Ghalia Ashoor

Chromosome-selective sequencing of maternal plasma cell-free DNA for first-trimester detection of trisomy 21 and trisomy 18

OBJECTIVE The purpose of this study was to assess the prenatal detection rate of trisomy 21 and 18 and the false-positive rate by chromosome-selective sequencing of maternal plasma cell-free DNA. STUDY DESIGN Nested case-control study of cell-free DNA was examined in plasma that was obtained at 11-13 weeks before chorionic villous sampling from 300 euploid pregnancies, 50 pregnancies with trisomy 21, and 50 pregnancies with trisomy 18. Laboratory personnel were blinded to fetal karyotype. RESULTS Risk scores for trisomy 21 and 18 were given for 397 of the 400 samples that were analyzed. In all 50 cases of trisomy 21, the risk score for trisomy 21 was ≥ 99%, and the risk score for trisomy 18 was ≤ 0.01%. In all 50 cases of trisomy 18, the risk score for trisomy 21 was ≤ 0.01%, and the risk score for trisomy 18 was ≥ 99% in 47 cases, 98.8% in 1 case, 88.5% in 1 case, and 0.11% in 1 case. In 3 of the 300 euploid pregnancies (1%), no risk score was provided, because there was failed amplification and sequencing. In the remaining 297 cases, the risk score for trisomy 21 was ≤ 0.01%, and the risk score for trisomy 18 was ≤ 0.01% in 295 cases, 0.04% in 1 case, and 0.23% in 1 case. Therefore, the sensitivity for detecting trisomy 21 was 100% (50/50 cases); the sensitivity for trisomy 18 was 98% (49/50 cases), and the specificity was 100% (297/297 cases). CONCLUSION In this study, chromosome-selective sequencing of cell-free DNA separated all cases of trisomy 21 and 98% of trisomy 18 from euploid pregnancies.

Fetal Fraction in Maternal Plasma Cell-Free DNA at 11-13 Weeks' Gestation: Effect of Maternal and Fetal Factors

Objective: It was the aim of this study to examine the possible effects of maternal and fetal characteristics on the fetal fraction in maternal plasma cell-free DNA (cfDNA) at 11–13 weeks’ gestation. Methods: In a nested case-control study, cfDNA was extracted from maternal plasma obtained before chorionic villous sampling from 300 euploid, 50 trisomy 21 and 50 trisomy 18 pregnancies at 11–13 weeks’ gestation. Chromosome-selective sequencing of maternal cfDNA non-polymorphic and polymorphic loci, where fetal alleles differ from maternal alleles, was used to determine the proportion of DNA which is of fetal origin. Multivariate regression analysis was used to determine which of the factors amongst maternal weight, racial origin, smoking status, plasma storage time, serum pregnancy-associated plasma protein (PAPP)-A and free β-subunit of human chorionic gonadotropin (β-hCG), fetal crown-rump length, nuchal translucency thickness, gender and karyotype were significant predictors of the fetal fraction. Results: Significant independent prediction of fetal fraction was provided by maternal weight, serum PAPP-A and serum free β-hCG multiples of the median, but not by other maternal characteristics, fetal karyotype, crown-rump length or nuchal translucency thickness. Fetal fraction increased with serum metabolite levels and decreased with maternal weight. Conclusions: The fetal fraction in maternal plasma cfDNA increases with serum PAPP-A and free β-hCG and decreases with maternal weight.

Trisomy 13 detection in the first trimester of pregnancy using a chromosome‐selective cell‐free DNA analysis method

To assess the performance of chromosome‐selective sequencing of maternal plasma cell‐free DNA (cfDNA) in non‐invasive prenatal testing for trisomy 13.

Maternal thyroid function at 11 to 13 weeks of gestation and subsequent fetal death.

BACKGROUND Studies have shown that overt hypothyroidism is associated with a substantial risk of miscarriage. There is controversy as to whether subclinical hypothyroidism has the same effect and whether such effect is mediated by the presence of antithyroid antibodies. Our hypothesis is that maternal thyroid function in the first trimester is altered in pregnancies ending in miscarriage or fetal death. METHODS Thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine, anti-thyroperoxidase antibody, and anti-thyroglobulin antibody at 11-13 weeks of gestation were measured in 202 singleton pregnancies that subsequently resulted in miscarriage or fetal death, and the values were compared with the results of 4318 normal pregnancies. RESULTS In the fetal loss group, compared to the unaffected group, there was an increase in median TSH multiple of the normal median (1.133 vs. 1.007 MoM), decrease in median FT4 MoM (0.958 vs. 0.992 MoM), and increase in the incidence of TSH above the 97.5th centile (5.9% vs. 2.5%) and FT4 below the 2.5th centile (5.0% vs. 2.5%). Logistic regression analysis demonstrated that in the prediction of fetal loss there were significant contributions from FT4 MoM, maternal black ethnic origin, history of chronic hypertension, and use of ovulation drugs. The prevalence of antithyroid antibody positivity was not significantly different in the fetal loss group compared to that of normal pregnancies (15.3% vs. 16.8%). CONCLUSIONS Impaired thyroid function may predispose to miscarriage and fetal death.

Maternal thyroid function at 11 to 13 weeks of gestation and subsequent development of preeclampsia

To determine if maternal thyroid function in the first trimester is altered in pregnancies that subsequently develop preeclampsia (PE).

Maternal Thyroid Function at 11-13 Weeks of Gestation and Spontaneous Preterm Delivery

OBJECTIVE: To estimate the possible association between spontaneous early preterm delivery and maternal thyroid dysfunction in early pregnancy. METHODS: Maternal serum concentrations of thyroid-stimulating hormone (TSH), free thyroxine, antithyroperoxidase, and antithyroglobulin antibodies at 11–13 weeks of gestation were compared in 102 singleton pregnancies, resulting in spontaneous delivery before 34 weeks and 4,318 normal pregnancies delivering after this gestation. RESULTS: In the preterm delivery group, compared with the normal outcome group, there was no significant difference in antithyroid antibody positivity (16.7% compared with 16.8%). In the antithyroid antibody-negative pregnancies in the preterm delivery group, compared with the normal outcome group, the median free thyroxine multiple of the median was reduced (0.94 compared with 0.99 multiple of the median, P<.001), but the median TSH multiple of the median was not significantly different (0.99 compared with 1.01 multiple of the median, P=.331). CONCLUSION: In pregnancies resulting in spontaneous early preterm delivery, there is no evidence of increased prevalence of antithyroid antibody positivity or maternal thyroid dysfunction at 11–13 weeks. LEVEL OF EVIDENCE: II

Maternal Thyroid Function at 11-13 Weeks of Gestation

Objective: To establish normal ranges of maternal serum thyroid-stimulating hormone (TSH), free thyroxine (FT4) and free triiodothyronine (FT3) at 11–13 weeks of gestation. Methods: Maternal serum concentrations of FT3, FT4, TSH, anti-thyroperoxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies were measured at 11–13 weeks. Normal ranges were constructed from the data of singleton pregnancies with no anti-thyroid antibodies resulting in live births after 34 weeks of phenotypically normal neonates with birth weight above the 5th percentile. Adjustments were made for maternal characteristics found by multiple regression analysis to affect the levels of TSH, FT3 and FT4. Results: 3,592 of the 4,318 pregnancies examined were antibody negative, and in this group serum TSH increased whereas FT3 and FT4 decreased with gestation, and all three were lower in black than in white women. Serum FT3 and FT4 decreased but TSH did not change significantly with maternal age; TSH and FT3 increased whereas FT4 decreased with body mass index; TSH decreased whereas FT3 and FT4 increased with serum free β-hCG. In the antibody-positive group, compared to the negative group, median TSH was higher and median FT3 and FT4 were lower. Conclusion: The study established normal ranges for maternal thyroid function at 11–13 weeks.

Maternal thyroid function at gestational weeks 11-13 in twin pregnancies.

BACKGROUND Thyroid disease during pregnancy may be associated with increased risk of various pregnancy complications. It is known that serum thyrotropin (TSH) is suppressed because of the increased hormone production induced by human chorionic gonadotrophin (hCG) in early pregnancy, and that higher hCG levels in twin pregnancies may cause a more pronounced physiologic suppression. The recognition of this phenomenon is important in order to avoid unnecessary concerns and to correctly establish the diagnosis of overt thyroid disease in twin pregnancies. The aim of this study was to establish reference ranges of maternal serum TSH and free thyroxine (FT4) at gestational weeks 11-13 in twin pregnancies. METHODS This is a case series of 177 dichorionic and 58 monochorionic twin pregnancies with normal outcomes, and 19 monochorionic pregnancies complicated by severe twin-twin transfusion syndrome. Maternal serum concentrations of TSH, FT4, antithyroperoxidase, and antithyroglobulin antibodies were measured at gestational weeks 11-13. The measured TSH and FT4 were converted to multiple of median (MoM) of normal singleton pregnancies and MoM values in the different groups were compared. RESULTS In the antibody-negative twin pregnancies with normal outcomes, compared to singletons, serum TSH MoM was lower (median 0.62 [interquartile range [IQR 0.16-1.18] vs. 1.01 [IQR 0.61-1.51]; p < 0.0001), FT4 MoM was not significantly different (median 0.98 [IQR 0.91-1.08] vs. 0.99 [IQR 0.91-1.09]; p = 0.975), and free β-hCG MoM was higher (median 1.91 [IQR 1.33-2.59] vs. 0.98 [IQR 0.66-1.50]; p < 0.0001). In the antibody-positive group (n = 37), compared to the negative group (n = 198), the median TSH was higher, but FT4 and free β-hCG were not significantly different. In the twin-twin transfusion syndrome group, compared to normal twin pregnancies, TSH, FT4, and free β-hCG were not significantly different. CONCLUSION In twins, compared to singleton pregnancies, TSH is lower but FT4 is not significantly different. These reference ranges of thyroid hormones in twins can form the basis for the study of early thyroid function in pathological pregnancies and the investigation of the consequences of overt and subclinical hypothyroidism on twin pregnancy outcome.

Maternal Thyroid Function at 11–13 Weeks of Gestation in Women with Hypothyroidism Treated by Thyroxine

Objective: The aim of this study in pregnant women with hypothyroidism treated by levothyroxine is to examine the interrelations between thyroid-stimulating hormone (TSH), free thyroxine (FT4) and free tri-iodothyronine (FT3), and examine whether in such patients the treatment is adequate. Methods: This was a retrospective cross-sectional study. Maternal serum concentrations of FT3, FT4 and TSH were measured at 11–13 weeks in 164 singleton pregnancies from women with hypothyroidism before pregnancy receiving treatment with thyroxine. The values were compared to the results in 4,318 normal singleton pregnancies. Results: In the hypothyroid group, compared to the normal group, there was an increase in median TSH (1.990 vs. 1.007 MoM) and FT4 (1.052 vs. 0.992 MoM) and decrease in FT3 (0.901 vs. 0.991 MoM). Serum FT4 was at or above the 2.5th centile in 158 (96.3%) cases but TSH was above the 97.5th centile in 48 (29.3%) and FT3 was below the 2.5th centile in 49 (29.9%) cases. In both the hypothyroid and unaffected groups there were significant associations between TSH and FT4, TSH and FT3 and between FT3 and FT4. Conclusions: In a high proportion of pregnant women with hypothyroidism treated with levothyroxine there is evidence of persistent hypothyroidism because the treatment is inadequate in correcting the levels of FT3.

Contents Vol. 31, 2012

R. Achiron, Tel Hashomer N.S. Adzick, Philadelphia, Pa. L. Allan, London A.A. Baschat, Baltimore, Md. K.J. Blakemore, Baltimore, Md. T.-H. Bui, Stockholm F.A. Chervenak, New York, N.Y. T. Chiba, Tokyo R. Chmait, Los Angeles, Calif. F. Crispi, Barcelona J.E. De Lia, Milwaukee, Wisc. J.A. Deprest, Leuven G.C. Di Renzo, Perugia J.W. Dudenhausen, Berlin N.M. Fisk, Brisbane, Qld. A.W. Flake, Philadelphia, Pa. U. Gembruch, Bonn M.R. Harrison, San Francisco, Calif. J.C. Hobbins, Denver, Colo. L.K. Hornberger, San Francisco, Calif. E.R.M. Jauniaux, London M.P. Johnson, Philadelphia, Pa. C. Jorgensen, Copenhagen J.-M. Jouannic, Paris P.M. Kyle, London O. Lapaire, Basel S. Lipitz, Tel-Hashomer G. Malinger, Holon G. Mari, Detroit, Mich. M. Martinez-Ferro, Buenos Aires K.J. Moise, Houston, Tex. F. Molina, Granada K.H. Nicolaides, London D. Oepkes, Leiden L. Otaño, Buenos Aires Z. Papp, Budapest R.A. Quintero, Miami, Fla. G. Ryan, Toronto J. Rychik, Philadelphia, Pa. H. Sago, Tokyo W. Sepulveda, Santiago P. Stone, Auckland D.V. Surbek, Bern B.J. Trudinger, Westmead, N.S.W. J.M.G. van Vugt, Amsterdam Y. Ville, Paris Clinical Advances and Basic Research