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49,XXXXY is an X and Y chromosome variation that occurs in 1:85,000 to 1:100,000 live male births. Previous case studies have described boys with this disorder to be shorter than average when compared with boys with only one extra chromosome and with the mean stature in a small cohort reported to range from the seventh to 33rd percentile. The origin behind the possible differences in height between boys with 47,XXY and 49,XXXXY is currently unknown, however one study hypothesized that it was due to a difference in the expression of the SHOX gene. This study reports on the anthropometric measurements of 84 boys with 49,XXXXY. Forty-five percent of children with 49,XXXXY were found to be below the third percentile in height at the time of evaluation. In addition, 7.14% of the cohort were diagnosed and given treatment for growth hormone deficiency (GHD). The analysis of this cohort demonstrates that the below average heights seen throughout childhood in this population potentially begins prenatally and suggests that boys with 49,XXXXY may be at a higher risk for intrauterine growth restriction (IUGR) and GHD. Future research is needed to investigate the etiology of the poor growth in boys with 49,XXXXY and evaluate the incidence of GHD and IUGR in this population., (© 2020 Wiley Periodicals LLC.)

Objective: We hypothesised that a multi-compartment magnetic resonance imaging (MRI) technique that is sensitive to fetal blood oxygenation would identify changes in placental blood volume and fetal blood oxygenation in pregnancies complicated by early-onset fetal growth restriction (FGR)., Design: Case-control study., Setting: London, UK., Population: Women with uncomplicated pregnancies (estimated fetal weight [EFW] >10th centile for gestational age [GA] and normal maternal and fetal Doppler ultrasound, n = 12) or early-onset FGR (EFW <3rd centile with or without abnormal Doppler ultrasound <32 weeks GA, n = 12) were studied., Methods: All women underwent MRI examination. Using a multi-compartment MRI technique, we quantified fetal and maternal blood volume and feto-placental blood oxygenation., Main Outcome Measures: Disease severity was stratified according to Doppler pulsatility index and the relationship to the MRI parameters was investigated, including the influence of GA at scan., Results: The FGR group (mean GA 27 +5  weeks, range 24 +2 to 33 +6  weeks) had a significantly lower EFW compared with the control group (mean GA 29 +1  weeks; -705 g, 95% CI -353 to -1057 g). MRI-derived feto-placental oxygen saturation was higher in controls compared with FGR (75 ± 9.6% versus 56 ± 16.2%, P = 0.02, 95% CI 7.8-30.3%). Feto-placental oxygen saturation estimation correlated strongly with GA at scan in controls (r = -0.83)., Conclusion: Using a novel multimodal MRI protocol we demonstrated reduced feto-placental blood oxygen saturation in pregnancies complicated by early-onset FGR. The degree of abnormality correlated with disease severity defined by ultrasound Doppler findings. Gestational age-dependent changes in oxygen saturation were also present in normal pregnancies., Tweetable Abstract: MRI reveals differences in feto-placental oxygen saturation between normal and FGR pregnancy that is associated with disease severity., (© 2020 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.)

Objectives: To review perinatal and neurodevelopmental outcome (NDO) following selective fetoscopic laser coagulation (SFLC), cord coagulation (CC) or expectant management of monochorionic diamniotic twin pregnancies complicated with selective intrauterine growth restriction (sIUGR) and absent or reverse end-diastolic flow (AREDF) in the umbilical arteries (UA)., Design and Setting: Single-centre retrospective observational study., Population: 108 cases of sIUGR diagnosed before 26 +6  weeks' gestation with AREDF in the UA., Methods: Survival rate and potential risk factors were analysed. NDO was assessed using parental questionnaires., Main Outcomes Measures: Survival, gestational age at delivery and NDO., Results: SFLC, CC and EM were performed in 13, 50 and 45 cases, respectively, with an overall survival of 23.1, 40 and 77.8% and intrauterine demise of the co-twin of 30.8, 10 and 6.7% respectively. Intrauterine demise of the sIUGR twin occurred in 76.9 and 17.8% following SFLC and EM, respectively. The discordance in EFW at diagnosis was higher and absent/negative a-wave in the ductus venosus (DV) was more prevalent in the surgical groups. NDO in survivors at follow up was abnormal in 0 and 18% in the smaller twin following SFLC and EM, respectively, and in 25, 24 and 21% in the larger twin following SFLC, CC and EM, respectively., Conclusion: SFLC yielded a poor result. EM seems a valid option when EFW discordance is <30% and a-wave in DV is positive. Otherwise, CC should be considered to protect the AGA co-twin. The long-term outcome of both small and large twins seems unaffected by the choice in primary prenatal management strategy., Tweetable Abstract: In type II sIUGR in MC twins, long-term neurodevelopment is normal in over 80% of the survivors., (© 2020 Royal College of Obstetricians and Gynaecologists.)

New Findings: What is the central question of this study? What is the effect in male and female offspring of a protein-deficient diet producing intrauterine growth restriction (IUGR) in maternal mice on morphometric, metabolic and behavioural parameters before and after a challenge with a fat diet? What is the main finding and its importance? Male and female mice presented different growth trajectories after birth. IUGR favoured increased adiposity in male mice, and high-fat diet-induced anxiety-like behaviour in female mice., Abstract: As there is sexual dimorphism in the response to maternal manipulations, we aimed to analyse the effects of intrauterine growth restriction (IUGR) in both sexes on morphometric, metabolic and behavioural parameters throughout postnatal development, and after challenge with a hyperlipidic diet. Female Swiss mice (n = 59) were distributed into two groups (SD: standard diet, n = 26; and PDD: isocaloric protein-deficient diet, n = 33), 2 weeks before mating and during the gestational period. After birth, offspring from SD and PDD dams were cross-fostered and nurtured by SD dams until postnatal day (PND) 28. At PND 60 all animals were challenged with a hypercaloric diet for 4 weeks. Offspring birth weight was significantly reduced in the PDD group compared to the SD group (P = 0.0001), but only male offspring presented a rapid catch-up during the first 21 days of development. Although no differences in body weight were observed between groups after the challenge with the hyperlipidic diet, an increase in the relative perigonadal white adipose tissue (P = 0.009) and a decrease in gross gastrocnemius muscle weight (P = 0.010) were observed in the PDD males. In relation to behavioural tests, there was an increase in locomotion in both sexes (P = 0.0001), and a decrease in female grooming (P = 0.006) in the PDD group. Additionally, females from the PDD group showed increased hyperlipidic food intake. In conclusion, IUGR affected both sexes, with females showing prominent behavioural modifications and males presenting altered body composition elicited by a hyperlipidic diet., (© 2020 The Authors. Experimental Physiology © 2020 The Physiological Society.)

Background There is little knowledge about the significance of extremely high values (>655) for the ratio of sFlt-1 (soluble fms-like tyrosine kinase 1) to PlGF (placental growth factor). We aim to describe the time-to-delivery interval and maternal and perinatal outcomes when such values are demonstrated while assessing suspected or confirmed placental dysfunction based on clinical or sonographic criteria. Methods and Results A multicenter retrospective cohort study was performed on 237 singleton gestations between 20+0 and 37+0 weeks included at the time of first demonstrating a sFlt-1/PlGF ratio >655. Clinicians were aware of this result, but standard protocols were followed for delivery indication. Main outcomes were compared for women with and without preeclampsia at inclusion. In those with preeclampsia (n=185, of whom 77.3% had fetal growth restriction), severe preeclampsia features and fetal growth restriction in stages III or IV were present in 49.2% and 13.5% cases, respectively, at inclusion and in 77.3% and 28.6% cases, respectively, at delivery. In the group without preeclampsia (n=52, 82.7% had fetal growth restriction), these figures were 0% and 30.8%, respectively, at inclusion and 21.2% and 50%, respectively, at delivery. Interestingly, 28% of women without initial preeclampsia developed it later. The median time to delivery was 4 days (interquartile range: 1-6 days) and 7 days (interquartile range: 3-12 days), respectively ( P <0.01). Overall, perinatal mortality was 62.1% before 24 weeks; severe morbidity surpassed 50% before 29 weeks but became absent from 34 weeks. Maternal serious morbidity was high at any gestational age. Conclusions An sFlt-1/PlGF ratio >655 is almost invariably associated with preeclampsia or fetal growth restriction that progresses rapidly. In our tertiary care settings, we observed that maternal adverse outcomes were high throughout gestation, whereas perinatal adverse outcomes diminished as pregnancy advanced.

Background Circulating levels of sFLT-1 (soluble fms-like tyrosine kinase 1), the extracellular domain of vascular endothelial growth factor (VEGF) receptor 1, and its ratio to levels of placental growth factor are markers of the occurrence and severity of preeclampsia. Methods and Results C57BL/6 pregnant mice on embryonic day 14.5 (E14.5), male, and non-pregnant female mice were exposed to air or to Br 2 at 600 ppm for 30 minutes and were treated with vehicle or with VEGF-121 (100 μg/kg, subcutaneously) daily, starting 48 hours post-exposure. Plasma, bronchoalveolar lavage fluid, lungs, fetuses, and placentas were collected 120 hours post-exposure. In Br 2 -exposed pregnant mice, there was a time-dependent and significant increase in plasma levels of sFLT-1 which correlated with increases in mouse lung wet/dry weights and bronchoalveolar lavage fluid protein content. Supplementation of exogenous VEGF-121 improved survival and weight gain, reduced lung wet/dry weights, decreased bronchoalveolar lavage fluid protein levels, enhanced placental development, and improved fetal growth in pregnant mice exposed to Br 2 . Exogenous VEGF-121 administration had no effect in non-pregnant mice. Conclusions These results implicate inhibition of VEGF signaling driven by sFLT-1 overexpression as a mechanism of pregnancy-specific injury leading to lung edema, maternal mortality, and fetal growth restriction after bromine gas exposure.

Objectives: The modified myocardial performance index (Mod-MPI) can be used to assess myocardial function. Fetal growth restriction can affect fetal myocardial function, thereby altering the Mod-MPI. The results of previous studies on the utility of the Mod-MPI in growth-restricted fetuses are conflicting. The aim of this study was to calculate the left modified-MPI in growth-restricted fetuses and to compare the results with those of healthy fetuses., Methods: This was a prospective cross-sectional case-control study. In total, 40 women with growth-restricted fetuses and 40 women with fetuses of normal weight (controls) at 29-39 gestational weeks were enrolled in the study. An experienced obstetrician calculated the Mod-MPI for each fetus. Women with systemic diseases or fetuses with chromosomal/structural abnormalities were excluded from the study. The results of Mod-MPI measurements of the two groups were compared., Results: The mean single deepest vertical pocket (SDVP) of amniotic fluid, estimated fetal weight (EFW), and isovolumetric relaxation time (IRT) was significantly lower in the fetal growth restriction (FGR) group as compared with these parameters in the control group (P < .05). The uterine artery (UtA) pulsatility index (PI) was significantly higher in the FGR group as compared with that in the control group (P < .05). There were six cases of absent end-diastolic flow (AED) in the FGR group. There were no statistically significant between-group differences in the Mod-MPI, isovolumetric contraction time (ICT), and ejection time (ET) (P > .05). There was also no statistically significant correlation between the Mod-MPI in the fetuses with AED and the control group for Mod-MPI (P > .05)., Conclusion: The utility of the Mod-MPI in FGR remains unclear. Future studies with larger populations are needed to determine the utility of the Mod-MPI as a predictor of cardiac compromise in FGR., (© 2019 Wiley Periodicals, Inc.)

Aim: To investigate the changes of modified myocardial performance index (Mod-MPI) in early-onset and late-onset fetal growth restriction (FGR) cases, and its association with adverse perinatal outcome., Methods: This was a prospective study on 77 early-onset and 100 late-onset FGR cases. Hundred normal fetuses were matched as control groups for early-onset and late-onset FGR groups, respectively. Mod-MPI and vessel Doppler parameters including umbilical artery (UA), ductus venosus (DV), and middle cerebral artery (MCA) were measured. Perinatal outcomes were followed up. Mod-MPI of FGR cases were compared in normal Doppler, abnormal Doppler, and control groups. The association of Mod-MPI and perinatal outcome was investigated, and further efficacy of Mod-MPI predicting adverse outcome was studied., Results: Compared with control groups, both abnormal and normal Doppler groups showed increased Mod-MPI in early-onset and late-onset FGR, respectively. Mod-MPI had no significant difference between abnormal and normal Doppler groups. Mod-MPI was associated with adverse outcome in early-onset FGR (OR = 3.307) and late-onset FGR (OR = 3.412). The sensitivity and specificity of Mod-MPI predicting adverse outcome were 60% and 80% when cutoff value was 0.47 in early-onset FGR. And they were 65% and 70% when cutoff value was 0.50 in late-onset FGR., Conclusion: Fetal growth restriction fetuses had increased Mod-MPI. Mod-MPI could be used to predict adverse perinatal outcome of FGR fetuses. Mod-MPI was an effective parameter to supplement vessels' Doppler parameters in monitoring FGR., (© 2019 The Authors. Echocardiography Published by Wiley Periodicals, Inc.)

Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyze the transfer of methyl groups from S-adenosyl-l-methionine to nitrogen atoms on arginine residues. Arginine methylation is involved in multiple biological processes, such as signal transduction, mRNA splicing, transcriptional control, DNA repair, and protein translocation. Currently, 10 patients have been described with mutations in PRMT7. The shared findings include: hypotonia, intellectual disability, short stature, brachydactyly, and mild dysmorphic features. We describe the prenatal, postnatal, and pathological findings in two male sibs homozygote for a mutation in PRMT7. Both had intrauterine growth restriction involving mainly the long bones. In addition, eye tumor was found in the first patient, and nonspecific brain calcifications and a systemic venous anomaly in the second. The pregnancy of the first child was terminated and we describe the autopsy findings. The second child had postnatal growth restriction of prenatal onset, hypotonia, strabismus, sensorineural hearing loss, genitourinary and skeletal involvement, and global developmental delay. He had dysmorphic features that included frontal bossing, upslanting palpebral fissures, small nose with depressed nasal bridge, and pectus excavatum. Our patients provide additional clinical and pathological data and expand the phenotypic manifestations associated with PRMT7 homozygote/compound heterozygote mutations to include brain calcifications and delayed myelination, and congenital orbital tumor., (© 2018 Wiley Periodicals, Inc.)

Aim: To investigate the effects of foetal growth restriction (FGR) and prematurity on cardiac morphology and function in infancy. We hypothesised that FGR and prematurity would both alter cardiac development., Methods: Cardiac morphology and function were evaluated in 24 preterm FGR infants (p-FGR) and 23 preterm and 19 term appropriately grown for gestational age infants (p-AGA and t-AGA, respectively) by conventional echocardiography and Tissue Doppler Imaging. p-FGR and p-AGA infants were studied on postnatal day 1 and all groups were studied at one-and six-months post-term age., Results: p-FGR infants demonstrated increased cardiac sphericity compared to AGA peers on postnatal day 1 (p = 0.004) and at one-month post-term age (p = 0.004). Posterior and relative wall thickness increased overtime in the p-FGR group only (p < 0.05). Systolic function was not different between groups. E/e' ratio was higher in both preterm groups compared to the term group at one-month post-term age (p = 0.01). No statistically significant group differences were found at six-months post-term age., Conclusion: Foetal growth restriction was associated with subtle cardiac morphological changes, whereas both prematurity and FGR were associated with subclinical alterations in diastolic function., (©2017 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

RNU4ATAC pathogenic variants to date have been associated with microcephalic osteodysplastic primordial dwarfism, type 1 and Roifman syndrome. Both conditions are clinically distinct skeletal dysplasias with microcephalic osteodysplastic primordial dwarfism, type 1 having a more severe phenotype than Roifman syndrome. Some of the overlapping features of the two conditions include developmental delay, microcephaly, and immune deficiency. The features also overlap with Lowry Wood syndrome, another rare but well-defined skeletal dysplasia for which the genetic etiology has not been identified. Characteristic features include multiple epiphyseal dysplasia and microcephaly. Here, we describe three patients with Lowry Wood syndrome with biallelic RNU4ATAC pathogenic variants. This report expands the phenotypic spectrum for biallelic RNU4ATAC disorder causing variants and is the first to establish the genetic cause for Lowry Wood syndrome., (© 2017 Wiley Periodicals, Inc.)

Aim: This study evaluated the role of preterm birth and fetal growth restriction on white matter maturation in schoolchildren without any severe neurodevelopmental impairment., Methods: The study group comprised 56 very preterm children and 21 term children born between November 1998 and November 2002 at Oulu University Hospital, Finland. The mean gestational age of the preterm children was 28.7 (24.1-31.9) weeks. All children underwent diffusion tensor imaging at a mean age of 9.0 (8.6-9.6) years. Voxel-wise statistical analyses of the imaging data were carried out using tract-based spatial statistics., Results: Preterm children with fetal growth restriction had lower fractional anisotropy and higher radial diffusivity than term controls (p < 0.05), bilaterally in several white matter areas. Preterm children without fetal growth restriction had higher mean diffusivity and axial diffusivity than term controls (p < 0.05) in analogous areas, but more asymmetrically., Conclusion: Preterm children had microstructural differences in white matter, compared to term-born children at a mean age of nine, and those with poor fetal growth showed widespread changes in white matter maturation compared to term-born children. Fetal growth and prematurity seemed to affect white matter maturation in a way that was still visible at that age., (©2017 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: Fetal growth impacts cardiovascular health throughout postnatal life in humans. Various animal models of intrauterine growth restriction exhibit reduced heart size at birth, which negatively influences cardiac function in adulthood. The mechanistic target of rapamycin complex 1 (mTORC1) integrates nutrient and growth factor availability with cell growth, thereby regulating organ size. This study aimed at elucidating a possible involvement of mTORC1 in intrauterine growth restriction and prenatal heart growth., Methods and Results: We inhibited mTORC1 in fetal mice by rapamycin treatment of pregnant dams in late gestation. Prenatal rapamycin treatment reduces mTORC1 activity in various organs at birth, which is fully restored by postnatal day 3. Rapamycin-treated neonates exhibit a 16% reduction in body weight compared with vehicle-treated controls. Heart weight decreases by 35%, resulting in a significantly reduced heart weight/body weight ratio, smaller left ventricular dimensions, and reduced cardiac output in rapamycin- versus vehicle-treated mice at birth. Although proliferation rates in neonatal rapamycin-treated hearts are unaffected, cardiomyocyte size is reduced, and apoptosis increased compared with vehicle-treated neonates. Rapamycin-treated mice exhibit postnatal catch-up growth, but body weight and left ventricular mass remain reduced in adulthood. Prenatal mTORC1 inhibition causes a reduction in cardiomyocyte number in adult hearts compared with controls, which is partially compensated for by an increased cardiomyocyte volume, resulting in normal cardiac function without maladaptive left ventricular remodeling., Conclusions: Prenatal rapamycin treatment of pregnant dams represents a new mouse model of intrauterine growth restriction and identifies an important role of mTORC1 in perinatal cardiac growth., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

The aim of this study was to investigate whether multiple corpora lutea (CL) in dromedary camels were associated with multiple pregnancies. Three experiments were carried out. In the first experiment, reproductive tracts of 124 slaughtered female camels were examined for the incidence of multiple CL and the pregnancy status. In the second experiment, uteri and ovaries of 50 females were examined by ultrasound between the fourth and fifteenth weeks of pregnancy to estimate the number and location of the embryos/fetuses and the number of associated CL. In the third experiment, 20 females were mated and the pregnant animals were followed weekly to estimate the pattern of embryonic and fetal growth. At the slaughterhouse, multiple CL were detected in 44.4% of the pregnant animals. By ultrasonography, the incidence of twinning and triplets was 52%. The incidence significantly (P < 0.05) decreased from the fourth to the thirteenth week of pregnancy. Intrauterine growth retardation (IUGR) was observed in all animals of twins and triplets. Only one viable fetus could be detected after the ninth week of pregnancy in each pregnant animal. Both conceptuses died in one animal. In conclusion, multiple CL in dromedary camels are usually associated with multiple pregnancies. IUGR occurred in all animals of twins/triplets, with only one fetus surviving after the ninth week of pregnancy., (© 2015 Blackwell Verlag GmbH.)

Objective: Phase rectified signal averaging (PRSA) is a new method of fetal heart rate variability (fHRV) analysis that quantifies the average acceleration (AC) and deceleration capacity (DC) of the heart. The aim of this study was to evaluate AC and DC of fHR [recorded by trans-abdominal fetal electrocardiogram (ta-fECG)] in relation to Doppler velocimetry characteristics of intrauterine growth restriction (IUGR)., Design: Prospective case-control study., Setting: Single third referral centre., Population: IUGR (n = 66) between 25 and 40 gestational weeks and uncomplicated pregnancies (n = 79)., Methods: In IUGR the nearest ta-fECG monitoring to delivery was used for PRSA analysis and Doppler velocimetry parameters obtained within 48 hours. AC and DC were computed at s = T = 9. The relation was evaluated between either AC or DC and Doppler velocimetry parameters adjusting for gestational age at monitoring, as well as the association between either AC or DC and IUGR with or without brain sparing., Results: In IUGRs there was a significant association between either AC and DC and middle cerebral artery pulsatility index (PI; P = 0.01; P = 0.005), but the same was not true for uterine or umbilical artery PI (P > 0.05). Both IUGR fetuses with and without brain sparing had lower AC and DC than controls, but this association was stronger for IUGRs with brain sparing., Conclusions: Our study observed for the first time that AC and DC at PRSA analysis are associated with middle cerebral artery PI, but not with uterine or umbilical artery PI, and that there is a significant decrease of AC and DC in association with brain sparing in IUGR fetuses from 25 weeks of gestation to term., Tweetable Abstract: Brain sparing in IUGR fetuses is associated with decreased acceleration and deceleration capacities of the heart., (© 2015 Royal College of Obstetricians and Gynaecologists.)

The aim of the current study was to examine the impact of antenatal iron-folic acid (IFA) supplementation on perceived birth size and birthweight in Pakistan over a 5-year period from 2002 to 2006. The data source was the Pakistan Demographic and Health Survey (PDHS) 2006-2007. Information from 5692 most recent live-born infants within 5 years prior to the survey was examined. The primary outcomes were maternal perception of birth size and birthweight, and the main exposure was any use of antenatal IFA supplements. Birthweight was reported for only 10% of the live births in the PDHS 2006-2007. Multivariate logistic regression analysis was adjusted for the cluster sampling design and for 13 potential confounders. The risk of having smaller than average birth size newborn was significantly reduced by 18% (adjusted odds ratio 0.82, 95% confidence interval 0.71, 0.96) for mothers who used any IFA supplements compared with those who did not. A similar (18%), but non-significant reduction in the risk of low birthweight, was found with the maternal use of IFA supplements. The risk of having smaller than average birth size babies was significantly reduced by 19% in those women who started IFA in the first trimester of pregnancy. About 11% of babies with smaller than average birth size were attributed to non-use of antenatal IFA supplements. Antenatal IFA supplementation significantly reduces the risk of a newborn of smaller than average birth size in Pakistan. Universal coverage of supplementation would improve birth size., (© 2014 John Wiley & Sons Ltd.)

Objective: To determine changes in plasma C-type natriuretic peptide (CNP), a paracrine product of the vascular endothelium, in pregnancies with vascular disorders, and relate these to time of presentation and severity., Design: Retrospective nested cases and controls., Setting: Community study, Auckland New Zealand., Population: Screening for Pregnancy Endpoints (SCOPE) data and bio-bank of maternal plasma., Methods: Maternal plasma amino terminal proCNP (NTproCNP) was measured by radioimmunoassay in early (14-16 weeks of gestation, and again at 19-21 weeks of gestation) and late (34-36 weeks of gestation) pregnancy in three groups of women (20 per group): pre-eclampsia (pre-eclampsia); gestational hypertension (GHT) with small for gestational age (SGA); and uncomplicated pregnancy., Main Outcome Measures: Change in NTproCNP and associations with concurrent blood pressure, time of case presentation, severity, and infant birthweight., Results: Plasma NTproCNP in early pregnancy in women with vascular disorders did not differ from those found in controls. In late pregnancy, levels in pre-eclampsia (28.8 ± 2.3 pM) and in GHT with SGA (28.6 ± 4.8 pM) were significantly increased (P = 0.01 and 0.027, respectively) compared with controls (21.3 ± 1 pM). In pre-eclampsia, levels were significantly higher (P < 0.03) at 14-16 weeks of gestation in women diagnosed prior to 34 weeks of gestation. Combining all three groups, associations of NTproCNP with concurrent diastolic and mean arterial pressure were found at 34-36 weeks of gestation (r = 0.46). No significant associations were identified with birthweight., Conclusions: CNP secretion during gestation is responsive to vascular stress. Plasma NTproCNP measurements may have clinical application in late pregnancy in defining the different phenotypes associated with pre-eclampsia., (© 2015 Royal College of Obstetricians and Gynaecologists.)

Objective: Fetal magnetoencephalography records fetal brain activity non-invasively. Delayed brain responses were reported for fetuses weighing below the tenth percentile. To investigate whether this delay indicates delayed brain maturation resulting from placental insufficiency, this study distinguished two groups of fetuses below the tenth percentile: growth-restricted fetuses with abnormal umbilical artery Doppler velocity (IUGR) and constitutionally small-for-gestational-age fetuses with normal umbilical artery Doppler findings (SGA) were compared with fetuses of adequate weight for gestational age (AGA), matched for age and behavioural state., Design: A case-control study of matched pairs., Setting: Fetal magnetoencephalography-Center at the University Hospital of Tuebingen., Population: Fourteen IUGR fetuses and 23 SGA fetuses were matched for gestational age and fetal behavioural state with 37 healthy, normal-sized fetuses., Methods: A 156-channel fetal magentoencephalography system was used to record fetal brain activity. Light flashes as visual stimulation were applied to the fetus. The Student's t-test for paired groups was performed., Main Outcome Measure: Latency of fetal visual evoked magnetic responses (VER)., Results: The IUGR fetuses showed delayed VERs compared with controls (IUGR, 233.1 ms; controls, 184.6 ms; P = 0.032). SGA fetuses had similar evoked response latencies compared with controls (SGA, 216.1 ms; controls, 219.9 ms; P = 0.828). Behavioural states were similarly distributed., Conclusion: Visual evoked responses are delayed in IUGR fetuses, but not in SGA. Fetal behavioural state as an influencing factor of brain response latency was accounted for in the comparison. This reinforces that delayed brain maturation is the result of placental insufficiency., (© 2015 Royal College of Obstetricians and Gynaecologists.)

A detailed analysis of the antenatal cardiotocographs (CTGs) in 57 patients with suspected fetal growth retardation is presented. Four traces were normal and 53 were 'non-reactive. 'Non-reactive' traces can be sub-divided into three categories, which, in order of severity are, 'suspect', 'flat' and 'ominous'. When compared with the 'suspect' group, perinatal mortality was significantly increased and the Apgar scores at one and five minutes significantly decreased in the 'flat' and 'ominous' groups. The presence of fetal distress in labour was significantly higher in the 'flat' group as compared with the 'suspect' group. Intrauterine deaths occurred only in the 'ominous' group. With experience, ten patients later in the series with 'ominous' patterns were delivered within 24 hours of the detection of such and nine infants survived. At follow-up between 6 and 34 months after birth, psychomotor development was normal in 47 of the 49 surviving infants., (Copyright © 1979 Royal College of Obstetricians and Gynaecologists.)

Epidemiological studies have shown an association between low birthweight and adult disease development with transmission to subsequent generations. The aim of the present study was to examine the effect of intrauterine growth restriction in rats, induced by uteroplacental insufficiency, on cardiac structure, number, size, nuclearity, and adult blood pressure in first (F1) and second (F2) generation male offspring. Uteroplacental insufficiency or sham surgery was induced in F0 Wistar-Kyoto pregnant rats in late gestation giving rise to F1 restricted and control offspring, respectively. F1 control and restricted females were mated with normal males, resulting in F2 control and restricted offspring, respectively. F1 restricted male offspring were significantly lighter at birth (P < 0.05), but there were no differences in birthweight of F2 offspring. Left ventricular weights and volumes were significantly increased (P < 0.05) in F1 and F2 restricted offspring at day 35. Left ventricular cardiomyocyte number was not different in F1 and F2 restricted offspring. At 6 months-of-age, F1 and F2 restricted offspring had elevated blood pressure (8-15 mmHg, P < 0.05). Our findings demonstrate the emergence of left ventricular hypertrophy and hypertension, with no change in cardiomyocyte number, in F1 restricted male offspring, and this was transmitted to the F2 offspring. The findings support transgenerational programming effects., (© 2014 Wiley Publishing Asia Pty Ltd.)

Aim: To investigate the effect of a nutritional mixture (bovine milk oligosaccharides, Lactobacillus rhamnosus NCC4007, arachidonic and docosahexaenoic acid) on growth of intrauterine growth-restricted (IUGR) rats., Methods: IUGR was induced by maternal food restriction. The offspring (males and females) were assigned to: REF (non-IUGR, no mixture), IUGRc (IUGR, no mixture), or IUGRmx (IUGR, mixture). The mixture was given from day 7 to day 58, when tissues and plasma from half of the animals were collected for hormones, metabolites and microarray analysis. The rest received a high-fat diet (HFD) until day 100. Glucose tolerance was measured at 56 and 98 days, and body fat content at 21, 52 and 97 days., Results: IUGRmx had the greatest growth during lactation, but from day 22 to day 54, both IUGR groups gained less body weight than the REF (P < 0.05). In the short-term (58 days), IUGRmx tended to be longer (P = 0.06) and had less body fat (P = 0.03) than IUGRc. These differences were not seen after HFD. Microarray analysis of hepatic mRNA expression at 58 and 100 days revealed a gender-dependent treatment effect, and expression of genes related to lipid metabolism was the most affected. Twelve of these genes were selected for studying differences in DNA methylation in the promoter region, for some, we observed age- and gender-related differences but none because of treatment., Conclusion: The nutritional intervention promoted catch-up growth and normalized excessive adiposity in IUGR animals at short-term. The benefits did not extend after a period of HFD. IUGR and early diet had gender-dependent effects on hepatic gene expression., (© 2013 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Remodeling of the maternal uterine vasculature during pregnancy is a unique cardiovascular process that occurs in the adult and results in significant structural and functional changes in large and small arteries and veins, and in the creation of the placenta--a new fetomaternal vascular organ. This expansive, hypertrophic process results in increases in both lumen circumference and length, and is effected through a combination of tissue and cellular hypertrophy, endothelial and vascular smooth muscle hyperplasia, and matrix remodeling. This review summarizes what is currently known about the time course and extent of the remodeling process, and how local vs. systemic factors influence its genesis. The main focus is on upstream maternal vessels rather than spiral artery changes, although the latter are considered from the overall hemodynamic perspective. We also consider some of the underlying mechanisms and provide a hypothetical scenario that integrates our current knowledge. Abrogation of this adaptive vascular process is associated with several human gestational pathologies such as preeclampsia and intrauterine growth restriction (IUGR), which not only raise the risk of infant mortality and morbidity but are also a significant source of maternal mortality and susceptibility to cardiovascular and other diseases for both mother and neonate later in life., (© 2013 John Wiley & Sons Ltd.)

Aim: The aim of this study was to assess the contribution of both foetal and/or post-natal nutritional periods on feeding regulation in adult rats., Methods: Body weight gain, adipose tissue development, food preferences and feeding pattern under regular chow or Western diets were characterized on four experimental groups of rats: pups born from protein-restricted dams (R) and weaned by control (RC) or R dams (RR) and pups born from control dams weaned by C (CC) or R dams (CR)., Results: Rats born with intrauterine growth restriction (IUGR) and fed a Western diet at adulthood appeared predisposed to body weight gain and more fat accretion, whereas CR rats, despite their preference for high-fat diet and their hyperphagia for Western diet, did not show significant increase in fat tissue. Daytime food intakes, as well as their speed of ingestion, were found modified in RC and RR. Alterations in the hypothalamic appetite regulatory mechanisms were investigated through neuropeptide expression analysis. IUGR rats showed altered expression of key elements of leptin and NPY signalling, while CR rats exhibited lesser expression of enterostatin, MC4r and HT-1Br mRNA., Conclusion: Altogether, these results indicate that peri-natal nutrition has different lasting effects on feeding pattern and hypothalamic appetite regulation, depending on the time window insult., (© 2013 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Suboptimal conditions in utero are associated with the development of adult-onset diseases in offspring. Uteroplacental insufficiency in rats is a well-established animal model used to mimic and study the effects of developmental insults relevant to countries of abundant nutrient supply. However, wide-ranging outcomes for the offspring are apparent between the different investigators that use this model and also between cohorts generated in our laboratory. We aimed to explore the reasons for variability in rat models of uteroplacental insufficiency between different investigators and also between our own animal cohorts. We suggest differences in growth and disease development reflect uniqueness in susceptibility and highlight the complexity of interactions between genetic potential and environmental exposures. The impact of adverse exposures in utero has been described as having far-reaching effects that extend well beyond the first, directly exposed generation. However, the resulting phenotypes are not consistent between generations. This suggests that programmed effects are established de novo in each generation and challenges the prediction of disease. Characterization of growth and disease in the numerous rat models has led to our understanding of the impact of early life experiences on adult health. In order to drive the development of preventative and/or treatment strategies, future studies should focus on identifying the initial cause(s) of uteroplacental insufficiency, including genetic origins and the influence of poor diets., (© 2013 Wiley Publishing Asia Pty Ltd.)

Aim: To detect predictors of feeding tolerance in intrauterine growth restriction (IUGR) infants with or without brain-sparing effect (BS)., Methods: We conducted a case-control study in 70 IUGR infants (35 IUGR with BS, matched for gestational age with 35 IUGR infants with no BS). BS was classified as pulsatility index (PI) ratio [umbilical artery (UAPI) to middle cerebral artery (MCAPI) (U/C ratio)] > 1. Clinical parameters of feeding tolerance - days to achieve full enteral feeding (FEF) - were compared between the IUGR with BS and IUGR without BS infants. Age at the start of minimal enteral feeding (MEF) was analysed., Results: Achievement of FEF was significantly shorter in IUGR infants without BS than in IUGR with BS. IUGR with BS started MEF later than IUGR without BS infants. Significant correlation of MEF and FEF with UA PI, U/C ratio and CRIB score was found. Multiple linear regression analysis showed significant correlations with CRIB score and caffeine administration (MEF only), and sepsis (FEF only) and U/C ratio (for both)., Conclusion: Impaired gut function can be early detected by monitoring Doppler patterns and clinical parameters., (©2013 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Objective: To evaluate the outcome of pregnancies complicated by placental insufficiency and abnormal umbilical artery Doppler prior to viability., Design: A retrospective cohort study., Setting: Italy., Population: Singleton pregnancies with fetal growth restriction and absence of end-diastolic velocities (AEDVs) in the umbilical arteries prior to 24 weeks., Methods: A retrospective cohort study of singleton pregnancies with fetal growth restriction and AEDVs in the umbilical arteries prior to 24 weeks., Main Outcome Measures: Fetal growth restriction and AEDVs in the umbilical arteries prior to 24 weeks., Results: Of 16 fetuses first seen at 20-23 weeks, only 12 survived and one of these developed cerebral palsy. Severe hypertensive disorders occurred in three mothers. In four women, the Doppler waveforms progressively improved and developed a normal pulsatility. These fetuses had a better outcome than those that had persistent alterations: they were delivered later (34 versus 28 weeks), had a larger birthweight (1598 versus 630 g) and developed fewer complications., Conclusions: Placental insufficiency with AEDV in the umbilical arteries prior to fetal viability is associated with a high probability of perinatal death and neonatal complications. However, progressive amelioration of Doppler indices occurs in a subset of women, and these fetuses have a much better outcome., (© 2013 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2013 RCOG.)

Background: Fetal alcohol-related growth restriction persists through infancy, but its impact later in life is less clear. Animal studies have demonstrated important roles for maternal nutrition in fetal alcohol spectrum disorders, but the impact of prenatal maternal body composition has not been studied in humans. This study examined the effects of prenatal alcohol exposure on longitudinal growth from birth through young adulthood and the degree to which maternal weight and body mass index (BMI) moderate these effects., Methods: Nearly 480 mothers were recruited at their first prenatal clinic visit to overrepresent moderate-to-heavy use of alcohol during pregnancy, including a 5% random sample of low-level drinkers and abstainers. They were interviewed at every prenatal visit about their alcohol consumption using a timeline follow-back approach. Their children were examined for weight, length/height, and head circumference at birth, 6.5 and 13 months, and 7.5, 14, and 19 years., Results: In multiple regression models with repeated measures (adjusted for confounders), prenatal alcohol exposure was associated with longitudinal reductions in weight, height, and weight-for-length/BMI that were largely determined at birth. At low-to-moderate levels of exposure, these effects were more severe in infancy than in later childhood. By contrast, effects persisted among children whose mothers drank at least monthly and among those born to women with alcohol abuse and/or dependence who had consumed ≥ 4 drinks/occasion. In addition, effects on weight, height, and head circumference were markedly stronger among children born to mothers with lower prepregnancy weight., Conclusions: These findings confirm prior studies demonstrating alcohol-related reductions in weight, height, weight-for-height/BMI, and head circumference that persist through young adulthood. Stronger effects were seen among children born to mothers with smaller prepregnancy weight, which may have been because of attainment of higher blood alcohol concentrations in smaller mothers for a given amount of alcohol intake or to increased vulnerability in infants born to women with poorer nutrition., (Copyright © 2012 by the Research Society on Alcoholism.)

Background: Prenatal alcohol exposure has been associated with pre- and postnatal growth restriction, but little is known about the natural history of this restriction throughout childhood or the effects of prenatal alcohol on body composition. The objective of this study was to examine the effects of heavy prenatal alcohol exposure on longitudinal growth and body composition., Methods: Eighty-five heavy drinking pregnant women (≥2 drinks/d or ≥4 drinks/occasion) and 63 abstaining and light-drinking controls (<1 drink/d, no binging) were recruited at initiation of prenatal care in an urban obstetrical clinic in Cape Town, South Africa and prospectively interviewed during pregnancy about alcohol, smoking, drug use, and demographics. Among their children, length/height, weight, and head circumference were measured at 6.5 and 12 months and at 5 and 9 years. Percent body fat (BF) was estimated at age 9 years using bioelectric impedance analysis., Results: In multiple regression models with repeated measures (adjusted for confounders), heavy alcohol exposure was associated with reductions in weight (0.6 SD), length/height (0.5 SD), and head circumference (0.9 cm) from 6.5 months to 9 years that were largely determined at birth. These effects were exacerbated by iron deficiency in infancy but were not modified by iron deficiency or measures of food security at 5 years. An alcohol-related postnatal delay in weight gain was seen at 12 months. Effects on head circumference were greater at age 9 than at other age points. Although heavy alcohol exposure was not associated with changes in body composition, children with fetal alcohol syndrome (FAS) and partial fetal alcohol syndrome (PFAS) had lower percent BF than heavy exposed nonsyndromal and control children., Conclusions: Heavy prenatal alcohol exposure is related to prenatal growth restriction that persists through age 9 years and an additional delay in weight gain during infancy. FAS and PFAS diagnoses are associated with leaner body composition in later childhood., (Copyright © 2012 by the Research Society on Alcoholism.)

1. World-wide epidemiological and experimental animal studies demonstrate that adversity in fetal life, resulting in intrauterine growth restriction, programmes the offspring for a greater susceptibility to ischaemic heart disease and heart failure in adult life. 2. After cardiogenesis, cardiomyocyte endowment is determined by a range of hormones and signalling pathways that regulate cardiomyocyte proliferation, apoptosis and the timing of multinucleation/terminal differentiation. 3. The small fetus may have reduced cardiomyocyte endowment owing to the impact of a suboptimal intrauterine environment on the signalling pathways that regulate cardiomyocyte proliferation, apoptosis and the timing of terminal differentiation., (Clinical and Experimental Pharmacology and Physiology © 2012 Blackwell Publishing Asia Pty Ltd.)

Objective: To study the consequences of glucocorticoid treatment in fetal growth restriction (FGR) on cardiac function., Setting: Laboratory., Sample: Sheep., Methods:   Growth restriction was induced in sheep fetuses using single umbilical artery ligation (SUAL) on days 105-110 of gestation (term 147). Control fetuses were not ligated. Betamethasone (BM) (11.4 mg intramuscularly) or saline was administered to ewes on days 5 and 6 after surgery. Ewes were anaesthetised on day 7, the fetuses were removed, and their hearts were mounted on a Langendorff apparatus. Balloon catheters were inserted into the right and left ventricles., Outcome Measures:   Ventricular contractile function and infarct area following ischaemia/reperfusion., Results:   The SUAL resulted in FGR (body weight 77% of control). The FGR was associated with increases in basal left ventricular pressure development and rates of contraction and relaxation. Right ventricular contraction was unaffected. Following brief ischaemia/reperfusion, the infarct area in FGR hearts was increased four-fold compared with controls. Antenatal BM resulted in a proportional increase in heart size and coronary flow, especially in FGR fetuses, and left ventricular pressure and heart rate responses to β-adrenoceptor activation were increased., Conclusions:   Fetal hearts rapidly adapt to FGR to maintain substrate delivery to the brain and heart. The FGR greatly enhanced the area of ischaemia, with implications for susceptibility in postnatal life. Antenatal BM treatment does not interfere with these cardiac changes but appears to increase left ventricle β-adrenoceptor responsiveness, which may render the offspring vulnerable to subsequent cardiac dysfunction., (© 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2012 RCOG.)

Objective: To assess placental perfusion with magnetic resonance imaging (MRI) and superparamagnetic iron oxide (SPIO) in a rat model of intrauterine growth restriction (IUGR)., Design: Experimental animal study., Setting: The study complied with US National Institutes of Health recommendations for animal care., Population: Thirty-two rats at day 16 of gestation underwent surgical ligation of the left uterine vessel to induce IUGR., Methods: Eighteen rats were examined by MRI 3 days later, after bolus injection of ferucarbotran., Main Outcome Measure: Signal intensities were measured in the maternal left ventricle and in the placentas of the two horns. Quantitative microcirculation parameters were calculated and compared between the placentas of the two horns., Results: Fifty-four kinetic curves of placental perfusion were obtained in 11 rats. The mean placental blood flow was significantly lower in the ligated horns than in the normal horns (108.1 versus 159.4 ml/minute/100 ml, p = 0.0004). The mean fractional volume of the maternal vascular placental compartment did not differ significantly between the pathological (42.8%) and normal placentas (39.2%)., Conclusions: Placental perfusion, including changes during experimental IUGR, can be measured in rats by using MRI with SPIO. These findings could have implications for human studies of placental microcirculation and for the management of disorders related to placental dysfunction., (© 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2012 RCOG.)

Taybi-Linder syndrome, also known as microcephalic osteodysplastic primordial dwarfism types I and III, is a rare disorder with presumed autosomal recessive inheritance. It is characterized by intrauterine growth retardation, distinctive bone dysplasia, and central nervous system malformations. We present two siblings with Taybi-Linder syndrome, with an emphasis on the neurological profile in this disease, which includes brain malformations, intractable epilepsy, sensory deficits, profound cognitive deficits, and neuroendocrine dysfunction. We also present distinctive correlative neuroimaging (MRI) and electroencephalographic (EEG) findings. Increased knowledge of the neurological profile of Taybi-Linder syndrome may be helpful for clinicians and genetic counselors managing these patients., (Copyright © 2012 Wiley Periodicals, Inc.)

Aims: To assess lung function at early school age in children delivered at very early gestation owing to intrauterine growth restriction and abnormal foetal blood flow (IUGR)., Methods: Spirometry was performed at median age 8.4 (range 6.5-10.7) years in 31 children born preterm with IUGR (PT-IUGR) with a median (range) birth weight (BW) of 650 (395-976) g and median (range) gestational age 27 (24-29) weeks. Control groups were matched for gender and age and had BW appropriate for gestational age (AGA); 31 children born preterm (PT-AGA) with BW of 1010 (660-1790) g matched for gestational age at birth, and 31 children born at term (T-AGA) with BW of 3530 (3000-4390) g., Results: The PT-IUGR group had lower mean (SD) values of z-scores for FEV(1), FEV(1)/FVC and forced mid-expiratory flow rate (FEF(25-75%)) compared to the T-AGA group, p = 0.003, p = 0.032 and p < 0.001, respectively, but did not differ from the PT-AGA group. PT-IUGR children delivered at ≥26 gestational weeks (GW) had lower FEF(25-75%) than PT-AGA children of corresponding GA, p = 0.014., Conclusion: Lung function was reduced in the PT-IUGR group at early school age compared to controls born at term. The influence of IUGR on later lung function was only apparent in children born preterm after 26 GW., (© 2011 The Author(s)/Acta Paediatrica © 2011 Foundation Acta Paediatrica.)

According to the "small baby syndrome hypothesis," low birthweight and intrauterine growth restriction (IUGR) occurring in westernized countries mainly through altered placental flow, have been linked to increased metabolic syndrome risk in later life. Independency and causal mechanisms of this phenomenological association are a matter of controversy. By means of epidemiological as well as experimental methods, using meta-analyses and different rodent models of pre- and/or neonatal malnutrition and altered placental flow (uterine artery ligation; Lig), we systematically addressed the phenomenon. Our data and systematic literature analysis revealed that neither epidemiological nor experimental evidence seems to exist linking prenatal underfeeding, low birthweight, IUGR, or decreased placental flow in rats (Lig-model) as independent risk factors to increased metabolic syndrome risk in later life. Rather, pre- and/or neonatal overfeeding, elevated birthweight, rapid neonatal weight gain, and especially increased adiposity during critical periods of perinatal life may increase long-term risks. Perinatally acquired microstructural and epigenomic alterations in regulatory systems of metabolism and body weight seem to be critical, leading to a cardiometabolic risk disposition throughout life. While experimental data in Lig-offspring seem to be considerably biased, prenatal stress and postnatal overfeeding/rapid neonatal weight gain might be causally linked to a long-term deleterious outcome in growth restricted newborns. From a clinical point of view, prevention of causes of IUGR, as well as avoidance of perinatal overnourishment, might be prophylactic approaches to avoid perinatal programming of cardiometabolic risks., (© 2011 John Wiley & Sons Ltd.)

Objective: To unravel the mechanisms underlying the previously demonstrated associations between low birthweight and cardiovascular disease in adulthood, we examined whether maternal smoking during pregnancy leads to fetal arterial resistance adaptations, and subsequently to fetal growth retardation and changes in postnatal blood pressure and cardiac development., Design: Prospective cohort study from early fetal life onwards., Setting: Academic hospital., Population: Analyses were based on 1120 children aged 2 years., Methods: Maternal smoking during pregnancy [non-smoking, first trimester smoking, continued smoking (< 5 and ≥ 5 cigarettes/day)] was assessed by questionnaire., Main Outcome Measures: Third trimester placental and fetal arterial resistance indices and fetal growth were assessed by ultrasound and Doppler measurements. Postnatal blood pressure and cardiac structures (aortic root diameter, left atrial diameter, left ventricular mass) were measured at 2 years of age., Results: First trimester smoking was not associated with third trimester placental and fetal blood flow adaptations. Continued smoking of ≥ 5 cigarettes/day was associated with an increased resistance in uterine, umbilical and middle cerebral arteries, and with a decreased flow and diameter of the ascending aorta. Among mothers who continued to smoke, the third trimester estimated fetal weights and birthweights were most affected in children with the highest umbilical artery resistance. Fetal arterial resistance indices were also associated with aortic root diameter and left atrial diameter., Conclusions: Fetal arterial resistance adaptations may be involved in the pathways leading from maternal smoking during pregnancy to low birthweight and cardiovascular developmental changes in childhood in the offspring., (© 2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2011 RCOG.)

Sildenafil citrate therapy for severe early-onset intrauterine growth restriction. BJOG 2011;118:624-628. Currently, there is no effective therapy for severe early-onset intrauterine growth restriction (IUGR). Sildenafil citrate vasodilates the myometrial arteries isolated from women with IUGR-complicated pregnancies. Women were offered Sildenafil (25 mg three times daily until delivery) if their pregnancy was complicated by early-onset IUGR [abdominal circumference (AC)< 5th percentile] and either the gestational age was <25(+0) weeks or an estimate of the fetal weight was <600 g (excluding known fetal anomaly/syndrome and/or planned termination). Sildenafil treatment was associated with increased fetal AC growth [odds ratio, 12.9; 95% confidence interval (CI), 1.3, 126; compared with institutional Sildenafil-naive early-onset IUGR controls]. Randomised controlled trial data are required to determine whether Sildenafil improves perinatal outcomes for early-onset IUGR-complicated pregnancies., (© 2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2011 RCOG.)

Maternal undernutrition during sensitive periods of pregnancy results in offspring predisposed towards the development of a number of diseases of adulthood, including hypertension and diabetes. In order to determine the nature of any gross alterations in fetal growth during early organogenesis, we supplied timed-mated pregnant mice with diets containing 6% protein (6%P), 9% protein (9%P) or 18% protein (18%P; control) from day 0 of pregnancy. At embryonic days 11 (E11), 12 (E12) and 13 (E13), females were killed and fetuses removed. Gross morphological analysis revealed that fetal limb growth was impaired between E11 and E12 in 6%P animals, but this recovered by E13. Likewise, fetal liver growth and lung branching morphogenesis were seen to exhibit an initial growth impairment at E12 followed by a rapid recovery by E13. Coincident with the observed changes in fetal growth, we noted an elevation in maternal hepatic triglyceride content, expression of the ketogenic 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2) and circulating plasma β-hydroxybutyrate (BOHB). In addition, fetal liver Hmgcs2 expression was switched on by E13 in both 6%P- and 9%P-exposed animals. Exogenous BOHB did not influence branching morphogenesis in fetal lung explant cultures; however, we cannot rule out the possibility that this may occur in vivo. In conclusion, we find that disturbance of fetal growth by maternal dietary protein restriction is associated and therefore potentially indicated by changes in maternal and fetal ketone body metabolism.

Aim: To evaluate the neurodevelopmental outcome at 12 months' corrected age in preterm infants with and without severe intrauterine growth restriction., Methods: This prospective follow-up study included 37 infants with severe intrauterine growth restriction and 36 appropriate-for-gestational-age infants born between 26 and 34 weeks. Neonatal and infant data were prospectively recorded. Infants were assessed at 12 ± 2 months' corrected age with the Hammersmith Infant Neurological Examination and the Bayley Scale for Infant Development version-II., Results: Both groups were similar in demographic characteristics and perinatal status. No significant differences in neurodevelopmental performance were found. The mental development index was 98.8 (SD 9.0) vs 98.4 (SD 13.1) (p = 0.9) and the psychomotor development index was 91.7 (SD 9.9) vs 95.5 (SD 13.4) (p = 0.2) for the study and reference groups respectively. Neurological assessment showed no significant differences between the two groups., Conclusion: Although the study group showed a non-significant trend towards a lower score in the psychomotor development index than the reference group, significant differences at 12 months could not be demonstrated. IUGR infants continued to have significantly lower weight, length and head circumference at 1 year., (© 2010 The Author(s)/Journal Compilation © 2010 Foundation Acta Paediatrica.)

Our aim was to define the association between early onset intra-uterine growth restriction (IUGR) due to placental insufficiency and hypospadias in males. We prospectively studied a cohort of small-for-gestational age (SGA) male infants with hypospadias managed by a multidisciplinary team over a 5-year period. Thirty SGA male infants were diagnosed with hypospadias/abnormal genitalia after birth, and four of them were diagnosed antenatally. Five cases occurred in the smaller pair of discordant IUGR twins, where the larger co-twin had normal male genitalia. Serial ultrasounds demonstrated features of early-onset IUGR in all cases at a median gestational age of 21 weeks (range 14-31weeks). Twenty-one (70%) pregnancies were subsequently complicated by absent/reversed end-diastolic flow in the umbilical arteries indicating severe IUGR, and 17 (57%) women developed severe pre-eclampsia. There were 27 (90%) live births at a median gestational age of 31 weeks (range 27-37); 23 (77%) of the neonates had birth weights <3rd centile. All newborns had normal male karyotypes. In 62% (18/29) the hypospadias was severe. A correlation was found between the severity of the IUGR and the severity of hypospadias as significantly more infants with severe hypospadias were less than the 3rd centile compared to the mild-moderate hypospadias group: 94% (17/18) versus 55% (6/11), respectively (P = 0.02). In conclusion, SGA male newborns with hypospadias exhibit a high rate of early-onset severe IUGR due to placental insufficiency. Early placental development likely influences male external genitalia formation. Careful sonographic evaluation of the genitalia is advised when early-onset placentally mediated IUGR is found.

Objectives: To compare umbilical and uterine artery Doppler waveforms and fetal size at 20 weeks between smokers and nonsmokers., Design: Prospective cohort study., Setting: Auckland, New Zealand and Adelaide, Australia., Population: Nulliparous participants in the Screening for Pregnancy Endpoints (SCOPE) study., Methods: Self-reported smoking status was determined at 15 +/- 1 weeks' gestation. At the 20 +/- 1 week anatomy scan, uterine and umbilical Doppler resistance indices (RI) and fetal measurements were compared between smokers and nonsmokers., Main Outcomes Measures: Umbilical and mean uterine artery Doppler RI values, abnormal umbilical and uterine Doppler (RI > 90th centile) and fetal biometry., Results: Among the 2459 women, 248 (10%) were smokers. Smokers had higher umbilical RI [0.75 (SD 0.06) versus 0.73 (0.06), P < 0.0001] and mean uterine RI [0.59 (0.09) versus 0.56 (0.10), P < 0.0001]. They were twice as likely to have an abnormal umbilical Doppler at 20 weeks compared with nonsmokers [n = 35 (14.6%) versus n = 156 (7.2%), OR 2.21, 95% CI 1.49-3.27]. This effect remained significant after adjusting for age, ethnicity, marital status, employment and BMI (adjusted OR 1.62, 95% CI 1.03-2.54). Smokers were more likely to have an abnormal mean uterine RI [n = 33 (13.7%) versus n = 198 (9.2%), OR 1.57, 95% CI 1.06-2.33], but this association was not significant after adjusting for confounders. Fetuses of women who smoked had a small reduction in femur length and estimated weight compared with nonsmokers., Conclusions: At 20 weeks' gestation, women who smoke have higher umbilical artery RI, a surrogate measure for an abnormal placental villous vascular tree. This may contribute to later fetal growth restriction among smokers. Further research is needed to explore the clinical significance of these findings.

1. Low birth weight (LBW) is associated with an increased risk of cardiovascular disease. Preterm birth is a major determinant of LBW and has been shown to result in elevated arterial pressure (AP) in humans, but few studies have investigated the effects of preterm birth in the absence of potentially confounding factors. Our aim was to determine whether moderately preterm birth per se alters the postnatal development of AP in lambs. 2. Preterm lambs were delivered approximately 14 days before term (i.e. approximately 133 days of gestation); controls were born at term (approximately 147 days). Mean arterial pressure (MAP), heart rate (HR), blood composition and indices of growth were measured at 4 and 8 weeks post term-equivalent age (PTEA). We also studied a separate cohort of preterm and term sheep as young adults (approximately 1.1 years). 3. Preterm lambs had significantly lower birth weights than term lambs, but bodyweights were not significantly different by Day 12 PTEA. In addition, MAP, HR and most blood variables did not differ between term and preterm lambs at 4 or 8 weeks PTEA. Preterm birth per se did not alter MAP or HR in young adult sheep. 4. Low birth weight due to preterm birth does not result in an altered AP during early postnatal life or at maturity. Moderate intrauterine growth restriction (IUGR) due to twinning, which further reduces birth weight, does not affect MAP in preterm lambs. Other factors, such as the degree of prematurity or IUGR, exposure to corticosteroids or postnatal nutrition, may be important in the later development of elevated AP.

Objective: To evaluate the association between growth status at birth and subsequent development of cerebral palsy in preterm and term infants., Design: Population-based case-controlled study., Setting: Cerebral palsy register in Western Sweden. Subjects Cohort of 334 singletons born between 1983 and 1990, with cerebral palsy diagnosed from age 4, and 668 singletons matched for gestation, gender and delivery unit., Method: Growth status at birth was determined using small for gestational age (SGA) categories, with customised birthweight percentiles (SGAcust) based on the Swedish population., Main Outcome Measures: Proportion of babies that were SGAcust, comparing cases and controls in three gestational age categories: early preterm (24-33 weeks), late preterm (34-36 weeks) and term (37+ weeks)., Results: Of the 334 children with cerebral palsy, 87 (26.6%) were born early preterm, 27 (8.1%) late preterm and 218 (66%) at term. Children who had been born at term were more likely to have been SGA <1st customised percentile (SGAcust1) than their matched controls (OR 6.6, 95% CI 2.3-18.6). In contrast, children with cerebral palsy born preterm were not more likely to have been SGAcust1 (OR 0.9, 95% CI 0.4-1.9), and this applied to early preterm as well as late preterm births. For less severely small babies (SGA between 1st and 5th customised percentiles), the association with cerebral palsy remained significant for term births (OR 5.2, 95% CI 2.7-10.1) but was again not significant for preterm births., Conclusions: Term singletons with severely SGA birthweights had a five- to seven-fold risk of developing cerebral palsy compared with gestational age-matched infants with birthweights within normal limits. For children born preterm, SGA was not more likely to be present in cases than in controls. These findings support the concept of cerebral palsy as a multifactorial condition and highlight the importance of antenatal surveillance of fetal growth.

Objective: To assess the clinical value of the short-term fetal heart rate variation (STV) for timing the delivery of severely growth-retarded fetuses, many associated with pre-eclampsia., Design: Retrospective cohort study., Setting: John Radcliffe Maternity Hospital, Oxford, UK., Population: Two hundred and fifty-seven fetuses with a birthweight less than third percentile and a last computerised cardiotocography performed within 24 h of delivery., Methods: Analysis of the relationship between antepartum STV and the perinatal outcome., Main Outcome Measures: Stillbirth rate and the acid-base status at birth., Results: There were no stillbirths or neonatal deaths (NNDs) within 24 h in the study population. Decreasing STV was correlated with earlier deliveries (P < 0.001), lower birthweight (P < 0.001), lower umbilical artery pH at birth (P < 0.001), worse acid-base status at birth (P < 0.001) and worse postnatal outcome (P < 0.002). The STV was able to predict the presence or absence of acidaemia and metabolic acidaemia (area under the receiver operating characteristic curve 0.70 and 0.75, respectively, P < 0.001). The risk of metabolic acidaemia increased as the antepartum STV decreased, the optimum cutoff level being < or = 3.0 milliseconds (positive and negative predictive values 64.6 and 86.6%). An STV < or = 3.0 milliseconds was associated with markedly higher rate of metabolic acidaemia and early NNDs compared with an STV > 3.0 milliseconds (54.2 versus 10.5% and 8.3 versus 0.5%, respectively; P < 0.001). The deaths of the former group were all due to extreme prematurity and very low birthweight., Conclusions: The antepartum STV is an important marker of perinatal outcome in severely growth-retarded fetuses. Timing the delivery of the most preterm and small fetuses remains a difficult task.

1. Intrauterine growth restriction (IUGR) has been associated with poor perinatal health outcomes. Animal models have been used to investigate why IUGR is associated with a poor prognosis. The sheep has been used extensively as an experimental model for IUGR with poor placental substrate supply to the fetus induced using a range of methods, including the surgical ablation of the majority of endometrial caruncles prior to conception, experimental induction of maternal hyperthermia, ligation of an umbilical artery or embolization of the placenta in late gestation and maternal overnutrition in the pregnant adolescent ewe. 2. Fetal adaptations to fetal hypoxia and hypoglycaemia include activation of the fetal hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system and an associated increase in circulating cortisol and noradrenaline concentrations. Fetal cardiovascular responses vary according to the method used to induce placental dysfunction. 3. Although an array of experimental models has been used to induce placental dysfunction at different stages of fetal development, each leads to remarkably similar fetal growth, metabolic, neuroendocrine and cardiovascular adaptations and consequences. The extent and range of the fetal physiological adaptations to chronic placental insufficiency are determined by the duration of exposure and the degree of the severity of substrate supply restriction. 4. The present review summarizes how sheep models of IUGR have provided an increased understanding of the nature of the fetal adaptations to IUGR, their longer-term physiological consequences and how to improve clinical management of IUGR in human pregnancies.

Objective: To examine the relationship between smallness at birth and the predictive value of umbilical artery Doppler., Design: Retrospective cohort., Setting: Tertiary referral university hospital, Barcelona., Population: A total of 7645 singleton pregnancies delivered between January 2002 and June 2004., Methods: The associations with adverse outcome were assessed for small-for-gestational-age (SGA) babies according to customised standards who had normal and abnormal umbilical artery Doppler., Main Outcome Measures: Neonatal morbidity and perinatal mortality., Results: Of the 369 SGA fetuses that had been identified antenatally, 70 (19%) had an abnormal umbilical artery Doppler and the babies from these pregnancies had a higher risk for neonatal morbidity when compared with babies with normal birthweight (OR 3.99, 95% CI 1.04-11.03). However, the remaining 299 (81%) fetuses with normal umbilical artery Doppler also had an elevated risk of neonatal morbidity (OR 2.26, 95% CI 1.04-4.39). Overall, many of the instances of adverse outcome associated with smallness for gestational age were attributable to the group with normal Doppler than to the group with abnormal Doppler., Conclusion: Normal antenatal umbilical artery Doppler cannot be taken as an indicator of low risk in pregnancies where the fetus is SGA according to customised percentiles.

Objective: To assess maternal cardiac function in nulliparous women in the first trimester of pregnancy and evaluate its potential role for predicting pre-eclampsia and small for gestational age (SGA)., Design: Prospective, observational, cross-sectional study., Setting: Maternity unit of a teaching hospital., Population: Nulliparous women with singleton pregnancies presenting consecutively for routine antenatal care (n= 534)., Methods: Two-dimensional and M-mode echocardiography and uterine artery Dopplers were carried out at 11-14 weeks., Main Outcome Measures: Cardiac output (CO), stroke volume (SV), mean arterial pressure (MAP), total vascular resistance and uterine artery pulsatility index (UAPI) were compared in four outcome groups according to the development of pre-eclampsia and/or SGA., Results: Compared with the normal outcome group (n= 457), in those with pre-eclampsia but not SGA (n = 8), CO and MAP were increased; in the group with pre-eclampsia and SGA (n= 19) MAP, TRP and UAPI were increased and in the group with SGA but no pre-eclampsia (n= 50) total peripheral resistance and UAPI were increased. Independent predictors of pre-eclampsia were MAP, SV and UAPI and of SGA SV and UAPI., Conclusions: Alterations in maternal cardiac function and UAPI are observed in the first trimester of pregnancy in nulliparous women that subsequently develop pre-eclampsia and/or SGA.

Aim: To investigate growth and neurodevelopment outcome of very low birth weight (VLBW) infants delivered by preeclamptic mothers., Methods: A cohort including all VLBW infants delivered between December 2003 and May 2005 was followed up to 12 and 18 months corrected age (CA)., Exclusion Criteria: death before 1 year corrected age, major malformations, deafness and blindness. Weight, length and head circumference were plotted on NCHS curves. Bayley Scales were performed at 12 and 18 months CA., Results: 40 infants in preeclamptic and 46 in control groups were studied. Birth weight and gestational age were 1148 g+/-236 and 1195 g+/-240, and 31.3 weeks+/-1 and 30.6 weeks+/-2 for preeclamptic and control groups, respectively. At 12 and 18 months, CA, weight for age (Z score) was significantly higher in control than in preeclamptic. PDI scores were higher in preeclamptic than in controls at 18 months CA., Conclusions: Catch-up of body weight did not occur in the first 18 months CA in preeclamptic infants. Neurodevelopment outcome was better in infants delivered by preeclamptic mothers than in controls at 18 months CA.

Aim: To compare the prevalence of transient periventricular echodensities (TPE), periventricular leukomalacia (PVL) and haemorrhagic brain lesions (HBL) in singleton intrauterine growth-restricted (IUGR) infants and in those appropriate for gestational age (AGA)., Methods: Thirty-five IUGR and 35 AGA singleton infants born between 24- and 34-week gestational age were studied. The presence of TPE, PVL and HBL was assessed with ultrasound (US) at day 3 (US-I), 2 weeks (US-II) after delivery and at term-equivalent age (US-III)., Results: IUGR neonates had an increased prevalence of TPE at US-I (18/35 vs. 8/35, p= 0.02) and an increased prevalence of PVL at US-II (8/32 vs. 1/31, p = 0.03) and US-III (8/29 vs. 1/29, p = 0.02). No significant differences in the prevalence of HBL were found between the two groups., Conclusions: IUGR is associated with an increased prevalence of white matter damage on US brain scans in preterm neonates.

1. Low birth weight is associated with an increased risk for the development of hypertension. Our laboratory uses a model of reduced uterine perfusion in the pregnant rat that results in intrauterine growth-restricted (IUGR) offspring that develop hypertension at a prepubertal age. Although hypertension develops in both prepubertal male and female IUGR offspring, only male IUGR offspring remain hypertensive after puberty. We reported previously that bilateral renal denervation abolishes hypertension in adult male IUGR offspring, indicating an important role for the renal nerves in the maintenance of established IUGR-induced hypertension. We also reported that angiotensin-converting enzyme inhibition abolishes hypertension in adult male IUGR offspring. However, activation of the renin-angiotensin system does not occur in male IUGR offspring until after puberty, or after the development of established IUGR-induced hypertension. Therefore, the mechanisms involved in the development of IUGR-induced hypertension may differ from those involved in the maintenance of established IUGR-induced hypertension. Thus, the purpose of the present study was to determine whether the renal nerves play a causative role in the early development of IUGR-induced hypertension in prepubertal IUGR offspring. 2. Intrauterine growth-restricted and control offspring were subjected to either bilateral renal denervation or sham denervation, respectively, at 4 weeks of age. Mean arterial pressure (MAP) was determined at 6 weeks of age in conscious, chronically instrumented animals. Adequacy of renal denervation was verified by renal noradrenaline content. 3. Whereas renal denervation had no effect on MAP in control offspring (103 +/- 2 vs 102 +/- 3 mmHg for sham vs denervated, respectively), it reduced blood pressure in growth-restricted offspring (114 +/- 3 vs 104 +/- 1 mmHg for sham vs denervated, respectively; P < 0.01). Renal noradrenaline content was significantly reduced in denervated animals relative to sham operated rats. 4. Thus, the data indicate a role for the renal nerves in the aetiology of IUGR-induced hypertension and suggest that the renal nerves may participate in the early development of hypertension in IUGR offspring in addition to established hypertension observed in adult male IUGR offspring.