Screening for trisomy 21 in twin pregnancies in the first trimester: does chorionicity impact on maternal serum free beta-hCG or PAPP-A levels?

In a study of 180 twin pregnancies I have examined the distribution of maternal serum free beta-human chorionic gonadotrophin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A), in addition to fetal nuchal translucency thickness (NT), in twins classified as monochorionic or dichorionic, based on ultrasound appearance at 10-14 weeks of gestation. In 45 monochorionic and 135 dichorionic twin pregnancies the median MoM free beta-hCG was not significantly different (1.00 vs 1.01), whilst that for PAPP-A was lower (0.89 vs 1.01) but again with no statistical significance. Previous reports of an increased fetal NT in monochorionic twins pregnancies could not be confirmed (1.03 vs 1.00). It is concluded that the existing pseudo risk twin correction algorithm is appropriate for both monochorionic and dichorionic twins in providing accurate first trimester risks for trisomy 21.     

Age related detection and false positive rates when screening for Down's Syndrome in the first trimester using fetal nuchal translucency and maternal serum free βhCG and PAPP-A

Objective To determine how first trimester detection rates for Down's Syndrome vary with maternal age and to calculate the predictive value of an increased risk report at various maternal ages.Design Mathematical modelling of first trimester screening performance using fetal nuchal translucency and maternal serum free βhCG and pregnancy associated plasma protein-A (PAPP-A).Methods From within the Gaussian distributions of each marker in normal pregnancies and those affected by Down's Syndrome a series of 15,000 marker multiple of the medians were obtained for each group. These markers were then used to calculate the risks of Down's Syndrome using maternal ages ranging from 15 to 49 and the background risk of Down's Syndrome at each age. Using a 1 in 300 risk cutoff (at time of sampling) the false positive rate and detection rate was assessed at each year of maternal age. The predictive value of a positive result was calculated using Baye's theorem.Outcome measures False positive rates and detection rates at each year of maternal age between 15 and 49; the predictive value of a positive result for each maternal age between 15 and 49.Results At 15 years of age the detection rate was 77% at a 1.9% false positive rate, 84% at a 4% false positive rate at age 30, rising to 100% at a 67% false positive rate at age 49. The probability of Down's Syndrome once identified with an increased risk was 1:34 at 15 years, 1:29 at 30 years and 1:6 at 49 years.Conclusions As with second trimester biochemical screening, the detection rate and false positive rate vary considerably with age. However, detection rates across all ages are significantly higher than with second trimester screening. The risk of a positive screening result being a Down's pregnancy is considerably greater than with second trimester screening with an average probability of 1:29, compared with 1:55 in the second trimester. This information may be useful in counselling women with an increased risk result in first trimester screening.     

Is maternal serum total hCG a marker of trisomy 21 in the first trimester of pregnancy?

In a study of 130 first trimester cases of trisomy 21 and 959 controls we have shown that the median MoM for alpha-fetoprotein (AFP) is lower (0.82) and that for total human chorionic gonadotrophin (hCG) is higher (1.31) than in the control group. For AFP 15.3% of cases were below the 5th centile and for total hCG 19. 8% were above the 95th centile. The median shift observed for AFP and total hCG is poorer than that for pregnancy associated plasma protein-A (PAPP-A) or free beta-hCG and together with maternal age, AFP and total hCG could only be expected to detect 40% of cases. In combination with PAPP-A, total hCG would identify 52% of cases, somewhat less than the 67% observed with free beta-hCG and PAPP-A. However, we have demonstrated for total hCG a significant temporal change in median MoM with gestational age. Before 70 days the median MoM was less than 0.5, between 70 and 83 days this increased to 1.13, and between 84 and 97 days this increased to 1.52. This median shift has significant implications for interpreting previous studies and even more significant implications for detection rates. When population parameters specific to the gestational age in question are used, detection rates with total hCG and PAPP-A increase from 47% at 70-83 days to 60% at 84-97 days. This observation explains much of the confusion around total hCG in the first trimester and shows the importance of selecting analyte pairs and population parameters appropriate to the time in gestation when screening is performed.     

Early signs of cardiac failure: a clue for parvovirus infection screening in the first trimester?

Parvovirus B19 is a small single-stranded DNA virus and a potent inhibitor of erythropoiesis due to its cytotoxicity to erythroid progenitor cells. Although adult disease is generally mild, fetal parvovirus B19 infection can cause spontaneous abortion in early pregnancy and aplastic anemia, nonimmune hydrops fetalis and in utero fetal demise. The prevalence of parvovirus B19 maternal infection during pregnancy is about 1-2%. The vertical transmission occurs in 10-35%, being highest in the first and second trimesters. The risk of adverse fetal outcome is 10%. In contrast to the second or third trimester, in pregnancies affected by increased nuchal translucency (NT) in the late first trimester, the prevalence of maternal infection was not higher than in the general population. We report a case of first-trimester parvovirus B19 infection with increased NT and reversed a-wave in the ductus venosus (DV) at 11 weeks, with fetal demise 2 weeks later.     

Is maternal anemia associated with small placental volume in the first trimester?

Aim

To clarify whether maternal anemia could reduce placental volume in the early gestation.

Methods

A prospective cross-sectional study was conducted. Consecutive women who visited at 11–13 + 6 weeks’ gestation were enrolled. Subjects were divided into two groups by maternal hemoglobin concentration. Cases with maternal anemia were defined as a hemoglobin level less than 11 g/dl on a blood test (cases), and the others were defined as controls. An ultrasound examination was performed to measure the placental volume and the uterine arterial blood flow. The three-dimensional volume of the placenta using virtual organ computer-aided analysis (VOCAL) technique was acquired by transabdominal ultrasonography. Placental volumes were compared in women with and without anemia.

Results

31 cases and 486 controls were analyzed. Maternal characteristics were not different between two groups except anemia. Placental volumes were 63.6 ± 22.2 and 60.9 ± 22.8 cm³ (ns), uterine arterial RIs were 0.7 ± 0.1 and 0.8 ± 0.1 (ns), and PIs were 1.7 ± 0.5 and 1.8 ± 0.6 (ns) in cases and controls, respectively.

Conclusions

Maternal anemia was not associated with reduced placental volume and uterine arterial Doppler wave form at 11–13 weeks’ gestation.

     

How important is consent in maternal serum screening for Down syndrome in France? Information and consent evaluation in maternal serum screening for Down syndrome: a French study

OBJECTIVES: To evaluate the level of information and informed consent for maternal serum screening (MSS) for Down syndrome (DS) in the second trimester of pregnancy and analyse the exercise of autonomy towards the test by the women concerned. METHODS: We studied the population of pregnant women attending obstetric consultations in two French hospitals over a 3-month period. The women were assigned to three groups according to MSS results for DS: women at high risk of having a child with DS (group 1), women at low risk (group 2) and women who did not undergo the test (group 3). A questionnaire was completed before the medical consultation, to assess the quality of consent before amniocentesis for the group at high risk and before the second-trimester ultrasound scan for the other two groups. RESULTS: We analysed 305 questionnaires for 89, 137 and 79 women belonging to groups 1, 2 and 3 respectively. In total, 123 women (40.3% [IC 95%, 35-46%]) were considered to be well informed; 33 (10%, [IC 95%, 8-12%]) had a high level of knowledge, but made choices not consistent with their stated attitude, and 149 (49.7% [IC 95%, 45-56%]) were considered uninformed. Logistic regression analysis showed that maternal consent depended on three independent components: The score attributed to the doctor for information about MSS (t = 4.216, p < 0.001).Whether the patient belonged to group 1 (t = -2.631, p < 0.009).Educational level (< high-school diploma, high-school diploma or at least two years of higher education after high school) (t = 2.324, p < 0.02). The rate of consent increased with educational level and was highest for the women in group 1 and for those whose doctor had a high information score. CONCLUSIONS: Our findings clearly show that women are provided with insufficient information concerning MSS screening for DS in the second trimester of pregnancy for real and valid consent to be obtained.     

Do the first,second and third trimester maternal serum hepcidin concentrations clarify obstetric complications?

Objective: To evaluate whether first, second, and third-trimester maternal serum hepcidin levels are different in pregnancies with and without adverse pregnancy outcomes (APO).

Methods: A 165 nullipar pregnant women were included in this prospective cohort study. Serum hepcidin, ferritin, IL-6, C-reactive protein (CRP) and Hb values were measured at 11–14, 24–28, and 30–34 weeks of gestation. The relation between these parameters and APO and neonatal outcomes were investigated. Preterm delivery, intrauterine growth restriction, pre-eclampsia, gestational hypertension and placental abruption were determined as adverse pregnancy outcomes.

Results: The risk of APO was three times higher in women with high IL-6 levels in the second trimester. High hepcidin levels in the second trimester were associated with a 1.6 times increased risk of APO. Newborns of women with high IL-6 levels in the third trimester had a 1.6-fold increased risk of neonatal complications. High ferritin levels in the third trimester were associated with minimally increased risk of neonatal complications.

Conclusions: Mean serum hepcidin levels were similar in all pregnant women, however, elevated second trimester serum hepcidin and IL-6 levels were associated with a higher risk of APO and high third trimester hepcidin, ferritin and IL-6 levels were associated with higher risk of neonatal complications.     

Can first trimester maternal serum follistatin like 3 levels predict developing gestational diabetes mellitus?

Purpose: The purpose of this study is to determine whether the first trimester maternal serum levels of follistatin like 3 (FSTL3) are altered in patients who develop gestational diabetes mellitus (GDM).

Methods: This is a prospective nested case-control study that included 170 singleton pregnant women recruited in their first trimester. All women were followed up until the delivery and 144 of them completed the study. The maternal serum levels of FSTL3 were measured at 11–14 weeks of gestation. The GDM-affected women (n?=?19) were compared with the GDM-free control women (n?=?125) for potential serum biomarkers including the FSTL3 levels.

Results: There were no significant differences in maternal age, maternal pre-pregnancy body mass index, and neonatal birth weight between the GDM group and the GDM-free control group. Women with GDM had significantly greater weight gain during pregnancy than the women without GDM. Serum concentration of glycosylated hemoglobin was significantly higher in women with GDM. There were no significant differences in serum FSTL3 levels (p?=?0.578) between the GDM group and the GDM-free control group.

Conclusions: Our results suggest that the first trimester maternal serum FSTL3 levels are not altered in women who develop GDM and thus do not support the use of serum FSTL3 levels for early prediction of GDM.     

CFTR DeltaF508 mutation detection from dried blood samples in the first trimester of pregnancy: a possible routine prenatal screening strategy for cystic fibrosis?

OBJECTIVE: The implementation and evaluation of a proposed wide-scale prenatal screening strategy, based on DNA isolated from dried blood spots in the first trimester of pregnancy, for the early detection of pregnancies at risk for cystic fibrosis (CF). METHODS: The screening was performed in conjunction with routine biochemical marker screening for Down's syndrome risk in the first trimester of pregnancy. DNA was isolated from 1,233 dried blood spots and analyzed for the presence of the CF transmembrane regulator DeltaF508 mutation. Women carriers were offered and accepted the option for additional full testing of their partners in order to assess the risk for the fetus. RESULTS: All 1,233 samples were successfully analyzed, identifying 23 DeltaF508 carriers, corresponding to a DeltaF508 carrier rate of approximately 1/55 (1.8%). All partners of the women carriers were further tested without revealing any need for further prenatal testing in this group. CONCLUSIONS: This study reveals the relatively high frequency of the DeltaF508 CF mutation in the Greek population. More importantly, we demonstrate that the proposed prenatal screening strategy, based on the ease and cost-effectiveness of the analysis for the detection of a single common mutation, can be considered as a feasible and practical approach for wide-scale prenatal screening for CF, following the sequential model. It is applied early on in pregnancy, allowing for the timely management of families at risk for the corresponding genetic disorders. Finally, it can easily be extended to include screening for other common genetic disorders in specific population groups.     

Is there a role for fetal ductus venosus and hepatic artery Doppler in screening for fetal aneuploidy in the first trimester?

Objective: The aim of the present study was to evaluate the utility of ductus venosus (DV) and hepatic artery (HA) doppler in pregnant women who have high risk for aneuploidy in first trimester combined screening.

Methods: This prospective study was performed between February 2011 and February-2012, at a tertiary referral hospital. Singleton pregnancies with high risk for aneuploidy in combined screening test and normal nuchal translucency (NT) measurements were included in the study group. Measurements of DV Pulsatility Index of Veins (PIV) and HA Pulsatility Index (PI) were compared between the study group and controls.

Results: Within the study period, 104 women with singleton pregnancies were evaluated for DV and HA measurements and among these, 64 women met the inclusion criteria. A control group that comprised 40 women with similar gestational age, normal NT measurements and low-risk in first trimester combined tests was generated. DV-PIV measurements were significantly higher (p?=?0.03), whereas HA-PI measurements were similar (p?>?0.05) in women who had high-risk for aneuploidy in first trimester combined test.

Conclusion: We concluded that the addition of DV-PIV and HA-PI measurements to the first trimester combined screening might increase the accuracy for Down syndrome detection.     

Could ovarian choriocarcinoma be detected by maternal serum screening for Down syndrome?

The incidence of ovarian malignancies during gestation ranges from 1 in 8000 to 1 in 20,000 deliveries. Ovarian malignancies that produce human chorionic gonadotropin (hCG) are limited to germ cell tumors, of which dysgerminoma is the most frequent (45%) malignant type encountered in pregnant patients, the others being ovarian choriocarcinoma and mixed germ cell tumors (Boulay and Podczaski, 1998). In women of childbearing age, it is hard to distinguish between metastatic choriocarcinoma on a complete mole and primary ovarian choriocarcinoma. Treatment is based on adnexectomy followed by chemotherapy. Given the extreme rarity of these tumors, the long-term prognosis is difficult to establish. Had the diagnosis for our patient been made during pregnancy, the therapeutic approach would have been discussed in terms of gestational age. In the last trimester, we could have suggested cesarean section followed by adnexectomy, and then chemotherapy. In the second-trimester, chemotherapy could have been discussed, although the fetal toxicity of cisplatin chemotherapy is not firmly defined (Ferrandina et al., 2005). This treatment is an alternative to termination of pregnancy. We retrospectively studied maternal serum biochemistry so as to assess the possibility of a diagnosis of ovarian choriocarcinoma at the time of maternal serum screening for Down syndrome.     

Maxillo–occipital line: a sonographic marker for screening of open spina bifida in the first trimester of pregnancy

Abstract

Objective: To describe a new first-trimester sonographic landmark the maxillo–occipital line which may be useful for early screening of open spina bifida.

Methods: Maxillo–occipital line was prospectively evaluated in 100 low-risk pregnancies at the time of first-trimester sonographic screening examination between 11 and 13?+?6 weeks’ gestation. All the pregnant women subsequently had a normal second-trimester scan and normal outcomes. Midsagittal brain images of 14 fetuses with known diagnosis of open spina bifida were evaluated retrospectively to review the maxillo–occipital line.

Results: None of the 100 fetuses evaluated prospectively with the maxillo–occipital line below the junction of the midbrain and brain stem were affected by open spina bifida. The aqueduct of Silvius to occiput distance measurement was not obtained in five cases. In all, 14 cases with a diagnosis of open spina bifida, the junction between the midbrain and brain stem, were below the maxilla–occipital line.

Conclusion: Maxillo–occipital line is an easy addition to the evaluation of first-trimester screening of open spina bifida. Further studies are needed to determine the false-positive and false-negative rates of this technique.     

Screening for fetal aneuploidy: is maternal age relevant?

The process of genetic screening has evolved from a simple notation of maternal age to a complex algorithm incorporating age, maternal serum screening, and sonographic findings. The extent to which each of these variables should contribute to the overall screening result is much debated and deserves continued research. It is clear that maternal age provides useful information when used as part of this equation but should not represent the sole screening modality. The use of genetic screening in a general population should be examined in terms of cost effectiveness without sacrificing patient preference and autonomy.     

Free fetal DNA in maternal circulation: a potential prognostic marker for chromosomal abnormalities?

OBJECTIVES: Previous studies on the association of fetal cell-free (cf)DNA levels in maternal circulation have produced conflicting results but the sample sizes were small and based on archived material. We aimed to quantify the levels of fetal and total cfDNA on prospectively collected samples, to understand their correlation with other variables and to clarify their diagnostic value. METHODS: DNA from pre-CVS maternal plasma was extracted from 264 controls, 72 trisomy 21, 24 trisomy 18, 12 trisomy 13, 16 Turner's syndrome and 8 triploidy first-trimester pregnancies and quantified using real-time PCR. beta-globin was used to determine total cfDNA levels and DYS14 and SRY assays to determine fetal cfDNA levels. RESULTS: Fetal cfDNA levels (DYS14) showed correlation with crown rump length (CRL) (p = 0.004), BMI (p = 0.01) and storage time (p = 0.007) while there was an inverse correlation of total cfDNA levels with nuchal translucency (NT) (p = 0.001). No significant difference was observed between the levels of fetal cfDNA in controls and aneuploidy cases. CONCLUSION: Quantification of fetal and total cfDNA in maternal circulation showed inverse correlation between NT and total cfDNA levels. Our results also suggest that fetal cfDNA is not an ideal prognostic marker for chromosomal abnormalities in first-trimester pregnancies.