Association between second-trimester isolated high maternal serum maternal serum human chorionic gonadotropin levels and obstetric complications in singleton and twin pregnancies

OBJECTIVE: The purpose of this study was to examine the clinical significance of high maternal serum human chorionic gonadotropin levels in the second trimester in singleton and twin pregnancies within the Ontario maternal serum screening program. STUDY DESIGN: The study group comprised 564 women with singleton pregnancies with total maternal serum human chorionic gonadotropin levels of > or =4.0 multiples of the median (MoM) and serum marker alpha-fetoprotein levels of <2.0 MoM. The cases were matched with 1692 control subjects who had both serum marker alpha-fetoprotein levels and maternal serum human chorionic gonadotropin levels of <2.0 MoM. The second part of the study comprised 93 twin pregnancies with maternal serum human chorionic gonadotropin levels of > or =5.0 MoM and serum marker alpha-fetoprotein levels of <4.0 MoM; the control group (n = 1496) had serum marker alpha-fetoprotein levels of <4.0 MoM and maternal serum human chorionic gonadotropin levels of <5.0 MoM. The final part of the study included 25 women with extremely high maternal serum human chorionic gonadotropin levels (> or = 14;10 MoM). RESULTS: Of the singleton pregnancies with maternal serum human chorionic gonadotropin levels of > or = 14;4.0 MoM, 22.5% had severe adverse obstetric outcomes, compared with only 10.9% of the matched control population (P =.001). Women with markedly elevated maternal serum human chorionic gonadotropin levels had significantly increased risks of having spontaneous miscarriage, small-for-gestational-age infants, pregnancy-associated hypertensive disorder, and preterm delivery. Of the women with twin pregnancies with high maternal serum human chorionic gonadotropin levels (> or =5.0 MoM), 71% had at least one complication (such as miscarriage and preterm delivery) compared with 55.3% in the control group. Finally, 23 of 25 women with extremely high maternal serum human chorionic gonadotropin levels (> or = 14;10 MoM) had serious adverse outcomes (such as fetal abnormalities, pregnancy-associated hypertensive disorder, premature separation of placenta, intrauterine growth restriction, neonatal respiratory distress syndrome, and neonatal jaundice). CONCLUSION: Pregnancies with an elevated maternal serum human chorionic gonadotropin level are associated with adverse obstetric outcomes. Increased maternal and fetal surveillance is warranted in these pregnancies.     

First-trimester maternal serum alpha-fetoprotein and chorionic gonadotropin in aneuploid pregnancies.

First-trimester maternal serum alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) levels were measured in samples from 29 women with cytogenetically abnormal pregnancies and 145 women with cytogenetically normal pregnancies matched for gestational age, race, and sample storage time. All patients had a risk of fetal aneuploidy greater than or equal to that of a mother 35 years of age. AFP was significantly lower in samples from pregnancies affected with trisomy 21 (0.67 MoM; p less than 0.05), while HCG values were no different from those of matched controls. Trisomies 13 and 18 could not be distinguished from matched controls by AFP. However, levels of HCG were significantly lower in such pregnancy samples, with median values of 0.65 MoM in trisomy 13 and 0.32 MoM in trisomy 18 (p less than 0.05). Variations in AFP and HCG levels suggest that expressed differences between autosomal aneuploidies include differences in fetal and placental protein production in the first trimester.     

Human chorionic gonadotropin in cord blood and peripheral maternal blood in singleton and twin pregnancies at delivery

The influence of fetal sex on human chorionic gonadotropin (hCG) in cord and peripheral maternal blood was studied at delivery in 57 twin and 66 singleton uncomplicated pregnancies. In twin pregnancies the hCG levels were about twice as high in female-female and in female-male vis-à-vis male-male combinations in both maternal and cord blood. In singleton pregnancies the hCG levels were significantly higher in maternal and in cord blood in cases of female vis-à-vis male infants. The ratio of maternal hCG/placental weight was also highest in the twin pregnancies when one or both infants were female. This suggests a "female effect", possibly genetically based.     

Second-trimester levels of maternal serum unconjugated oestriol and human chorionic gonadotropin in pregnancies affected by fetal anencephaly and open spina bifida

Unconjugated oestriol (uE3) and human chorionic gonadotropin (hCG) levels were determined in second-trimester maternal serum (MS) samples from 21 pregnancies associated with fetal anencephaly and 15 pregnancies associated with fetal open spina bifida. Each measurement was expressed as a multiple of the median (MoM) for unaffected pregnancies for each completed week of gestation. In pregnancies associated with anencephaly, the median value for MSuE3 was very low (0.17 MoM, range less than 0.12-0.33 MoM), suggesting a functional defect in the fetal adrenal prior to 20 weeks' gestation; the median value for MShCG was also low (0.73 MoM), although not to the same extent as for MSuE3. A biological explanation for the hCG result is not apparent. In pregnancies associated with open spina bifida, the MSuE3 and MShCG values were unremarkable, consistent with a lack of involvement of these open fetal defects in the synthesis and secretion of uE3 and hCG.     

Human chorionic gonadotropin rise in normal and vanishing twin pregnancies

OBJECTIVE: The purpose of the study was to describe and to compare the rate of rise of human chorionic gonadotropin (hCG) in vanishing twin and normally progressing twin pregnancies during the first trimester. DESIGN: All patients with twin pregnancies between 1985 and 1989 were prospectively studied. Human chorionic gonadotropin was measured one to three times per week between days 12 and 52 after luteinizing hormone (LH) surge or day of hCG administration (day 0). Pelvic ultrasound (US) was performed weekly beginning on day 24. SETTING: The study was performed at Rush-Presbyterian-St. Luke's Medical Center in an academic private practice setting of the Section of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology. PATIENTS: Forty patients who conceived after treatment of infertility and who had two gestational sacs on US examination were included in the study after the following criteria were met: (1) both sacs progressed to exhibit a fetal pole and (2) day of LH surge and/or day of hCG administration was known. MAIN OUTCOME MEASURE: The rate of rise of hCG was slower in vanishing twin pregnancies than in normally progressing twin gestations for the entire time period studied (P less than 0.05). RESULTS: A vanishing twin occurred in one third of the twin pregnancies. Forty-six percent of these losses occurred after fetal heart activity had been established. CONCLUSIONS: Vanishing twin phenomenon occurred in a large proportion of twin pregnancies in this infertility population. Fetal heart activity was not a reliable predictor of continuing fetal viability in early twin gestations. Vanishing twin conceptions were characterized by a slower rate of rise of hCG than normally progressing twin pregnancies.     

Abnormal maternal serum chorionic gonadotropin levels in pregnancies with fetal chromosome abnormalities

The alpha subunit of human chorionic gonadotropin (alpha-hCG), human chorionic gonadotropin (hCG) and alpha fetoprotein (AFP) were measured in the serum of 25 women with chromosomally abnormal fetuses between 18 and 25 weeks of gestation and in 74 normal pregnancies. AFP levels less than 0.5 multiples of the median (MoM) or greater than 2.5 MoM were observed in 24 per cent of the abnormal pregnancies and in 6.76 per cent of the normal pregnancies. A low concentration of hCG (less than 0.25 MoM) was observed in 8 per cent of abnormals and in 2.7 per cent of normals while an elevated concentration of hCG (greater than 2.5 MoM) was observed in 56 per cent of abnormals and in 1.35 per cent of normals. Elevated hCG-alpha (greater than 2.5 MoM) was observed in 28 per cent of abnormals and in none of the normals. Determination of elevated levels of hCG-alpha or hCG resulted in detection of 68 per cent of pregnancies with chromosomally abnormal fetuses with a false positive rate of 1.35 per cent. Determination of both elevated and depressed gonadotropin levels resulted in detection of 76 per cent of abnormal pregnancies with a false positive rate of 4.05 per cent. Measurement of hCG and hCG-alpha in maternal serum samples can be used as a screening procedure for detecting pregnancies at risk for fetal chromosome abnormalities.     

Prospective evaluation of maternal serum human chorionic gonadotropin levels in 3428 pregnancies.

As part of a multicenter prospective study, second-trimester human chorionic gonadotropin and alpha-fetoprotein concentrations were evaluated. Data included maternal age, human chorionic gonadotropin level, alpha-fetoprotein level, weight, race, and pregnancy outcome of 3428 pregnancies at between 15 and 20 weeks' gestation. The results of the study indicate that human chorionic gonadotropin levels decrease as maternal weight increases, that weight-adjusted human chorionic gonadotropin levels for Oriental and black women are higher than for white or Hispanic women, and that twin pregnancies have higher human chorionic gonadotropin levels than singleton pregnancies. Of 255 pregnancies that did not have normal outcomes, 54 (21.2%) had human chorionic gonadotropin levels greater than 2.0 multiples of the median and 26 (10.2%) had alpha-fetoprotein levels greater than 2.5 multiples of the median. Of 11 pregnancies with fetal aneuploidy, 6 (54.5%) had human chorionic gonadotropin levels greater than 2.0 multiples of the median. It is concluded that in human chorionic gonadotropin screening programs for fetal Down syndrome, weight and race adjustments are necessary for accurate risk assessment.     

A comparison between maternal serum free beta-human chorionic gonadotrophin and pregnancy-associated plasma protein A levels in first-trimester twin and singleton pregnancies

OBJECTIVES: To determine the levels of first-trimester free beta-human chorionic gonadotrophin (free betahCG), pregnancy-associated plasma protein A (PAPP-A) and nuchal translucency (NT) in twin pregnancies. METHODS: The study included 93 patients with twin pregnancy and 4,977 with singletons who underwent first-trimester testing using free betahCG, PAPP-A and NT at 10-13 weeks of gestational age. RESULTS: In twin pregnancies, the maternal serum free betahCG level was 2.18 higher and the PAPP-A level was 2.38 higher than in singleton pregnancies. These marker levels were significantly higher than the expected 2.0 multiples of the median (MoM). In contrast, NT values did not differ between twins and singletons. CONCLUSION: These data may be used to establish first-trimester combined screening for twin pregnancies.     

Maternal serum alpha-fetoprotein levels in low birth weight singleton pregnancies

Maternal serum alpha fetoprotein (MSAFP) measurement between 16 and 21 weeks gestation is used to define a group of women with an increased risk of fetal abnormality, particularly open neural tube defect. The test is strongly gestation dependent and women with high MSAFP levels require sonar scan examination to define gestation, exclude twins and examine the fetus for obvious malformation or death. It has been reported that women with no primary cause for raised MSAFP have an increased incidence of low birth weight babies. Conflicting reports have separately ascribed these to premature delivery and to intra-uterine growth retardation. We have studied the relationship between MSAFP and low birth weight infants with respect to both prematurity and retarded fetal growth. MSAFP values were expressed as multiples of the appropriate weekly median (MOM) values relating to normal pregnancies with normal outcomes at term. For our normal population an MSAFP value of 2 MOM is the 95% centile, i.e. 5% of normal outcome pregnancies of sure gestation will have MSAFP values in the second trimester which are at or above 2 MOM. Information was available on 389 women whose infants were liveborn singletons weighing 2.5 kg or less. 33 (8.5%) of these women had MSAFP greater than 2 MOM (p less than 0.005) and of the 145 women whose babies weighed less than 2 kg, 17 (11.7%) had MSAFP at this level (p less than 0.001) Tab. I).(ABSTRACT TRUNCATED AT 250 WORDS)     

Second-trimester Down syndrome maternal serum screening in twin pregnancies: impact of chorionicity

OBJECTIVE: To evaluate the diagnostic value of second-trimester maternal serum screening for Down syndrome in twin pregnancies. METHOD: On the basis of a prospective study of second-trimester maternal serum screening, we studied the distribution of alpha-fetoprotein (AFP) and free ss hCG in 3043 twin pregnancies with known outcome. There were 1561 dichorionic and 244 monochorionic pregnancies. The placental type was not available in 1238 cases. We compared 5 screening policies with the same risk, 1/250, cut-off: maternal age, maternal age corrected for the risk of having at least one affected twin in dichorionic pregnancies, maternal serum marker screening using observed AFP and free ss-hCG values divided by a factor of 2, by using the median values actually observed in the global twin population, or by the median values specific to mono- or dichorionic twins. RESULTS: When expressed in singleton-derived MoMs, the median was 2.10 for AFP and 2.11 for free ss-hCG. The median AFP did not differ between monochorionic and dichorionic pregnancies. The distribution of free ss-hCG was significantly shifted towards greater values in monochorionic (2.16 MoM) compared to dichorionic (2.07) pregnancies (p < 0.0001). Screened-positive and detection rates were, respectively, 6.6% and 27.3% using maternal age alone, 24.6% and 54.5% using maternal age corrected for the risk of having at least one affected twin in dichorionic pregnancies, 7.75% and 54.5% using observed AFP and free beta-hCG values divided by a factor of 2, 8.05% and 54.5% using the median values actually observed in the global twin population, and 7.75% and 54.5% using the median values specific to mono- or dichorionic twins. CONCLUSION: Trisomy 21 second-trimester maternal serum screening is feasible in twins, and is better than a policy based on maternal age alone.     

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.     

A comparison of maternal serum levels of alpha-fetoprotein in normal and pre-eclamptic pregnancies.

Alpha-fetoprotein (AFP) concentrations were measured by radioimmunoassay in serum from women with normal and pre-eclamptic pregnancies. An analysis of the results obtained in normal pregnancy was made using arithmetic and semi-logarithmic scales, and a statistical conversion of the AFP values in relation to gestational age was introduced to allow an easier interpretation of results. In pre-eclampsia, significantly lower mean AFP values were obtained, with the majority of individual values being lower than the mean for normal pregnancy. These low levels were not associated with fetal death, but appeared to be related to the severity of disease. The significance of these findings remains to be evaluated.     

Significance of raised maternal serum alpha-fetoprotein in singleton pregnancies with normally formed fetuses

One hundred eighty-six pregnancies with elevated maternal serum alpha-fetoprotein (AFP) between 16 and 20 weeks' gestation, but with normally formed single fetuses, were analyzed retrospectively. In comparison with matched control subjects, there was an increased incidence of low birth weight, preterm delivery, intrauterine growth retardation, and other clinical complications, especially when maternal serum AFP was abnormally high on more than one occasion. These findings could not be explained by the occurrence of threatened abortion or the performance of amniocentesis. It is suggested that where maternal serum AFP screening for fetal neural tube defects is already established as a cost-effective routine procedure, the additional recognition of some pregnancies at very high risk of other, perinatal complications is of practical value. However, maternal serum AFP testing in the second trimester cannot be recommended as a cost-effective screening method for detecting low birth weight infants, having a sensitivity in this series of only 11%. Many (33%) of the low birth weight infants detected in this way were very small (birth weights less than 1.5 kg); 73% of the predicted preterm births were very premature (before 34 weeks of gestation), and 72% of the identified growth-retarded infants were severely effected (weighing less than the fifth percentile for gestational age).     

Second-trimester levels of maternal serum human chorionic gonadotropin and inhibin a as predictors of preeclampsia in the third trimester of pregnancy

OBJECTIVE: To determine whether second-trimester maternal serum levels of inhibin A, human chorionic gonadotropin (hCG), unconjugated estriol (uE3), and alpha-fetoprotein (AFP) are predictive of the later onset of preeclampsia in pregnancy. METHODS: Retrospective evaluation of serum analyte levels in 60 women with preeclampsia compared with 300 controls. Levels of each analyte were compared in women with preeclampsia and controls using matched rank analysis. Analytes that were significantly different between groups were examined with univariate and bivariate Gaussian distribution analysis. RESULTS: Second-trimester inhibin A (1.36 multiples of the median [MoM]) and hCG (1.40 MoM) levels were significantly but modestly elevated in women who later developed preeclampsia. A combination test of maternal age plus inhibin A and hCG predicted 23% of cases of preeclampsia with 95% specificity. There was a statistically significant trend for inhibin A, but not hCG, levels to be higher when the onset of preeclampsia occurred within a shorter (<17 weeks) interval after collection of the second-trimester screening sample. CONCLUSIONS: Second-trimester serum levels of inhibin A and hCG are modest predictors of the later onset of preeclampsia. Inhibin A may be a better predictor of early-onset preeclampsia, which is associated with a higher maternal and perinatal morbidity and mortality, than preeclampsia at or near term.     

Maternal serum alpha-fetoprotein, beta-human chorionic gonadotropin, and unconjugated estriol levels in midtrimester trisomy 18 pregnancies.

OBJECTIVE: The purpose was to evaluate the levels of maternal serum human chorionic gonadotropin, alpha-fetoprotein, and unconjugated estriol in trisomy 18 pregnancies compared with normal singleton pregnancies. STUDY DESIGN: Sera from 14 trisomy 18 pregnancies (13 retrospectively and one prospectively ascertained) were analyzed for human chorionic gonadotropin, alpha-fetoprotein, and unconjugated estriol. RESULTS: The alpha-fetoprotein levels in the 10 trisomy 18 pregnancies without open neural tube or ventral wall defect had a median of 0.65 multiple of the median, although two had alpha-fetoprotein levels above 2.5 multiples of the median. The human chorionic gonadotropin levels had a median of 0.32 multiple of the median and the unconjugated estriol levels had a median of 0.56 multiple of the median. Although most women with trisomy 18 pregnancies had serum human chorionic gonadotropin levels that were less than 1.0 multiple of the median, three had markedly elevated human chorionic gonadotropin levels (greater than 5.0 multiples of the median). CONCLUSION: Our data are partially consistent with those previously published but suggest the possibility of a bimodal distribution of alpha-fetoprotein and human chorionic gonadotropin levels in trisomy 18-affected pregnancies, unrelated to a neural tube or abdominal wall defect. The efficiency of screening for trisomy 18 prospectively, using the three serum markers, requires further evaluation.     

2nd-trimester maternal serum human chorionic gonadotropin and alpha-fetoprotein levels in male and female fetuses with Down syndrome

BACKGROUND/OBJECTIVE: Several studies have shown that the 2nd-trimester maternal serum alpha-fetoprotein (AFP) level is significantly lower and that the maternal serum human chorionic gonadotropin (hCG) level is significantly higher in the presence of a female fetus. This may potentially affect Down syndrome (DS) screening such that a higher false-positive rate may occur in women carrying a female fetus, whereas a lower detection rate may result in those carrying males. The purpose of this study was to evaluate the gender impact on marker levels in DS pregnancies and its effect on DS screening. METHODS: The study included 62 DS pregnancies with a single fetus of known gender (31 male and 31 female). Only pregnancies with chromosomal analysis showing trisomy 21 were included. The maternal serum levels of hCG, AFP, and unconjugated estriol were measured at 16-20 weeks of pregnancy. These levels were expressed as gestational-age-corrected multiples of the median. RESULTS: No statistically significant differences were noted in maternal serum levels of hCG or AFP in DS pregnancies between women carrying a female and those carrying a male DS fetus. No statistically significant differences in 'screen-negative' rates were noted among male and female fetuses. CONCLUSIONS: In normal pregnancies, the maternal serum hCG level is higher, and the AFP level is lower in the presence of a female fetus. However, this gender-related difference is not apparent in DS pregnancies. Therefore, the gender-related differences in serum marker levels would not result in a lower detection rate of DS in male fetuses.     

First-trimester maternal serum alpha-fetoprotein and human chorionic gonadotropin screening for chromosome defects.

The aim of this study was to determine the efficacy of combined maternal serum alpha-fetoprotein (MSAFP) and maternal serum human chorionic gonadotropin (MShCG) screening in detecting chromosome defects in the first trimester of pregnancy. Sera of 492 women (previously assayed for MSAFP) were analysed for MShCG under code without knowledge of cytogenetic results. Overall, 48 of 492 patients (9.8 per cent) had either an MSAFP multiple of the median less than or equal to 0.5 or an MShCG beta/alpha ratio multiple of the median less than or equal to 0.25, eight of whom had a fetus with a serious chromosome defect. A third of fetuses with Down's syndrome and 83 per cent with trisomy 18 were detected at a potential 'cost' of providing chorionic villus sampling or amniocentesis in 8.6 per cent of women screened.     

Increased maternal serum alpha-fetoprotein and human chorionic gonadotropin in compromised pregnancies other than for neural tube defects or Down syndrome.

Intrauterine fetal death occurred in four women who were 'screen-positive' in a screening programme for neural tube defects (NTDs) and Down syndrome (DS). These women had very high levels of maternal serum alpha-fetoprotein (MSAFP) and maternal serum human chorionic gonadotropin (MShCG). Therefore, we evaluated all 'screen-positive' women in whom both of these markers were greater than or equal to 2.0 multiples of the median. The cases fulfilling these criteria totalled 11, and only one of them had no complications. High concentrations of both MSAFP and MShCG in a number of these cases might have been caused by an increased placental volume, which, in turn, might have been induced by decreased perfusion of the placenta. We conclude that screening programmes wrongly determine a high risk of fetal NTD or DS if the concentrations of both these parameters are very high. Invasive diagnostic procedures should be avoided in these cases, particularly in view of the increased risk of an adverse pregnancy outcome.     

Clinical follow-up of high mid-trimester maternal serum intact human chorionic gonadotrophin concentrations in singleton pregnancies

Mid-trimester biochemical screening of 38 143 pregnancies in south-east Scotland revealed 127 cases (0.34 per cent) in which the maternal serum (MS) intact human chorionic gonadotrophin (hCG) concentration was > or = 4 multiples of the median in singleton pregnancies (MOM). Three were lost to follow-up but in 72 (58 per cent) complications developed or there were associated fetal abnormalities. This percentage was greatest at very high hCG concentrations, 92 per cent with hCG > or = 10 MOM (n = 12) compared with 48 per cent with hCG concentrations of 4-4.99 MOM (n=69). 22 cases had an MS alpha-fetoprotein > or = 2 MOM in addition to an MS hCG > or = 4 MOM, and in only 3 of these was the pregnancy uneventful; 86 per cent were associated with abnormalities or pregnancy complications.