The association between serum progesterone level and preterm delivery.

OBJECTIVE: To investigate the association of serum progesterone level and preterm delivery. METHODS: The present prospective cohort study enrolled women with singleton pregnancies attending their first prenatal visit at the outpatient specialist clinics at KK Women's and Children's Hospital, Singapore, between September 1, 2010, and August 31, 2014. Progesterone levels were measured at four clinical visits (visit 1: 9-14 weeks; visit 2: 18-22 weeks; visit 3: 28-32 weeks; visit 4: >34 weeks) and were compared (after adjusting for potential confounders) between patients who had term and preterm deliveries, and among subgroups of spontaneous preterm and iatrogenic preterm deliveries. RESULTS: There were 708 patients included. Serum progesterone levels at visit 3 were higher in the preterm delivery group than in the term delivery group (P=0.036). The levels did not differ between the two groups at other visits (all P>0.05). In the subgroup analysis, progesterone levels were higher in the iatrogenic preterm delivery subgroup than the term subgroup at visits 1 and 3. A progesterone cut-off level of 304.5 nmol/L demonstrated 81.8% sensitivity, 40.1% specificity, and negative and positive predictive values of 97.5% and 7.2%, respectively, as a predictor of preterm delivery. CONCLUSION: Higher serum progesterone levels at 28-32 weeks of pregnancy were observed in women who had preterm deliveries; it was weakly predictive of preterm delivery.

Gestational age-specific reference intervals for serum thyroid hormone levels in a multi-ethnic population.

BACKGROUND: Thyroid disorders are common during pregnancy. To date, a limited number of studies have reported differences in serum thyroid hormone concentrations between different ethnic groups. We sought to establish gestational age-specific reference intervals for serum levels of thyroid hormones in a multi-ethnic population and investigate whether separate reference intervals should be used for different ethnic groups. METHODS: A total of 926 pregnant women from multiple ethnic groups attended four separate study visits spanning the three trimesters. Venous blood samples were taken at 9 to 14 weeks, 18 to 22 weeks, 28 to 32 weeks, and 34 to 39 weeks of gestation. Serum concentrations of thyroid-stimulating hormone (TSH), free thyroxine (T4), free triiodothyronine (T3), total T4, total T3, thyroid peroxidase antibody and thyroglobulin antibody were measured using Abbott Architect immunoassays. A total of 562 women with singleton pregnancies were found to be negative for both thyroid autoantibodies at all four study visits and thus included in the reference sample group for the establishment of reference intervals (2.5th to 97.5th percentiles). RESULTS: Reference intervals for serum thyroid hormones at 9-14 weeks of gestation derived from the combined group of pregnant women are as follows: TSH, 0.01-2.39 mIU/L; free T4, 11.4-19.5 pmol/L; free T3, 4.23-6.69 pmol/L; total T4, 77.8-182.4 nmol/L; total T3, 1.39-2.97 nmol/L. No differences in the five thyroid parameters' reference intervals are detectable among the ethnic groups except that at study visit 3 (28-32 weeks of gestation), the upper reference limit of total T3 in Malays (3.20 nmol/L; 90% CI, 2.99-3.76 nmol/L) is slightly higher than that in Chinese (2.86 nmol/L; 90% CI, 2.70-2.98 nmol/L). CONCLUSIONS: The findings from this study on a multi-ethnic cohort highlight the importance of establishing locally derived and gestational age-specific reference intervals for the five thyroid hormone parameters.

ANXIETY AND DEPRESSION DURING PREGNANCY AND TEMPERAMENT IN EARLY INFANCY: FINDINGS FROM A MULTI-ETHNIC, ASIAN, PROSPECTIVE BIRTH COHORT STUDY.

Maternal antenatal mood is associated with negative infant temperament. This link has not been substantiated in Asian populations. We evaluated the association between antenatal maternal mood and infant temperament among Asian mother-infant pairs. Antenatal maternal depression and anxiety were assessed using the Edinburgh Postnatal Depression Scale (J. Cox, J. Holden, & R. Sagovsky, 1987) and the State-Trait Anxiety Inventory (C. Spielberger, R. Gorsuch, R. Lushene, P. Vagg, & G. Jacobs, 1983), respectively, at 26 weeks of pregnancy and 3 months' postnatally. Infant temperament was evaluated with the Early Infant Temperament Questionnaire (B. Medoff-Cooper, W.B. Carey, & S.C. McDevitt, 1993) at 3 months. Factor analysis was performed to extract culturally relevant categories of temperamental traits. Linear regression was performed to examine the influences of antenatal maternal mood on the factor-model-derived infant temperament. Of the 609 mothers, 11% met risk criteria for depression, 17% for state-anxiety, and 19% for trait-anxiety during pregnancy. Factor analysis yielded three infant temperament factors: Emotionality and Attentional Regulation, Sensory Reactivity, and Regularity and Motor Expression, Cronbach's αs = 0.613, 0.712, and 0.752, respectively. Maternal antenatal state-anxiety, p < .001, and trait anxiety, p = .005, were associated with negative emotionality and poor attentional regulation, especially among Chinese, whereas depression was not, p = .090. There was an association between maternal antenatal anxiety and negative infant temperamental traits in this Asian sample.

Incremental Cost-Effectiveness Analysis of Gestational Diabetes Mellitus Screening Strategies in Singapore.

The objective of this study was to conduct an incremental cost-effectiveness analysis from the payer's perspective in Singapore of 3 gestational diabetes mellitus screening strategies: universal, targeted, or no screening. A decision tree model assessed the primary outcome: incremental cost per quality-adjusted life year (QALY) gained. Probabilities, costs, and utilities were derived from the literature, the Growing Up in Singapore Towards healthy Outcomes (GUSTO) birth cohort study, and the KK Women's and Children's Hospital's database. Relative to targeted screening using risk factors, universal screening generates an incremental cost-effectiveness ratio (ICER) of $USD10,630/QALY gained. Sensitivity analyses show that disease prevalence rates and intervention effectiveness of glycemic management have the biggest impacts on the ICERs. Based on the model and best available data, universal screening is a cost-effective approach for reducing the complications of gestational diabetes mellitus in Singapore as compared with the targeted screening approach or no screening.

Unconditional and conditional standards for fetal abdominal circumference and estimated fetal weight in an ethnic Chinese population: a birth cohort study.

BACKGROUND: Diagnosis of intrauterine fetal growth restriction and prediction of small-for-gestation age are often based on fetal abdominal circumference or estimated fetal weight (EFW). The present study aims to create unconditional (cross-sectional) and conditional (longitudinal) standards of fetal abdominal circumference and EFW for use in an ethnic Chinese population. METHODS: In the Growing Up in Singapore Towards healthy Outcome (GUSTO) birth cohort study in Singapore, fetal biometric measurements were obtained at enrolment to antenatal care (11-12 weeks) and up to three more time points during pregnancy. Singleton pregnancies with a healthy profile defined by maternal, pregnancy and fetal characteristics and birth outcomes were selected for this analysis. The Hadlock algorithm was used to calculate EFW. Mixed effects model was used to establish unconditional and conditional standards in z-scores and percentiles for both genders pooled and for each gender separately. RESULTS: A total of 313 women were included, of whom 294 had 3 and 19 had 2 ultrasound scans other than the gestational age dating scan. Fetal abdominal circumference showed a roughly linear trajectory from 18 to 36 weeks of gestation, while EFW showed an accelerating trajectory. Gender differences were more pronounced in the 10(th) percentile than the 50(th) or 90(th) percentiles. As compared to other published charts, this population showed growth trajectories that started low but caught up at later gestations. CONCLUSIONS: Unconditional and conditional standards for monitoring fetal size and fetal growth in terms of abdominal circumference and EFW are available for this ethnic-Chinese population. Electronic spreadsheets are provided for their implementation.

The hollow fiber bioreactor as a stroma-supported, serum-free ex vivo expansion platform for human umbilical cord blood cells.

The bone marrow microenvironment plays an integral role in the regulation of hematopoiesis. Residing stromal cells and the extracellular matrix in the bone marrow microenvironment provide biological signals that control hematopoietic stem cell (HSC) function. In this study, we developed a bio-mimetic co-culture platform using the hollow fiber bioreactor (HFBR) for ex vivo expansion of HSCs. We evaluated the efficacy of such a platform in comparison to standard cultures performed on tissue culture polystyrene (TCP), using a human stromal cell line (HS-5) as stromal support, co-cultured with lineage-depleted human cord blood cells in serum-free medium supplemented with a cytokine cocktail. Our results showed that the performance of the HFBR in supporting total cell and CD34(+) progenitor cell expansion was comparable to that of cultures on TCP. Cells harvested from the HFBR had a higher clonogenic ability. The performance of ex vivo-expanded cells from the HFBR in hematopoietic reconstitution in humanized mice was comparable to that of the TCP control. Scanning electron microscopy revealed that stroma cell growth inside the HFBR created a three-dimensional cell matrix architecture. These findings demonstrate the feasibility of utilizing the HFBR for creating a complex cell matrix architecture, which may provide good in vitro mimicry of the bone marrow, supporting large-scale expansion of HSCs.

Global DNA hypermethylation in down syndrome placenta.

Down syndrome (DS), commonly caused by an extra copy of chromosome 21 (chr21), occurs in approximately one out of 700 live births. Precisely how an extra chr21 causes over 80 clinically defined phenotypes is not yet clear. Reduced representation bisulfite sequencing (RRBS) analysis at single base resolution revealed DNA hypermethylation in all autosomes in DS samples. We hypothesize that such global hypermethylation may be mediated by down-regulation of TET family genes involved in DNA demethylation, and down-regulation of REST/NRSF involved in transcriptional and epigenetic regulation. Genes located on chr21 were up-regulated by an average of 53% in DS compared to normal villi, while genes with promoter hypermethylation were modestly down-regulated. DNA methylation perturbation was conserved in DS placenta villi and in adult DS peripheral blood leukocytes, and enriched for genes known to be causally associated with DS phenotypes. Our data suggest that global epigenetic changes may occur early in development and contribute to DS phenotypes.

A cohort evaluation on arterial stiffness and hypertensive disorders in pregnancy.

BACKGROUND: Hypertensive disorders in pregnancy are associated with systemic endothelial dysfunction leading to impaired physiological vasodilation. Recent evidence has shown central aortic pressures obtained through pulse wave analysis, at less than 14 weeks of gestation, to be predictive of pre-eclampsia. In light of this, we aimed to evaluate the role of central aortic stiffness in the prediction and discrimination of hypertensive disorders in pregnancy. METHODS: A cohort study of women with viable, singleton pregnancies at less than 14 weeks of amenorrhoea, and without multiple pregnancies, autoimmune or renal disease, diagnosed with aneuploidy or fetal anomaly will be recruited from a single maternity hospital and followed up till delivery and puerperium. A targeted sample size of 1000 eligible pregnant women will be enrolled into the study from antenatal clinics. Main exposure under study is central aortic pulse pressure using radial pulse wave recording, and the outcomes under follow-up are gestational hypertension and pre-eclampsia. Other measures include lifestyle factors such as smoking, physical exercise, psychometric evaluations, vasoactive factors, uterine artery pulsatility index, height and weight measurements. These measures will be repeated over 4 antenatal visits at 11-14, 18-22, 28-32 and above 34 weeks of gestation. Double data entry will be performed on Microsoft Access, and analysis of data will include the use of random effect models and receiver operating characteristic curves on Stata 11.2. DISCUSSION: The proposed study design will enable a longitudinal evaluation of the central aortic pressure changes as a marker for vascular compliance during pregnancy. As measures are repeated over time, the timing and severity of changes are detectable, and findings may yield important information on how aberrant vascular responses occur and its role in the early detection and prediction of hypertensive disorders.

Further improvement in quantifying male fetal DNA in maternal plasma.

BACKGROUND: Cell-free fetal DNA (cffDNA) in maternal plasma can be clinically useful for detecting prenatal disorders and pregnancy monitoring. More sensitive, specific, and quantitative detection of cffDNA in maternal plasma may expand the clinical utility of such measurements. METHODS: We developed a quantitative real-time PCR (qPCR) assay [Y chromosome repetitive sequence (YRS) assay] based on a highly repetitive short sequence specific for the Y chromosome. Both standard qPCR and digital qPCR were performed to compare the sensitivity and specificity of this new assay against already established male DNA-specific assays. RESULTS: The YRS assay was at least 10-fold more sensitive than the currently most sensitive DYS14 assay. The YRS assay was able to detect 0.5 genome equivalents (GE) per PCR reaction when fetal DNA was present at 0.2% of the total DNA. The background noise for the YRS assay was much lower than for the DYS14 assay in analyses of plasma samples from pregnancies with female fetuses. CONCLUSIONS: The YRS assay is a substantial improvement for quantifying rare male fetal DNA in maternal plasma. The higher sensitivity and specificity may expand the clinical and research utility of cffDNA.

Recurrent non-immune fetal hydrops: A case report.

INTRODUCTION: Recurrent non-immune fetal hydrops (NIH) has been reported in the literature but is a rare entity, with fewer than 6 reported cases so far. It has been postulated to be related to a recessive gene. CLINICAL PICTURE: We report a case of recurrent fetal hydrops in a multigravida with no medical history of note. She presented in her current pregnancy with a significant history of having 4 (out of 7) previous pregnancies affected by hydrops. TREATMENT: All the affected pregnancies resulted in mid-trimester pregnancy termination (MTPT) following diagnosis in the second trimester. Previous investigations for hydrops did not yield any obvious cause. OUTCOME: Her most recent pregnancy was unaffected. We discuss the possible differential diagnoses and the likelihood of autosomal recessive metabolic diseases being the aetiological factor. CONCLUSION: Rare causes of fetal hydrops need to be excluded in cases of recurrent non-immune hydrops with no obvious aetiology following routine investigations.