Maternal perception of reduced fetal movements is associated with altered placental structure and function

Background

Maternal perception of reduced fetal movement (RFM) is associated with increased risk of stillbirth and fetal growth restriction (FGR). DFM is thought to represent fetal compensation to conserve energy due to insufficient oxygen and nutrient transfer resulting from placental insufficiency. To date there have been no studies of placental structure in cases of DFM.

Objective

To determine whether maternal perception of reduced fetal movements (RFM) is associated with abnormalities in placental structure and function.

Design

Placentas were collected from women with RFM after 28 weeks gestation if delivery occurred within 1 week. Women with normal movements served as a control group. Placentas were weighed and photographs taken. Microscopic structure was evaluated by immunohistochemical staining and image analysis. System A amino acid transporter activity was measured as a marker of placental function.Placentas from all pregnancies with RFM (irrespective of outcome) had greater area with signs of infarction (3.5% vs. 0.6%; p<0.01), a higher density of syncytial knots (p<0.001) and greater proliferation index (p<0.01). Villous vascularity (p<0.001), trophoblast area (p<0.01) and system A activity (p<0.01) were decreased in placentas from RFM compared to controls irrespective of outcome of pregnancy.

Conclusions

This study provides evidence of abnormal placental morphology and function in women with RFM and supports the proposition of a causal association between placental insufficiency and RFM. This suggests that women presenting with RFM require further investigation to identify those with placental insufficiency.     

Predictors of poor perinatal outcome following maternal perception of reduced fetal movements--a prospective cohort study

Background

Maternal perception of reduced fetal movement (RFM) is associated with increased risk of stillbirth and fetal growth restriction (FGR). RFM is thought to represent fetal compensation to conserve energy due to insufficient oxygen and nutrient transfer resulting from placental insufficiency.

Objective

To identify predictors of poor perinatal outcome after maternal perception of reduced fetal movements (RFM).

Design

Prospective cohort study.

Methods

305 women presenting with RFM after 28 weeks of gestation were recruited. Demographic factors and clinical history were recorded and ultrasound performed to assess fetal biometry, liquor volume and umbilical artery Doppler. A maternal serum sample was obtained for measurement of placentally-derived or modified proteins including: alpha fetoprotein (AFP), human chorionic gonadotrophin (hCG), human placental lactogen (hPL), ischaemia-modified albumin (IMA), pregnancy associated plasma protein A (PAPP-A) and progesterone. Factors related to poor perinatal outcome were determined by logistic regression.

Results

22.1% of pregnancies ended in a poor perinatal outcome after RFM. The most common complication was small-for-gestational age infants. Pregnancy outcome after maternal perception of RFM was related to amount of fetal activity while being monitored, abnormal fetal heart rate trace, diastolic blood pressure, estimated fetal weight, liquor volume, serum hCG and hPL. Following multiple logistic regression abnormal fetal heart rate trace (Odds ratio 7.08, 95% Confidence Interval 1.31–38.18), (OR) diastolic blood pressure (OR 1.04 (95% CI 1.01–1.09), estimated fetal weight centile (OR 0.95, 95% CI 0.94–0.97) and log maternal serum hPL (OR 0.13, 95% CI 0.02–0.99) were independently related to pregnancy outcome. hPL was related to placental mass.

Conclusion

Poor perinatal outcome after maternal perception of RFM is closely related to factors which are connected to placental dysfunction. Novel tests of placental function and associated fetal response may provide improved means to detect fetuses at greatest risk of poor perinatal outcome after RFM.     

Increased autophagy in placentas of intrauterine growth-restricted pregnancies

Background

Unexplained intrauterine growth restriction (IUGR) may be a consequence of placental insufficiency; however, its etiology is not fully understood. We surmised that defective placentation in IUGR dysregulates cellular bioenergic homeostasis, leading to increased autophagy in the villous trophoblast. The aims of this work were (1) to compare the differences in autophagy, p53 expression, and apoptosis between placentas of women with normal or IUGR pregnancies; (2) to study the effects of hypoxia and the role of p53 in regulating trophoblast autophagy; and (3) to investigate the relationship between autophagy and apoptosis in hypoxic trophoblasts.

Methodology/Principal Findings

Compared with normal pregnant women, women with IUGR had higher placental levels of autophagy-related proteins LC3B-II, beclin-1, and damage-regulated autophagy modulator (DRAM), with increased p53 and caspase-cleaved cytokeratin 18 (M30). Furthermore, cytotrophoblasts cultured under hypoxia (2% oxygen) in the presence or absence of nutlin-3 (a p53 activity stimulator) had higher levels of LC3B-II, DRAM, and M30 proteins and increased Bax mRNA expression compared with controls cultured under standard conditions. In contrast, administration of pifithrin-α (a p53 activity inhibitor) during hypoxia resulted in protein levels that were similar to those of the control groups. Moreover, cytotrophoblasts transfected with LC3B, beclin-1, or DRAM siRNA had higher levels of M30 compared with the controls under hypoxia. However, transfection with Bcl-2 or Bax siRNA did not cause any significant change in the levels of LC3B-II in hypoxic cytotrophoblasts.

Conclusions/Significance

Together, these results suggest that there is a crosstalk between autophagy and apoptosis in IUGR and that p53 plays a pivotal and complex role in regulating trophoblast cell turnover in response to hypoxic stress.     

Short fetal leukocyte telomere length and preterm prelabor rupture of the membranes

Background

Rupture of the fetal membranes is a common harbinger of imminent labor and delivery. Telomere shortening is a surrogate for oxidative stress (OS) and senescence. Fetal leukocyte and placental membrane DNA telomere lengths were evaluated to determine their association with preterm prelabor rupture of the membranes (pPROM) or spontaneous preterm births with intact membranes (PTB), compared to term birth.

Methods

Telomere lengths were quantified in cord blood leukocytes (n = 133) from three major groups: 1) pPROM (n = 28), 2) PTB (n = 69) and 3) uncomplicated full term births (controls, n = 35), using real-time quantitative PCR. Placental membrane specimens (n = 18) were used to correlate fetal leukocyte and placental telomere lengths. Telomere length differences among the groups were analyzed by ANOVA. Pearson correlation coefficients determined relationships between leukocyte and placental membrane telomere lengths.

Results

In pregnancies with intact membranes, fetal leukocyte telomere length was inversely proportional to gestational age. The mean telomere length decreased as gestation progressed, with the shortest at term. pPROM had telomere lengths (9962±3124 bp) that were significantly shorter than gestational age-matched PTB (11546±4348 bp, p = 0.04), but comparable to term births (9011±2497 bp, p = 0.31). Secondary analyses revealed no effects of race (African American vs. Caucasian) or intraamniotic infection on telomere length. A strong Pearson''s correlation was noted between fetal leukocyte and placental membrane telomere lengths (ρ = 0.77; p<0.01).

Conclusions

Fetal leukocyte telomere length is reduced in pPROM compared to PTB but is similar to term births. pPROM represents a placental membrane disease likely mediated by OS-induced senescence.     

Skeletal muscle phosphodiester content relates to body mass and glycemic control

Background

Aging and insulin resistance have been related to reduced mitochondrial function and oxidative stress. Muscular phosphodiesters (PDE) are comprised of metabolites of phospholipid breakdown and may reflect membrane damage. We aimed to test the hypothesis that myocellular PDE are increased in patients with type 2 diabetes (T2D) and correlate inversely with mitochondrial ATP turnover.

Methods

A Cross-sectional study in the Clinical Research Facility of an University hospital was performed. 10 nonobese middle-aged patients with T2D, 10 healthy humans matched for sex, age and physical activity index (CONm) and 18 young healthy humans (CONy) were included. Myocellular PDE and unidirectional flux through ATP synthase (fATP) were measured with ³¹P magnetic resonance spectroscopy (MRS). Intramyocellular (IMCL) and hepatocellular lipid deposition (HCL) were quantified with ¹H MRS. Insulin sensitivity (Rd) was assessed from hyperinsulinemic-euglycemic clamp tests in 10 T2D, 10 CONm and 11 CONy.

Results

During fasting, T2D and CONm had 1.5 fold greater PDE than CONy (2.8±0.2, 2.5±0.2, 1.7±0.1 mmol/l, P = 0.004). Stimulation by insulin did not affect PDE in any group. PDE correlated negatively with Rd (r = −0.552, p<0.005) and fATP (r = −0.396, p<0.05) and positively with age (r = 0.656, p<0.001) and body mass (r = 0.597, p<0.001). PDE also related positively to HbA1c (r = 0.674, p<0.001) and fasting plasma glucose (r = 0.629, p<0.001) within T2D and across all participants.

Conclusions

Muscular PDE concentrations associate with age, lower resting mitochondrial activity and insulin resistance, which is determined mainly by body mass and glycemia.     

Maternal Circulating Levels of Activin A,Inhibin A,sFlt-1 and Endoglin at Parturition in Normal Pregnancy and Pre-Eclampsia

Background

Maternal circulating levels of anti-angiogenic factors such as soluble fms-like tyrosine kinase-1 (sFlt-1), endoglin (sEng) and placental proteins like activin A and inhibin A are increased before the onset of pre-eclampsia. There is evidence for oxidative stress in pre eclampsia. Recently it was shown that placental oxygen concentration is related to sFlt-1 and inhibin A. In addition it is reported that oxidative stress markers are increased in placental tissue delivered after labour. Therefore, the objective of this study is to investigate if these proteins are altered in maternal circulation of labouring pre-eclampsia and normal pregnancies.

Methodology

To assess the effects of labour, samples were taken from 10 normal pregnant (NP) and 10 pre-eclamptic (PE) women pre-labour, full dilation, placental delivery and 24 h. To assess the effects of placental delivery, plasma samples were taken from 10NP and 10PE women undergoing elective Caesarean section, pre-delivery, placental delivery and 10 min, 60 min and 24 h post delivery. SFlt-1 and sEng and activin A and inhibin A were measured using commercial and in house ELISA''s respectively.

Results

The levels of sFlt-1 and sEng were significantly higher in PE compared to NP women in both groups. In labour, sFlt-1 levels increased significantly at full dilatation in PE women, before declining by 24 hr. However there was no significant rise in sEng levels in labour. Activin A and inhibin A levels declined rapidly with placental delivery in NP and PE pregnancies. There was a significant rise in activin A levels during labour in PE compared to pre labour, but inhibin levels did not increase.

Conclusion

Labour in pre-eclamptic women increases the levels of sFlt-1 and activin A. This pilot data suggests that increase in the maternal levels of these factors in labour could predict and/or contribute to the maternal syndrome postpartum.     

Nocturnal hypoxia and loss of kidney function

Background

Although obstructive sleep apnea (OSA) is more common in patients with kidney disease, whether nocturnal hypoxia affects kidney function is unknown.

Methods

We studied all adult subjects referred for diagnostic testing of sleep apnea between July 2005 and December 31 2007 who had serial measurement of their kidney function. Nocturnal hypoxia was defined as oxygen saturation (SaO2) below 90% for ≥12% of the nocturnal monitoring time. The primary outcome, accelerated loss of kidney function, was defined as a decline in estimated glomerular filtration rate (eGFR) ≥4 ml/min/1.73 m² per year.

Results

858 participants were included and followed for a mean study period of 2.1 years. Overall 374 (44%) had nocturnal hypoxia, and 49 (5.7%) had accelerated loss of kidney function. Compared to controls without hypoxia, patients with nocturnal hypoxia had a significant increase in the adjusted risk of accelerated kidney function loss (odds ratio (OR) 2.89, 95% confidence interval [CI] 1.25, 6.67).

Conclusion

Nocturnal hypoxia was independently associated with an increased risk of accelerated kidney function loss. Further studies are required to determine whether treatment and correction of nocturnal hypoxia reduces loss of kidney function.     

Minocycline inhibition of monocyte activation correlates with neuronal protection in SIV neuroAIDS

Background

Minocycline is a tetracycline antibiotic that has been proposed as a potential conjunctive therapy for HIV-1 associated cognitive disorders. Precise mechanism(s) of minocycline''s functions are not well defined.

Methods

Fourteen rhesus macaques were SIV infected and neuronal metabolites measured by proton magnetic resonance spectroscopy (¹H MRS). Seven received minocycline (4 mg/kg) daily starting at day 28 post-infection (pi). Monocyte expansion and activation were assessed by flow cytometry, cell traffic to lymph nodes, CD16 regulation, viral replication, and cytokine production were studied.

Results

Minocycline treatment decreased plasma virus and pro-inflammatory CD14+CD16+ and CD14^loCD16+ monocytes, and reduced their expression of CD11b, CD163, CD64, CCR2 and HLA-DR. There was reduced recruitment of monocyte/macrophages and productively infected cells in axillary lymph nodes. There was an inverse correlation between brain NAA/Cr (neuronal injury) and circulating CD14+CD16+ and CD14^loCD16+ monocytes. Minocycline treatment in vitro reduced SIV replication CD16 expression on activated CD14+CD16+ monocytes, and IL-6 production by monocytes following LPS stimulation.

Conclusion

Neuroprotective effects of minocycline are due in part to reduction of activated monocytes, monocyte traffic. Mechanisms for these effects include CD16 regulation, reduced viral replication, and inhibited immune activation.     

High prevalence of hypertension and placental insufficiency, but no in utero HIV transmission, among women on HAART with stillbirths in Botswana

Background

Increased stillbirth rates occur among HIV-infected women, but no studies have evaluated the pathological basis for this increase, or whether highly active antiretroviral therapy (HAART) influences the etiology of stillbirths. It is also unknown whether HIV infection of the fetus is associated with stillbirth.

Methods

HIV-infected women and a comparator group of HIV-uninfected women who delivered stillbirths were enrolled at the largest referral hospital in Botswana between January and November 2010. Obstetrical records, including antiretroviral use in pregnancy, were extracted at enrollment. Verbal autopsies; maternal HIV, CD4 and HIV RNA testing; stillbirth HIV PCR testing; and placental pathology (blinded to HIV and treatment status) were performed.

Results

Ninety-nine stillbirths were evaluated, including 62 from HIV-infected women (34% on HAART from conception, 8% on HAART started in pregnancy, 23% on zidovudine started in pregnancy, and 35% on no antiretrovirals) and 37 from a comparator group of HIV-uninfected women. Only 2 (3.7%) of 53 tested stillbirths from HIV-infected women were HIV PCR positive, and both were born to women not receiving HAART. Placental insufficiency associated with hypertension accounted for most stillbirths. Placental findings consistent with chronic hypertension were common among HIV-infected women who received HAART and among HIV-uninfected women (65% vs. 54%, p = 0.37), but less common among HIV-infected women not receiving HAART (28%, p = 0.003 vs. women on HAART).

Conclusions

In utero HIV infection was rarely associated with stillbirths, and did not occur among women receiving HAART. Hypertension and placental insufficiency were associated with most stillbirths in this tertiary care setting.     

Perinatal mortality in eastern Uganda: a community based prospective cohort study

Background

To achieve a child mortality reduction according to millennium development goal 4, it is necessary to considerably reduce neonatal mortality. We report stillbirth and early neonatal mortality risks as well as determinants of perinatal mortality in Eastern Uganda.

Methods

A community-based prospective cohort study was conducted between 2006 and 2008. A total of 835 pregnant women were followed up for pregnancy outcome and survival of their children until 7 days after delivery. Mother''s residence, age, parity, bed net use and whether delivery took place at home were included in multivariable regression analyses to identify risk factors for perinatal death.

Results

The stillbirth risk was 19 per 1,000 pregnancies and the early neonatal death risk 22 per 1,000 live births. Overall, the perinatal mortality risk was 41 [95%CI: 27, 54] per 1,000 pregnancies. Of the deaths, 47% followed complicated deliveries and 24% preterm births. Perinatal mortality was 63/1,000 pregnancies among teenage mothers, 76/1,000 pregnancies among nulliparous women and 61/1,000 pregnancies among women delivering at home who, after controlling for potential confounders, had a 3.7 (95%CI: 1.8, 7.4) times higher perinatal mortality than women who gave birth in a health facility. This association was considerably stronger among nulliparous women [RR 8.0 (95%CI: 2.9, 21.6)] than among women with a previous live birth [RR 1.8 (95%CI: 0.7, 4.5)]. All perinatal deaths occurred among women who did not sleep under a mosquito net. Women living in urban slums had a higher risk of losing their babies than those in rural areas [RR: 2.7 (95%CI: 1.4, 5.3)].

Conclusion

Our findings strengthen arguments for ensuring that pregnant women have access to and use adequate delivery facilities and bed nets.     

Cysteinyl leukotriene signaling aggravates myocardial hypoxia in experimental atherosclerotic heart disease

Background

Cysteinyl-leukotrienes (cys-LT) are powerful spasmogenic and immune modulating lipid mediators involved in inflammatory diseases, in particular asthma. Here, we investigated whether cys-LT signaling, in the context of atherosclerotic heart disease, compromises the myocardial microcirculation and its response to hypoxic stress. To this end, we examined Apoe^−/− mice fed a hypercholesterolemic diet and analysed the expression of key enzymes of the cys-LT pathway and their receptors (CysLT1/CysLT2) in normal and hypoxic myocardium as well as the potential contribution of cys-LT signaling to the acute myocardial response to hypoxia.

Methods and principal findings

Myocardial biopsies from Apoe^−/− mice demonstrated signs of chronic inflammation with fibrosis, increased apoptosis and expression of IL-6, as compared to biopsies from C57BL/6J control mice. In addition, we found increased leukotriene C₄ synthase (LTC₄S) and CysLT1 expression in the myocardium of Apoe^−/− mice. Acute bouts of hypoxia further induced LTC₄S expression, increased LTC₄S enzyme activity and CysLT1 expression, and were associated with increased extension of hypoxic areas within the myocardium. Inhibition of cys-LT signaling by treatment with montelukast, a selective CysLT1 receptor antagonist, during acute bouts of hypoxic stress reduced myocardial hypoxic areas in Apoe^−/− mice to levels equal to those observed under normoxic conditions. In human heart biopsies from 14 patients with chronic coronary artery disease mRNA expression levels of LTC₄S and CysLT1 were increased in chronic ischemic compared to non-ischemic myocardium, constituting a molecular basis for increased cys-LT signaling.

Conclusion

Our results suggest that CysLT1 antagonists may have protective effects on the hypoxic heart, and improve the oxygen supply to areas of myocardial ischemia, for instance during episodes of sleep apnea.     

Effects of post-resuscitation treatment with N-acetylcysteine on cardiac recovery in hypoxic newborn piglets

Aims

Although N-acetylcysteine (NAC) can decrease reactive oxygen species and improve myocardial recovery after ischemia/hypoxia in various acute animal models, little is known regarding its long-term effect in neonatal subjects. We investigated whether NAC provides prolonged protective effect on hemodynamics and oxidative stress using a surviving swine model of neonatal asphyxia.

Methods and Results

Newborn piglets were anesthetized and acutely instrumented for measurement of systemic hemodynamics and oxygen transport. Animals were block-randomized into a sham-operated group (without hypoxia-reoxygenation [H–R, n = 6]) and two H-R groups (2 h normocapnic alveolar hypoxia followed by 48 h reoxygenation, n = 8/group). All piglets were acidotic and in cardiogenic shock after hypoxia. At 5 min after reoxygenation, piglets were given either saline or NAC (intravenous 150 mg/kg bolus + 20 mg/kg/h infusion) via for 24 h in a blinded, randomized fashion. Both cardiac index and stroke volume of H-R controls remained lower than the pre-hypoxic values throughout recovery. Treating the piglets with NAC significantly improved cardiac index, stroke volume and systemic oxygen delivery to levels not different from those of sham-operated piglets. Accompanied with the hemodynamic improvement, NAC-treated piglets had significantly lower plasma cardiac troponin-I, myocardial lipid hydroperoxides, activated caspase-3 and lactate levels (vs. H-R controls). The change in cardiac index after H-R correlated with myocardial lipid hydroperoxides, caspase-3 and lactate levels (all p<0.05).

Conclusions

Post-resuscitation administration of NAC reduces myocardial oxidative stress and caused a prolonged improvement in cardiac function and in newborn piglets with H-R insults.     

Maternal and fetal placental growth hormone and IGF axis in type 1 diabetic pregnancy

Aim

Placental growth hormone (PGH) is a major growth hormone in pregnancy and acts with Insulin Like Growth Factor I (IGF-I) and Insulin Like Growth Hormone Binding Protein 3 (IGFBP3). The aim of this study was to investigate PGH, IGF-I and IGFBP3 in non-diabetic (ND) compared to Type 1 Diabetic (T1DM) pregnancies.

Methods

This is a prospective study. Maternal samples were obtained from 25 ND and 25 T1DM mothers at 36 weeks gestation. Cord blood was obtained after delivery. PGH, IGF-I and IGFBP3 were measured using ELISA.

Results

There was no difference in delivery type, gender of infants or birth weight between groups. In T1DM, maternal PGH significantly correlated with ultrasound estimated fetal weight (r = 0.4, p = 0.02), birth weight (r = 0.51, p<0.05) and birth weight centile (r = 0.41, p = 0.03) PGH did not correlate with HbA1c.Maternal IGF-I was lower in T1DM (p = 0.03). Maternal and fetal serum IGFBP3 was higher in T1DM. Maternal third trimester T1DM serum had a significant band at 16 kD on western blot, which was not present in ND.

Conclusion

Maternal T1DM PGH correlated with both antenatal fetal weight and birth weight, suggesting a significant role for PGH in growth in diabetic pregnancy.IGFBP3 is significantly increased in maternal and fetal serum in T1DM pregnancies compared to ND controls, which was explained by increased proteolysis in maternal but not fetal serum. These results suggest that the normal PGH-IGF-I-IGFBP3 axis in pregnancy is abnormal in T1DM pregnancies, which are at higher risk of macrosomia.     

Adverse events following pandemic A (H1N1) 2009 monovalent vaccines in pregnant women--Taiwan, November 2009-August 2010

Background

During the 2009 H1N1 pandemic, pregnant women were prioritized to receive the unadjuvanted or MF59®-adjuvanted pandemic A (H1N1) 2009 monovalent vaccines (“2009 H1N1 vaccines”) in Taiwan regardless of stage of pregnancy. Monitoring adverse events following 2009 H1N1 vaccination in pregnant women was a priority for the mass immunization campaign beginning November 2009.

Methods/Findings

We characterized reports to the national passive surveillance from November 2009 through August 2010 involving adverse events following 2009 H1N1 vaccines among pregnant women. Reports from the passive surveillance were matched to a large-linked database on a unique identifier, date of vaccination, and date of diagnosis in a capture-recapture analysis to estimate the true number of spontaneous abortion after 2009 H1N1 vaccination. We verified 16 spontaneous abortions, 11 stillbirths, 4 neonatal deaths, 4 nonpregnancy-specific adverse events, and 2 inadvertent immunizations in recipients who were unaware of pregnancy at time of vaccination. The Chapman capture-recapture estimator of true number of spontaneous abortion after 2009 H1N1 vaccination was 329 (95% confidence interval [CI] 196–553). Of the 14,474 pregnant women who received the 2009 H1N1 vaccines, the estimated risk of spontaneous abortion was 2.3 (95% CI, 1.4–3.8) per 100 pregnancies, compared with a local background rate of 12.8 (95% CI, 12.8–12.9) per 100 pregnancies.

Conclusions

The passive surveillance provided rapid initial assessment of adverse events after 2009 H1N1 vaccination among pregnant women. Its findings were reassuring for the safety of 2009 H1N1 vaccines in pregnancy.     

Early second trimester maternal plasma choline and betaine are related to measures of early cognitive development in term infants

Background

The importance of maternal dietary choline for fetal neural development and later cognitive function has been well-documented in experimental studies. Although choline is an essential dietary nutrient for humans, evidence that low maternal choline in pregnancy impacts neurodevelopment in human infants is lacking. We determined potential associations between maternal plasma free choline and its metabolites betaine and dimethylglycine in pregnancy and infant neurodevelopment at 18 months of age.

Methodology

This was a prospective study of healthy pregnant women and their full-term, single birth infants. Maternal blood was collected at 16 and 36 weeks of gestation and infant neurodevelopment was assessed at 18 months of age for 154 mother-infant pairs. Maternal plasma choline, betaine, dimethylglycine, methionine, homocysteine, cysteine, total B12, holotranscobalamin and folate were quantified. Infant neurodevelopment was evaluated using the Bayley Scales of Infant Development–III. Multivariate regression, adjusting for covariates that impact development, was used to determine the associations between maternal plasma choline, betaine and dimethylglycine and infant neurodevelopment.

Results

The maternal plasma free choline at 16 and 36 weeks gestation was median (interquartile range) 6.70 (5.78–8.03) and 9.40 (8.10–11.3) µmol/L, respectively. Estimated choline intakes were (mean ±SD) 383±98.6 mg/day, and lower than the recommended 450 mg/day. Betaine intakes were 142±70.2 mg/day. Significant positive associations were found between infant cognitive test scores and maternal plasma free choline (B = 6.054, SE = 2.283, p = 0.009) and betaine (B = 7.350, SE = 1.933, p = 0.0002) at 16 weeks of gestation. Maternal folate, total B12, or holotranscobalamin were not related to infant development.

Conclusion

We show that choline status in the first half of pregnancy is associated with cognitive development among healthy term gestation infants. More work is needed on the potential limitation of choline or betaine in the diets of pregnant women.     

Beneficial metabolic effects of 2',3',5'-tri-acetyl-N6- (3-hydroxylaniline) adenosine in the liver and plasma of hyperlipidemic hamsters

Background

Pharmaceutical research of hyperlipidemia has been commonly pursued using traditional approaches. However, unbiased metabonomics attempts to explore the metabolic signature of hyperlipidemia in a high-throughput manner to understand pathophysiology of the disease process.

Methodology/Principal Findings

As a new way, we performed ¹H NMR-based metabonomics to evaluate the beneficial effects of 2′,3′,5′-tri-acetyl-N₆- (3-hydroxylaniline) adenosine (WS070117) on plasma and liver from hyperlipidemic Syrian golden hamsters. Both plasma and liver profiles provided a clearer distinction between the control and hyperlipidemic hamsters. Compared to control animals, hyperlipidemic hamsters showed a higher content of lipids (triglyceride and cholesterol), lactate and alanine together with a lower content of choline-containing compounds (e.g., phosphocholine, phosphatidylcholine, and glycerophosphocholine) and betaine. As a result, metabonomics-based findings such as the PCA and OPLS-DA plotting of metabolic state and analysis of potential biomarkers in plasma and liver correlated well to the assessment of biochemical assays, Oil Red O staining and in vivo ultrasonographic imaging suggesting that WS070117 was able to regulate lipid content and displayed more beneficial effects on plasma and liver than simvastatin.

Conclusions/Significance

This work demonstrates the promise of applying ¹H NMR metabonomics to evaluate the beneficial effects of WS070117 which may be a good drug candidate for hyperlipidemia.     

Sex Specific Differences in Fetal Middle Cerebral Artery and Umbilical Venous Doppler

Background

The incidence of several adverse pregnancy outcomes including fetal growth restriction are higher in pregnancies where the fetus is male, leading to suggestions that placental insufficiency is more common in these fetuses. Placental insufficiency associated with fetal growth restriction may be identified by multi-vessel Doppler assessment, but little evidence exists regarding sex specific differences in these Doppler indices or placental function. This study aims to investigate sex specific differences in fetal and placental perfusion and to correlate these changes with intra-partum outcome.

Methods and Findings

This is a prospective cohort study. We measured Doppler indices of 388 term pregnancies immediately prior to the onset of active labour (≤3 cm dilatation). Fetal sex was unknown at the time of the ultrasound assessment. Information from the ultrasound scan was not made available to clinical staff. Case notes and electronic records were reviewed following delivery. We report significantly lower Middle Cerebral artery pulsatility index (1.34 vs. 1.43, p = 0.004), Middle Cerebral artery peak velocity (53.47 cm/s vs. 58.10 cm/s, p = <0.001), and Umbilical venous flow/kg (56 ml/min/kg vs. 61 ml/min/kg, p = 0.02) in male fetuses. These differences however, were not associated with significant differences in intra-partum outcome.

Conclusion

Sex specific differences in feto-placental perfusion indices exist. Whilst the physiological relevance of these is currently unknown, the identification of these differences adds to our knowledge of the physiology of male and female fetuses in utero. A number of disease processes have now been shown to have an association with changes in fetal haemodynamics in-utero, as well as having a sex bias, making further investigation of the sex specific differences present during fetal life important. Whilst the clinical application of these findings is currently limited, the results from this study do provide further insight into the gender specific circulatory differences present in the fetal period.