographic features are reported. These include: (A) gigantic enlargement with multiple sonolucent spaces of different size and shape (n = 2; Swiss cheese); (B) placental masses of variable echogenicity (n = 5); (C) cord masses with central echo-dense zone and peripheral hypoechoic areas (n = 2); (D) enlarged placentas with patchy decrease of echogenicity (n = 6; jelly-like); and (E) large sonolucent spaces with turbulent blood flow surrounded by normal placental tissue (n = 5; placental lakes). After delivery, these ultrasound features were compared with pathologic findings. Diffuse mesenchymal hyperplasia of the stem villi were found in the gigantic placentas (n = 2). The placental masses corresponded to chorioangiomas (n = 3), infarct (n = 1) or subamniotic hematoma (n = 1) and the cord masses to angiomyxomas (n = 2). The 'jelly-like' placentas were related to subchorial thrombosis (n = 2), massive fibrin deposition (n = 1) or hypertrophy with no obvious abnormalities (n = 3). Large subchorial thrombosis (n = 2), or no obvious abnormalities (n = 3) were observed in placentas with large lakes. These findings suggest that a large range of placental and cord anomalies are associated with elevated MSAFP and are potentially diagnosable by routine sonographic examination at the time of AFP screening.     

The relation between maternal serum alpha-fetoprotein levels and fetomaternal haemorrhage.

Spontaneous fetomaternal haemorrhage at 14 to 20 weeks gestation resulted in raised serum alpha-fetoprotein (AFP) levels in 13 of 150 patients attending a genetic counselling clinic. In all 13 patients, the placenta was anterior or fundal in position. By allowing for a rise in serum AFP levels of 4 microgram/l for each fetal cell seen in 30 high power fields (Kleihauer test), a 62.5 per cent reduction in the number of patients selected for amniocentesis because of raised serum AFP levels would have been achieved. The occurrence of fetomaternal haemorrhages at the time of amniocentesis can be detected by either the Kleihauer technique or the measurement of maternal serum AFP levels.     

Prediction of pregnancy outcome with single versus serial maternal serum alpha-fetoprotein tests.

OBJECTIVE: The purpose of our study was to determine whether the trend of three maternal serum alpha-fetoprotein samples was more predictive of pregnancy outcome than the initial sample in the evaluation of patients with unexplained alpha-fetoprotein elevations. STUDY DESIGN: A total of 432 patients with unexplained elevation of their first two maternal serum alpha-fetoprotein samples had a third sample drawn. Pregnancy outcomes were determined. Patients were grouped for analysis according to the level of the initial sample, the final sample, and the trend of three samples. Statistical analysis was by chi 2 and logistic regression, with p < 0.05 considered significant. RESULTS: The initial maternal serum alpha-fetoprotein was most predictive of preterm delivery (p < 0.001), size small for gestational age (p < 0.001), and intrauterine fetal death (p = 0.009). Neither the final value nor the trend of three values was as prognostic. CONCLUSION: The first maternal serum alpha-fetoprotein is the best predictor of pregnancy outcome. Obtaining a second sample to confirm the elevation is appropriate, but additional samples provide minimal information.     

An association between low maternal serum alpha-fetoprotein and fetal chromosomal abnormalities

An index case of "undetectable" maternal serum alpha-fetoprotein at 16 weeks in the first pregnancy of a 28-year-old woman was associated with birth of an infant with trisomy 18. This fortuitous finding stimulated a retrospective study of prenatally diagnosed chromosomal abnormalities. From among a series of 3,862 genetic amniocenteses, 32 cases of fetal autosomal trisomy were diagnosed for which corresponding maternal serum and amniotic fluid alpha-fetoprotein data could be retrieved. From a second laboratory, nine additional cases were added. The maternal serum alpha-fetoprotein levels expressed as multiples of the median were significantly lower in distribution for these 41 women than those from a group of normal matched control subjects (p less than 0.001). Since maternal age is shown to be a less than adequate predictor of autosomal trisomic birth, we proposed that a low level of maternal serum alpha-fetoprotein obtained through routine screening may prove to be valuable in improving the prenatal detection of these serious anomalies.     

Elevated maternal serum alpha-fetoprotein with low unconjugated estriol and the risk for lethal perinatal outcome

OBJECTIVE: To determine whether a combination of elevated maternal serum alpha-fetoprotein (MSAFP) and low unconjugated estriol (E3) concentration identifies pregnancies at particularly high risk for fetal abnormality or poor outcome. METHODS: Pregnancy outcomes were reviewed for women with elevated MSAFP (> or =2.0 MoM) from our database of 50,315 women who had received triple marker testing from 1993-1998. Outcomes for those with low E3 (< or =0.7 MoM) were compared with those with normal E3 (>0.7 MoM). The incidences of fetal death, neural tube defects, chromosome abnormalities, congenital abnormalities, preterm birth, small-for-gestational age (SGA), twins, and inaccurate dates were compared in the two groups using Fisher's exact test with P < 0.05 considered significant. RESULTS: Of the 50,315 women screened, 1,435 (2.85%) had an elevated MSAFP. Pregnancy outcomes were obtained in 94% of those with elevated MSAFP and 70% of all patients screened. Neural tube defects were present in 57 fetuses/infants (21 anencephalic, 29 spina bifida, 7 encephalocele) of which 46 (81%) had an elevated MSAFP. Of the 1,435 women with an elevated MSAFP, 199 (14%) had a low E3. Compared to those women with elevated MSAFP but normal E3, women with elevated MSAFP and low E3 were at significantly increased risk for fetal death (20.6% vs. 2.8%, relative risk (RR) 8.9), anencephaly (9.0% vs. 0.1%, RR 122.8) and chromosome abnormality (2.5% vs. 0.6%, RR 4.0). CONCLUSIONS: Pregnancies complicated by elevated second trimester MSAFP and low E3 are at a particularly high risk (32%) for lethal perinatal outcomes. Twins, while a common cause of elevated MSAFP, are rarely found when an elevated MSAFP is associated with low E3.     

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 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.     

Nonimmune hydrops fetalis caused by a massive fetomaternal hemorrhage associated with elevated maternal serum alpha-fetoprotein levels. A case report.

Chronic fetomaternal hemorrhage led to the development of fetal anemia and nonimmune hydrops fetalis in a term neonate. Antenatal maternal serum alpha-fetoprotein levels were abnormally elevated, with normal amniotic fluid levels. Kleihauer-Betke staining was performed as part of the evaluation. Serial ultrasound examinations can be useful for unexplained elevations in maternal serum alpha-fetoprotein because of the associated increased fetal loss in those pregnancies. If fetomaternal hemorrhage is identified, serial ultrasound examinations are indicated for the detection of fetal hydrops.     

Elevated maternal serum alpha-fetoprotein levels in patients with subchorionic hematoma

Subchorionic hematoma might be associated with poor pregnancy outcome. Two intra cytoplasmic sperm injection pregnancies complicated with subchorionic hematoma were found to have elevated mid-trimester maternal serum alpha-fetoprotein levels. One of them had miscarriage at 16 weeks' gestation and the other delivered a healthy baby by cesarean section. The valid interpretation of triple test result might be complicated by subchorionic hematoma. Therefore, it is better not to order triple test in such cases to avoid unnecessarily provoking the anxiety of the couple.     

Second-trimester maternal serum marker screening: maternal serum alpha-fetoprotein, beta-human chorionic gonadotropin, estriol, and their various combinations as predictors of pregnancy outcome.

OBJECTIVE: We evaluated the value of all 3 common biochemical serum markers, maternal serum alpha-fetoprotein, beta-human chorionic gonadotropin, and unconjugated estriol, and combinations thereof as predictors of pregnancy outcome. STUDY DESIGN: A total of 60,040 patients underwent maternal serum screening. All patients had maternal serum alpha-fetoprotein measurements; beta-human chorionic gonadotropin was measured in 45,565 patients, and 24,504 patients had determination of all 3 markers, including unconjugated estriol. The incidences of various pregnancy outcomes were evaluated according to the serum marker levels by using clinically applied cutoff points. RESULTS: In confirmation of previous observations, increased maternal serum alpha-fetoprotein levels (>2.5 multiples of the median) were found to be significantly associated with pregnancy-induced hypertension, miscarriage, preterm delivery, intrauterine growth restriction, intrauterine fetal death, oligohydramnios, and abruptio placentae. Increased beta-human chorionic gonadotropin levels (>2.5 multiples of the median [MoM]) were significantly associated with pregnancy-induced hypertension, miscarriage, preterm delivery, and intrauterine fetal death. Finally, decreased unconjugated estriol levels (<0.5 MoM) were found to be significantly associated with pregnancy-induced hypertension, miscarriage, intrauterine growth restriction, and intrauterine fetal death. As with increased second-trimester maternal serum alpha-fetoprotein levels, increased serum beta-human chorionic gonadotropin and low unconjugated estriol levels are significantly associated with adverse pregnancy outcomes. These are most likely attributed to placental dysfunction. CONCLUSION: Multiple-marker screening can be used not only for the detection of fetal anomalies and aneu-ploidy but also for detection of high-risk pregnancies.     

Low birth weight and preterm delivery in relation to early-gestation vaginal bleeding and elevated maternal serum alpha-fetoprotein.

OBJECTIVE: To determine whether early-gestation vaginal bleeding and elevated maternal serum alpha-fetoprotein (MSAFP) are independent risk factors for adverse infant outcomes. METHODS: We conducted a cohort study of 201 women with an elevated MSAFP (at least 2.0 multiples of the median [MOM]) and a second-trimester ultrasound evaluation at Swedish Hospital Medical Center between January 1989 and March 1991, and 211 women with MSAFP levels below 2.0 MOM who had also undergone ultrasound evaluations during the same period. RESULTS: Stratified analyses demonstrated that early-gestation bleeding and elevated MSAFP were independent risk factors for the delivery of both preterm and low birth weight infants. Compared with women with no history of early-gestation bleeding or elevated MSAFP, women with early-gestation bleeding alone had a relative risk (RR) of preterm delivery of 4.3 (95% confidence interval [CI] 1.5-12.1); non-bleeders with elevated MSAFP had an RR of 4.6 (95% CI 1.9-10.9). A combined history of early-gestation bleeding and elevated MSAFP was associated with an almost sixfold increased risk of preterm delivery (RR 5.8; 95% CI 2.2-15.6). Analyses restricted to women with normal-appearing appearing placentas by second-trimester ultrasound evaluations yielded similar results. CONCLUSIONS: These findings support an earlier report documenting the independence of early-gestation bleeding and elevated MSAFP as predictors of adverse infant outcomes.     

Persistent fetal hemoglobin in maternal circulation complicating the diagnosis of fetomaternal hemorrhage

BACKGROUND: Transplacental hemorrhage can be life threatening to a fetus and has important maternal treatment implications. In contrast, hereditary persistence of fetal hemoglobin is a condition that has little consequence. The Kleihauer-Betke test, which is routinely used to document transplacental hemorrhage, will be positive in either case. CASES: We report two cases in which maternal persistence of fetal hemoglobin was unknown and led to the erroneous diagnosis of fetomaternal hemorrhage. These cases highlight both the limitations of the Kleihauer-Betke test and the role of flow cytometry in diagnosing fetomaternal hemorrhage. CONCLUSION: The use of flow cytometry can clarify Kleihauer-Betke test results when there is known maternal persistence of fetal hemoglobin and can more precisely quantify a fetomaternal hemorrhage for accurate Rh immune globulin dosing.     

Evaluation of postterm pregnancies with maternal serum placental lactogen and alpha-fetoprotein concentrations.

Studies of maternal serum placental lactogen (hPL) levels in 70 women delivering beyond 42 weeks of gestation revealed significantly lower levels of hPL when the offspring had one or more of ten signs of postmaturity or distress. A sequential combination of hPL measurements and intrapartum fetal heart rate monitoring (FHRM) (performed in 61 patients) gave a high degree of prognosis (75% of abnormalities detected, 88% with normal tests having no abnormalities). Considered separately, neither maternal serum hPL levels nor FHRM predicted abnormalities in the offspring to the same high degree. On the other hand, hPL could not be correlated with staining, desquamation, and the presence of meconium in the amniotic fluid at delivery, these criteria being considered separately or in combination. Maternal serum alpha-fetoprotein (AFP) levels during late gestation showed considerable variation and did not permit distinction between pregnancies with or without an abnormality in the offspring.