Wide Range Of Gestational Ages Research Articles

A noninvasive prenatal test pipeline with a well-generalized machine-learning approach for accurate fetal trisomy detection using low-depth short sequence data

Noninvasive prenatal test (NIPT) reduces the associated risk of procedure-related miscarriage. However, due to accuracy, special fetuses, economic and policy gaps, NIPT still cannot replace traditional surgical methods. Developing a pipeline with low cost, low technical difficulty, stability and high accuracy is a major challenge for NIPT to be widely used. This study proposes a new pipeline for the detection of fetal trisomy which includes 3 steps: 1. 40 bp single-end sequencing, 2. PchrN calculations, and 3. logisticregression (LR) models. Part of the public dataset (100 out of 144 samples) was used to train models and select features in the machine learning pipeline. 314 samples from different sources were used for independent testing. We compare the performance of our method with the bioinformatics method widely used today. Our model shows high robustness to data from different sources. The final best model achieved an AUC of 99.85 % in predicting T21 using chr21 features which are the DNA fragment concentrations. The AUC is 99.50 %, and 97.70 % in predicting T18 and T13 with all features from 24 chromosomes. The PPV of T21, T18 and T13 was predicted to be 91.67 %, 93.33 % and 83.33 %, respectively, which was higher than that obtained by standard bioinformatics methods. The NPV to identify T21, T18, and T13 were 100 %, 99.33 %, and 98.70 %, respectively. Our approach does not need to calculate fetal fraction (FF) and can handle samples from a wide range of gestational ages (GA), twin pregnancies and fetal mosaicism. Our approach can achieve comparable accuracy with the current standard bioinformatics analysis in low-depth sequencing data. This convenient pipeline can be used independently of traditional bioinformatics methods, and its performance has been tested in real clinical practice. Our pipeline can be an important aid for the detection of fetal trisomy in clinical NIPT, which will help further popularize NIPT.

Simplifying Hyperbilirubinemia Risk Estimation.

Jaundice impacts more than half of term and late preterm newborns in the first week of life. Although in most cases, jaundice is benign, the consequences of severe hyperbilirubinemia are debilitating; thus, identification of newborns likely to exceed bilirubin treatment thresholds is needed. The American Academy of Pediatrics (AAP) recommends stratification of predischarge total serum bilirubin (TSB) levels by using the Bhutani Nomogram to help determine the appropriate timing of newborn follow-up. A separate nomogram is then used to determine if an infant meets criteria for phototherapy.1Kuzniewicz et al2 aim to simplify the process and more precisely determine when a newborn requires outpatient follow-up for jaundice with a simple equation. Starting with a retrospective cohort study of a diverse sample of 148 162 newborns born at ≥35 weeks’ gestation at 11 Kaiser Permanente Northern California facilities from 2012 to 2017, the researchers identified newborns whose TSB measurements did not exceed phototherapy levels and did not receive phototherapy during the birth hospitalization. Using the newborn’s last TSB value before hospital discharge (predischarge TSB), the authors calculated the difference between the predischarge total serum bilirubin and the corresponding American Academy of Pediatrics phototherapy threshold (in milligrams/deciliter) (Δ-TSB). Newborns who required phototherapy after discharge were identified. The authors compared the ability of the Δ-TSB model to predict postdischarge TSB above phototherapy thresholds to the Bhutani Nomogram. Examining additional variables, they also compared a more complicated Δ-TSB-Plus model. Although all 3 models performed well for those at highest and lowest risk of subsequent severe hyperbilirubinemia, both Δ-TSB and Δ-TSB-Plus models differentiated newborns in the intermediate zones better than the Bhutani Nomogram. Forty-four percent of newborns in Bhutani’s high-intermediate risk zone (who would have follow-up recommended within 48 hours) had a Δ-TSB between −4 and −5 mg/dL. In these newborns, the risk of ever having a subsequent TSB measurement greater than the AAP threshold was only 1.6%, suggesting follow-up within 48 hours might not be indicated.The Δ-TSB measurements used in this study relied on clinician discretion in follow-up; therefore, the predictive accuracy of the Δ-TSB models may be inflated because of differential verification bias as the authors mention. Only TSB measurements were included, but many hospitals and clinics use transcutaneous bilirubinometry.3 Although one can extrapolate the Δ-TSB for low bilirubin levels, the additional uncertainty involved when transcutaneous bilirubin measurements are used to approximate TSB levels has the potential to impact effective implementation of the Δ-TSB risk prediction approach.4 The 2004 AAP bilirubin thresholds were used in this study, but some clinicians caring for the patients studied may have followed other recommendations. For example, if the Northern California Neonatal Consortium criteria were used,5 some newborns may not have received a TSB assessment. Because nearly half of treated newborns were provided home phototherapy, we suspect their bilirubin levels were close to AAP thresholds. Clinicians may want to understand which newborns returned with bilirubin levels nearing or exceeding exchange thresholds and if they were predictable6; these data were not provided. Given the wide range of gestational ages in the AAP phototherapy risk strata (35–38 weeks; >38 weeks), a more delineated approach by gestational age and sex would be helpful because we know lower gestational age and male sex contribute to a higher risk of hyperbilirubinemia.7,8 An implementation study across different health systems will improve the generalizability of the Δ-TSB strategy.Despite any limitations, this study could have significant impact on the experience of care for new families and curb health care overuse. Currently, the AAP Bright Futures Guidelines recommend timing the initial newborn posthospitalization continuing care visit within 3 to 5 days after birth and 48 to 72 hours after discharge. This recommendation is based primarily on concern for jaundice and feeding problems leading to excessive weight loss.9 Implementation of a Δ-TSB approach has the potential to simplify postdischarge phototherapy risk estimation and might decrease unnecessary health care visits and extra hospital days for newborns previously stratified to the high-intermediate and low-intermediate risk zones on the Bhutani Nomogram. Select newborns could be discharged at 24 hours rather than 48 hours given this new evidence supporting an enhanced understanding of bilirubin trajectories. Some newborns with intermediate risk could safely defer in-person follow-up through weekends, holidays, and inclement weather days, whereas others may avoid daily outpatient bilirubin sampling with more optimally timed follow-up. This research also highlights, with large numbers, how truly low risk some newborns are for developing significant hyperbilirubinemia. With increasing adoption of telemedicine,10 those newborns who are also at low risk of feeding problems could be safely cared for in their homes.We thank Arthur Jaffe, MD, for reviewing and editing this commentary.

Neonatal Risk, Maternal Sensitive-Responsiveness and Infants' Joint Attention: Moderation by Stressful Contexts.

Neonatal risk factors have been associated with atypical development in various areas of social communication, including joint attention (JA), but little is known about factors in the early caregiving environment that can modify the negative implications of neonatal risk. The present study examines the links between neonatal risk and infants' JA, while considering the mediating role of maternal sensitive-responsiveness and the moderating roles of stressful contexts. One hundred and eighty-two families with infants (50% female) born in a wide range of gestational ages and birthweights participated in the study. Neonatal risk was assessed shortly after birth using three indicators: birthweight, gestational age, and degree of medical risk. At age 6 months, maternal sensitive-responsiveness to infants' foci of attention was rated and maternal anxiety and household chaos were measured. Infants' JA behaviors were assessed at age 12 months. A moderated-mediation model revealed that maternal anxiety symptoms and household chaos moderated the links between neonatal risk, maternal sensitive-responsiveness, and infants' responding to JA. Specifically, neonatal risk was related to less maternal sensitive-responsiveness only when maternal anxiety symptoms were above average levels, but not when anxiety symptoms were low. Moreover, maternal sensitive-responsiveness was positively related to infants' responding to JA behaviors when household chaos was low but not when it was high. These findings highlight the complex nature of the links between infants' early biological risk and caregiving environments in the development of social communication skills.

Automatic, Age Consistent Reconstruction of the Corpus Callosum Guided by Coherency From In Utero Diffusion-Weighted MRI.

Reconstruction of white matter connectivity in the fetal brain from in utero diffusion-weighted magnetic resonance imaging (MRI) faces many challenges, including subject motion, small anatomical scale, and limited image resolution and signal. These issues are compounded by the need to track significant changes in structural connectivity throughout development. We present an automated method for improved reliability and completeness of tract extraction across a wide range of gestational ages, based on the geometry of coherent patterns in streamline tractography, and apply it to the reconstruction of the corpus callosum. This method, focused specifically at addressing the challenges of fetal brain imaging, avoids depending on a tractography atlas, and handles variations in size, shape, and tissue properties of developing brains, both between subjects and across ages. Although tractography from in utero MRI generally suffers from a significant number of misleading and missing pathways, we demonstrate the feasibility of extracting the coherent bundle of the corpus callosum while avoiding inappropriate diversions into other tracts.

Effect of prematurity on genome wide methylation in the placenta

BackgroundPreterm birth is a significant clinical problem and an enormous burden on society, affecting one in eight pregnant women and their newborns. Despite decades of research, the molecular mechanism underlying its pathogenesis remains unclear. Many studies have shown that preterm birth is associated with health risks across the later life course. The “fetal origins” hypothesis postulates that adverse intrauterine exposures are associated with later disease susceptibility. Our recent studies have focused on the placental epigenome at term. We extended these studies to genome-wide placental DNA methylation across a wide range of gestational ages. We applied methylation dependent immunoprecipitation/DNA sequencing (MeDIP-seq) to 9 placentas with gestational age from 25 weeks to term to identify differentially methylated regions (DMRs).ResultsEnrichment analysis revealed 427 DMRs with nominally significant differences in methylation between preterm and term placentas (p < 0.01) and 21 statistically significant DMRs after multiple comparison correction (FDR p < 0.05), of which 62% were hypo-methylated in preterm placentas vs term placentas. The majority of DMRs were in distal intergenic regions and introns. Significantly enriched pathways identified by Ingenuity Pathway Analysis (IPA) included Citrulline-Nitric Oxide Cycle and Fcy Receptor Mediated Phagocytosis in macrophages. The DMR gene set overlapped placental gene expression data, genes and pathways associated evolutionarily with preterm birth.ConclusionThese studies form the basis for future studies on the epigenetics of preterm birth, “fetal programming” and the impact of environment exposures on this important clinical challenge.

Optimal reference genes for RT-qPCR normalization in the newborn

It is difficult to identify reliable reference genes for transcriptomic analyses in biofluids such as saliva. This situation is particularly relevant for the newborn population, where rapid development is associated with dynamic changes in gene expression. Real-time gene expression monitoring holds great promise for elucidating disrupted pathways that result in morbidities unique to this population, such as retinopathy of prematurity, but its impact depends on identifying stable and consistently expressed genes across a wide range of gestational ages. We extracted total RNA from 400 neonatal saliva samples (postconceptional ages: 32 5/7 to 48 2/7 weeks), converted it to cDNA, and pre-amplified and analyzed it by qPCR for three commonly used reference genes, ACTB, GAPDH, and YWHAZ. Relative quantification was determined using the Δ Ct method. Data were analyzed as a whole and also stratified by age and sex. Descriptive statistics and homogeneity of variance were performed to identify optimal reference genes. Data analyzed from all ages and both sexes showed significant expression variation for ACTB, while GAPDH and YWHAZ showed greater stability. Male infants exhibited increased expression variation compared to females for ACTB, but neither GAPDH nor YWHAZ showed significant variance for either sex. We suggest that ACTB is an unreliable reference gene for the newborn population. Males showed significantly more variation in ACTB expression compared to females, which suggests a sex-specific developmental role for this biomarker. By contrast, GAPDH and YWHAZ were less variable and therefore preferable for use in neonates. Our findings may improve the use of reference genes for the RT-qPCR platform in the newborn over a wide range of gestational ages, thereby minimizing the likelihood of erroneous interpretation of gene expression during rapid growth, development, and differentiation.

Region-specific growth restriction of brain following preterm birth.

Regional brain sizes of very-preterm infants at term-equivalent age differ from those of term-born peers, which have been linked with later cognitive impairments. However, dependence of regional brain volume loss on gestational age has not been studied in detail. To investigate the spatial pattern of brain growth in neonates without destructive brain lesions, head MRI of 189 neonates with a wide range of gestational age (24–42 weeks gestation) was assessed using simple metrics measurements. Dependence of MRI findings on gestational age at birth (Agebirth) and the corrected age at MRI scan (AgeMRI) were assessed. The head circumference was positively correlated with AgeMRI, but not Agebirth. The bi-parietal width, deep grey matter area and the trans-cerebellar diameter were positively correlated with both Agebirth and AgeMRI. The callosal thickness (positive), atrial width of lateral ventricle (negative) and the inter-hemispheric distance (negative) were exclusively correlated with Agebirth. The callosal thickness and cerebral/cerebellar transverse diameters showed predominant dependence on Agebirth over AgeMRI, suggesting that brain growth after preterm-birth was considerably restricted or even became negligible compared with that in utero. Such growth restriction after preterm birth may extensively affect relatively more matured infants, considering the linear relationships observed between brain sizes and Agebirth.

Automatic whole brain MRI segmentation of the developing neonatal brain.

Magnetic resonance (MR) imaging is increasingly being used to assess brain growth and development in infants. Such studies are often based on quantitative analysis of anatomical segmentations of brain MR images. However, the large changes in brain shape and appearance associated with development, the lower signal to noise ratio and partial volume effects in the neonatal brain present challenges for automatic segmentation of neonatal MR imaging data. In this study, we propose a framework for accurate intensity-based segmentation of the developing neonatal brain, from the early preterm period to term-equivalent age, into 50 brain regions. We present a novel segmentation algorithm that models the intensities across the whole brain by introducing a structural hierarchy and anatomical constraints. The proposed method is compared to standard atlas-based techniques and improves label overlaps with respect to manual reference segmentations. We demonstrate that the proposed technique achieves highly accurate results and is very robust across a wide range of gestational ages, from 24 weeks gestational age to term-equivalent age.

Gestational age-dependent risk factors for preterm birth: associations with maternal education and age early in gestation

ObjectivesPreterm birth (PTB) before 37 weeks can occur over a wide range of gestational ages, but few studies have assessed if associations between risk factors and PTB vary over the duration of gestation. We sought to evaluate if associations between two major risk factors (maternal education and age) and PTB depend on gestational age at delivery. Study designWe estimated hazard ratios of PTB for education and age in a time-to-event analysis using a retrospective cohort of 223,756 live singleton births from the province of Québec, Canada for the years 2001–2005. Differences in hazards of maternal education and age with PTB were assessed over gestational age in a Cox proportional hazards model using linear and nonlinear time interaction terms, adjusting for maternal characteristics. ResultsAssociations of PTB with lower (vs. higher) education and older (vs. younger) age strengthened progressively at earlier gestational ages, such that the risk of PTB for maternal education and age was not constant over the course of gestation. ConclusionsAssociations of PTB with risk factors such as maternal low education and older age may be stronger early in gestation. Models that capture the time-dependent nature of PTB may be useful when the goal is to assess associations at low gestational ages, and to avoid masked or biased associations early in gestation.

Mode of Delivery and Neonatal Outcomes in Preterm, Small-for-Gestational-Age Newborns

More than 50% of neonates born before 34 weeks of gestation in the United States are delivered by cesarean section (CS). When intrauterine growth restriction is present or the neonate is small for gestational age (SGA), vaginal delivery has been reported to be associated with increased odds of neonatal mortality. Given the increased risk of morbidity and mortality for SGA newborns and the relative impossibility of a conclusive randomized controlled trial, this study was performed to examine the association between route of delivery and neonatal outcomes, particularly neonatal death, intraventricular hemorrhage (IVH), and respiratory distress syndrome (RDS), in a large, diverse cohort of preterm SGA newborns. Data on 1,025,903 singleton live births from 1995 to 2003 were obtained from a data set linking birth certificate and hospital discharge data in New York City. The study population included only women delivering vertex-presenting, singleton neonates between 25 and 34 6/7 weeks of gestation (n = 31,135). Of 23,144 neonates meeting the inclusion criteria, 2885 met the definition for SGA at delivery. Small for gestational age was used as a surrogate for intrauterine growth restriction. Because of the wide range of gestational ages, a subanalysis was done for those with a gestational age less than 30 weeks (n = 359). Another study population included all operative deliveries (n = 2927). Main outcomes included neonatal death before discharge, neonatal RDS, sepsis, IVH, seizure, subdural hemorrhage, or 5-minute Apgar score less than 7. Maternal characteristics included age, parity, race and ethnicity, level of education, insurance status, and prepregnancy weight. Covariates included diabetes, hypertension, and gestational age of delivery. Of the 2885 neonates, 1214 (42.1%) were delivered vaginally, and 1671 (57.9%) were delivered by CS. All maternal and pregnancy characteristics differed significantly between the 2 groups (P < 0.05). Women who underwent CS were older, heavier, better educated, more likely to be white, and more often had diabetes or hypertension. The rate of CS rose in SGA newborns born at 34 weeks of gestation or less during the course of the study (1995–2003; 50% and 61% in 1995 and 2003). Neonates delivered by CS had a higher incidence of RDS and 5-minute Apgar scores of less than 7 compared with those delivered vaginally (odds ratio [OR], 1.49; 95% confidence interval [CI], 1.25–1.76; and OR 1.42; 95% CI, 1.07–1.87, respectively). After adjustment for maternal age, race, parity, education, insurance status, prepregnancy weight, diabetes, hypertension, and gestational age at delivery, CS was still associated with increased odds of RDS compared with vaginal delivery (adjusted OR, 1.32; 95% CI, 1.07–1.63) and tended to be associated with slightly elevated risks for all outcomes except IVH and neonatal death. When forceps and vacuum deliveries were included in the analysis, results were not altered significantly. The fact that CS is associated with more RDS indicates that CS is not necessarily beneficial to SGA preterm neonates. The known risks and costs of CS might be justified if CS improves neonatal outcomes. However, these results show that CS compared with vaginal delivery was not associated with any statistically significant benefit for preterm SGA neonates. Further research is necessary to evaluate the effects of the rising CS rate in preterm SGA neonates. As with full-term newborns, vaginal delivery offers neonates an early respiratory advantage compared with CS.

Population pharmacokinetic analysis of vancomycin in neonates. A new proposal of initial dosage guideline

To determine the population pharmacokinetic parameters of vancomycin in neonatal patients with a wide range of gestational age and birth weight, and subsequently to design an initial dosing schedule for vancomycin in neonates. Using nonlinear mixed-effects modelling (NONMEM VI), the pharmacokinetics of vancomycin were investigated in 70 neonates with postmenstrual age and body weight ranging 25.1-48.1 weeks and 0.7-3.7kg, respectively. A one-compartment linear disposition model with zero order input and first-order elimination was used to describe the data. Nine demographic characteristics and 21 co-administered drugs were evaluated as covariates of clearance (CL) and distribution volume (V(d) ) of vancomycin. Weight-normalized clearance of vancomycin was influenced by postmenstrual age (PMA) and co-administration of amoxicillin-clavulanic acid. Weight-normalized volume of distribution was influenced by co-administration of spironolactone. CL and V(d) of the typical individual in this study population (PMA = 34.6 weeks, weight = 1.7kg) were estimated to be 0.066lh(-1) kg(-1) (95% CI 0.059, 0.073lh(-1) kg(-1) ) and 0.572lkg(-1) (95% CI 0.505, 0.639lkg(-1) ), respectively. This model was used to predict a priori serum vancomycin concentrations in a validation group (n= 41), which were compared with observed concentrations to determine the predictive performance of the model. The 95% confidence interval of mean prediction error included zero for both peak and trough vancomycin concentrations. Postmenstrual age, co-administration of amoxicillin-clavulanic acid and spironolactone have a significant effect on the weight-normalized CL and V(d) . An initial dosage guideline for vancomycin is proposed for preterm and full-term neonates, whereas the population pharmacokinetic model can be used for dosage individualization of vancomycin.

Comment on “Longitudinal reference ranges for estimated fetal weight” by Johnsen et al. (Acta Obstetricia et Gynecologica Scandinavica 2006; 85: 286–97)

Dear Sir, We read with interest the March article in which Johnsen and colleagues described reference ranges for fetal weight by gestational age. We particularly commend the authors’ use of a longitudinal approach, which can provide insights not readily observed with cross-sectional techniques. However, we were surprised that, after controlling for fetal dimensions as measured by ultrasound, the authors found no relationship between maternal and pregnancy-specific characteristics and fetal weight. In our own studies, which have now been replicated in two additional independent patient samples, maternal and pregnancy-specific characteristics explain unique portions of the variance in fetal weight not captured by ultrasonographic measurements 1-3. Thus, by combining ultrasonographic and maternal/pregnancy-specific characteristics, birth-weight estimates are far more accurate than can be achieved by considering either set of predictors in isolation 4. We have used these findings to create a set of prediction algorithms together with selection logic to identify the available information for a given patient that selects the optimal prediction equation from 61 possibilities 5. This system, which is currently available on the Internet at http://www.BabyWeightFinder.com, is capable of predicting birth weight with a high degree of accuracy (±6.0%, ±213 g) up to 3 months before delivery. Fetal macrosomia can also be predicted with >83% sensitivity and >95% specificity 4, 5. We suspect that the failure of the current study to identify significant correlations of fetal weight with maternal weight, maternal body mass index, and parity resulted in part from the characteristics of their patient sample. Modeling approaches that have predicted term birth weight have uncovered these dependencies previously 1-3, but the authors’ study included patients who had deliveries as early as 27 and as late as 44 weeks. This wide range of gestational ages at delivery predisposed their analysis to identify the well known dominant effect of gestational age on birth weight at the cost of identifying other variables that account independently for significant portions of the variance. These additional factors are readily seen to be important among neonates born over a more narrow range of gestational ages. In addition to these issues concerning patient selection, the statistical methods used by the authors also contributed to the study's failure to identify significant effects of maternal and pregnancy-specific characteristics on birth weight. By failing to model maternal factors as interactions with gestational age, the authors tested physiologically implausible models that assume the impact of maternal factors is independent of gestational age, despite it having been shown previously that maternal factors are strongly correlated with the rate of fetal weight gain and have larger effects with increasing gestational age 1, 2. The authors also converted maternal height and weight to ternary variables, while parity was converted to a binary variable. These changes eliminated much of the variability – and, thus, the predictive power – of these maternal characteristics. Furthermore, the authors introduced substantial multicollinearity by including both parity and age in their analyses. These two variables are so highly intercorrelated that neither can achieve statistical significance as an independent predictor of fetal weight in an equation that contains the other factor. Had Johnsen and colleagues limited their sample to deliveries that occurred within a narrow range of gestational ages, eliminated age from the analysis, and entered the maternal characteristics as ratio-level variables, it is highly likely that maternal weight, maternal body mass index, and parity would have been significant predictors of the rate of fetal weight gain, beyond the information provided by ultrasonographic fetal measurements.

Abnormal arterial flows by a distributed model of the fetal circulation

Modeling the propagation of blood pressure and flow along the fetoplacental arterial tree may improve interpretation of abnormal flow velocity waveforms in fetuses. The current models, however, either do not include a wide range of gestational ages or do not account for variation in anatomical, vascular, or rheological parameters. We developed a mathematical model of the pulsating fetoumbilical arterial circulation using Womersley's oscillatory flow theory and viscoelastic arterial wall properties. Arterial flow waves are calculated at different arterial locations from which the pulsatility index (PI) can be determined. We varied blood viscosity, placental and brain resistances, placental compliance, heart rate, stiffness of the arterial wall, and length of the umbilical arteries. The PI increases in the umbilical artery and decreases in the cerebral arteries, as a result of increasing placental resistance or decreasing brain resistance. Both changes in resistance decrease the flow through the placenta. An increased arterial stiffness increases the PIs in the entire fetoplacental circulation. Blood viscosity and peripheral bed compliance have limited influence on the flow profiles. Bradycardia and tachycardia increase and decrease the PI in all arteries, respectively. Umbilical arterial length has limited influence on the PI but affects the mean arterial pressure at the placental cord insertion. The model may improve the interpretation of arterial flow pulsations and thus may advance both the understanding of pathophysiological processes and clinical management.

Gestational diabetes mellitus remains a riddle wrapped in a mystery inside an enigma

Dear Sir, We appreciate the comments of Dr. Ozteikin about our paper on HbA1c as a screening test for gestational diabetes mellitus (GDM), which was recently published in this journal. Despite four decades of research, GDM remains, ‘a riddle wrapped in a mystery inside an enigma,’ without any consensus on the screening, diagnosis, and follow-up guidelines of the various expert panels (1). In high-risk populations like the one in our study, the American Diabetes Association and the American College of Obstetricians and Gynecologists recommend screening all pregnant women (i.e. universal screening) with the one-step oral glucose tolerance test (OGTT) at first booking, as early in the pregnancy as possible. All women testing negative need to repeat the OGTT between 24 and 28 weeks’ gestation to rule out GDM. Thus, every pregnant woman has the potential to undergo two OGTTs in the antenatal period. This approach, though conceptually sound, is very demanding and difficult to follow in clinical practice. We tend to follow a practical approach that is a hybrid of these guidelines. Our study was done in a clinical setting with the OGTT being scheduled between 24 and 28 weeks. However, many women were tested earlier due to a clinical decision, as they were at a much higher risk for GDM. Many pregnant women presented for the first time and for first booking anywhere between 28 and 40 weeks. This is the reason for the wide range of gestational ages (16–40 weeks) seen in our study. We repeated the analyses of our data using only women between gestational ages 24 and 28 weeks, who constituted 44% of all the pregnant women in our study. The area under the receiver operating characteristic curve of HbA1c to detect GDM was 0.50 (95% CI 0.38–0.62). This was no different than the AUC for the entire cohort (0.54) as stated in our paper, signifying again that HbA1c is a test of no value in screening for GDM. Thus, our basic message remains the same, i.e. despite all the progress in technology, HbA1c remains a poor test to screen for GDM.

Secondary predictors of preterm labour

In addition to primary predictors of preterm birth which are used to estimate the baseline risk of preterm birth, secondary predictors (based on examinations done during the current pregnancy) allow a more accurate assessment of the risk of preterm birth in individual women. Screening for early signs of spontaneous preterm labour has always been an important topic in obstetric care. During the last two decades, the detection of fetal fibronectin (FFN) from cervicovaginal secretions and cervical shortening diagnosed by transvaginal ultrasonography have emerged as the major secondary predictors of preterm birth. Both markers have been extensively studied and consistently shown to be strong short term predictors of preterm birth across a wide range of gestational ages. Other secondary predictors that confirm the role of intrauterine infection in the pathogenesis of preterm birth are bacterial vaginosis (BV) and elevated levels of interleukin (IL)-6, IL-8, ferritin and granulocyte colony-stimulating factor. Apart from BV, inflammatory markers are still not routinely used. The sensitivity of single markers in predicting preterm birth is only moderate and serial examinations of markers, combinations of different markers and multiple marker tests have been studied, with limited results. Studies of interventions in order to prevent preterm birth have also yielded mixed benefits, as a consequence of which the use of these markers to screen low risk pregnancies is generally not recommended. Currently, secondary predictors of preterm birth are used mainly to design new intervention studies tailored to specific high risk populations and to avoid unnecessary interventions in the management of high risk women.

Patterns of Thrombocytosis and Thrombocytopenia in Hospitalized Neonates

We sought to identify changes in platelet (PLT) counts over time, and to evaluate the patterns of thrombocytopenia and thrombocytosis in hospitalized infants 23.8 weeks to term gestation. Neonates were divided into four gestational age groups and their PLT counts were retrospectively compared for prevalence of thrombocytopenia, thrombocytosis, and associated conditions. Postconceptional age, postnatal age, and sepsis (among other factors) affected PLT counts. When counts from noninfected appropriately grown infants were evaluated, the risk of thrombocytopenia and thrombocytosis were highest in the most preterm infants, and these risks changed with corrected gestational age. PLT counts increased weekly over the first 4 weeks of life for all but the most preterm infants. These data characterize the incidence of thrombocytopenia and thrombocytosis across a wide range of gestational ages and show that, even in noninfected neonates, these conditions are common, and risk decreases with increasing maturity. The age-related changes in PLT patterns may reflect maturation of platelet regulation.

THE INFLUENCE OF GESTATIONAL AGE ON THE EFFICACY AND SHORT-TERM SAFETY OF SUCROSE FOR PROCEDURAL PAIN RELIEF

Physiologic and behavioral responses to procedural pain are influenced by gestational age (GA). Compared with term neonates, hospitalized preterm neonates are subjected to more painful procedures aimed at improving their clinical outcome. Although several trials to determine the efficacy of sucrose for managing procedural pain have been conducted, none have examined the influence of GA. To examine the influence of GA on the efficacy and short-term safety of oral sucrose for relieving procedural pain associated with heel lances. To explore GA differences in behavioral and physiologic indicators of pain. As part of a larger randomized controlled trial (RCT) to examine the efficacy and safety of sucrose during heel lance, 190 neonates were stratified by GA: (a) 27 to 316/7 weeks (group 1; n = 63), (b) 32 to 356/7 weeks (group 2; n = 63), and (c) >36 weeks (group 3; n = 64). They were then randomized to receive (a) oral sucrose and non-nutritive sucking (NNS), (b) sucrose alone, or (c) sterile water and NNS (control) for a heel lance. The influence of GA was determined by examining the short-term safety, as defined by the number of associated adverse events (choking, coughing or vomiting, sustained tachycardia, sustained tachypnea or dyspnea, or sustained oxygen desaturation). The efficacy was measured by changes in a validated pain measure, scored during each phase of the intervention and analyzed according to GA groups. Significant differences in pain response existed in each GA group, with the lowest mean pain scores in the sucrose and NNS group. Significant GA differences in behavioral and physiologic responses were found, with the most mature neonates demonstrating the greatest magnitude of pain response. The greatest number of short-term adverse effects to treatment occurred in the lowest GA group. In a secondary analysis of a larger RCT, sucrose and NNS was the most efficacious intervention for single heel lances in each of 3 GA groups. However, infants of lower GA experienced more adverse events. Research on the efficacy and safety of repeated doses of oral sucrose, tested in infants from a wide range of GA, is required.

Inter-α inhibitor proteins in infants and decreased levels in neonatal sepsis

Objective Adjunctive tests are needed to predict sepsis in the newborn and to lower the rate or duration of unnecessary antibiotic use. We evaluated the normal Inter-α inhibitor protein (IaIp) values in infants and the association of plasma levels of IaIp with sepsis in term and preterm newborns.Methods Plasma IaIp levels were measured by enzyme-linked immunosorbent assay in samples from 135 newborn infants at a wide range of gestational ages (24–42 weeks). IaIp levels were also determined in 19 infants undergoing prospective evaluation for sepsis.ResultsIaIp levels in umbilical cord blood and circulating peripheral blood of healthy newborn infants (525±66 mg/L) were not significantly different from the level in healthy adults (691±80 mg/L). IaIp levels were similar in infants between 24 and 42 weeks gestational age. There was a significant reduction in IaIp levels in infants with sepsis compared with nonseptic controls (169±126 mg/L vs 613±286 mg/L, P<.0001).ConclusionsIaIp levels in the blood of newborns are independent of gestational age and similar to adults. IaIp levels are significantly reduced in infants with bacterial sepsis and might serve as an adjunctive diagnostic marker to allow prospective reduction of antibiotic use.

Normal Fetal Cardiac Dimensions Obtained by Perpendicular Imaging

This study provides normal fetal cardiac dimensional data in a large patient group over a wide range of gestational ages. Perpendicular imaging decreased lateral resolution error, resulting in normal values with narrower confidence limits than in prior studies.

Prenatal diagnosis using fetal cells isolated from maternal peripheral blood: a review.

Many questions remain about the feasibility of using fetal cells from maternal blood for prenatal diagnosis. Although recently there has been more focus on clinically relevant methods, many studies have been performed using blood drawn after invasive procedures, and over a wide range of gestational ages. For methods to be applicable to clinical use, more work is needed on isolating cells early in pregnancy, when termination is still an option for parents who are found to have an affected pregnancy. It is generally agreed that fetal nucleated erythrocytes are the most efficacious cell type for prenatal diagnosis, but it has not yet been shown definitively whether there is an ideal gestational age for sampling, whether ABO incompatibility might limit availability of fetal cells, or whether the number of cells present might be different in normal versus abnormal pregnancies. PCR has been shown to be a powerful tool in allowing amplification and identification of very small amounts of fetal DNA. However, this is limited to cases in which a specific and unique gene from the father is sought. This means that there is the potential to diagnose many paternally inherited autosomal dominant diseases and some autosomal recessive diseases, in which the parents have different and identifiable mutations. However, when parents are both carriers of the same autosomal recessive mutations, or when the disease is X linked, PCR will not aid in prenatal diagnosis. Cytogenetic analysis of fetal cells by FISH after cell sorting is another potentially useful method of prenatal diagnosis, but requires relatively pure samples of fetal cells or an independent marker that allows easy microscopic identification. The latter might be accomplished by identifying fetal cells through their expression of embryonic hemoglobins or because they contain HLA-G mRNA. In addition, current techniques of cell sorting must be improved so that a higher percentage of fetal cells can be isolated. Currently, the best cell sorting techniques usually produce a maximum purity of 10% fetal cells. Commonly, in normal pregnancies, fewer than 0.1% of the cells isolated after sorting are fetal in origin. Improving the concentration and quantity of fetal cells will improve the accuracy of FISH. Methods such as immunophenotyping that allow the selective identification of fetal cells by microscopy, and can be used in conjunction with FISH, may be extremely valuable because they may allow the genetic analysis of only the few fetal cells within a background preponderance of maternal cells. Although the retrieval of fetal cells from maternal blood is an attractive concept, it must be clearly stated that presently it is only in the investigational phase because of the low sensitivity and specificity. There is no current application for these methods in clinical practice. It remains to be determined whether testing maternal blood for fetal cells or DNA will be used as a screening tool, similar to the maternal serum screening currently in use, or whether the accuracy can be improved to a level such that the techniques can be used diagnostically. Although there are many questions that remain unanswered at this time, the outlook for noninvasive prenatal genetic testing in the future is optimistic.