Francesc Figueras

Fetal Growth Restriction Results in Remodeled and Less Efficient Hearts in Children

Background— Fetal growth restriction (FGR) affects 5% to 10% of newborns and is associated with increased cardiovascular mortality in adulthood. The most commonly accepted hypothesis is that fetal metabolic programming leads secondarily to diseases associated with cardiovascular disease, such as obesity, diabetes mellitus, and hypertension. Our main objective was to evaluate the alternative hypothesis that FGR induces primary cardiac changes that persist into childhood. Methods and Results— Within a cohort of fetuses with growth restriction identified in fetal life and followed up into childhood, we randomly selected 80 subjects with FGR and compared them with 120 normally grown fetuses, matched for gender, birth date, and gestational age at birth. Cardiovascular assessment was performed in childhood (mean age of 5 years). Compared with control subjects, children with FGR had a different cardiac shape, with increased transversal diameters and more globular cardiac ventricles. Although left ejection fraction was similar among the study groups, stroke volume was reduced significantly, which was compensated for by an increased heart rate to maintain output in severe FGR. This was associated with subclinical longitudinal systolic dysfunction (decreased myocardial peak velocities) and diastolic changes (increased E/E′ ratio and E deceleration time). Children with FGR also had higher blood pressure and increased intima-media thickness. For all parameters evaluated, there was a linear increase with the severity of growth restriction. Conclusions— These findings suggest that FGR induces primary cardiac and vascular changes that could explain the increased predisposition to cardiovascular disease in adult life. If these results are confirmed, the impact of strategies with beneficial effects on cardiac remodeling should be explored in children with FGR.

Intrauterine growth restriction: new concepts in antenatal surveillance, diagnosis, and management

Intrauterine growth restriction (IUGR) remains one of the main challenges in maternity care. Improvements have to start from a better definition of IUGR, applying the concept of the fetal growth potential. Customized standards for fetal growth and birthweight improve the detection of IUGR by better distinction between physiological and pathological smallness and have led to internationally applicable norms. Such developments have resulted in new insights in the assessment of risk and surveillance during pregnancy. Serial fundal height measurement plotted on customized charts is a useful screening tool, whereas fetal biometry and Doppler flow are the mainstay for investigation and diagnosis of IUGR. Appropriate protocols based on available evidence as well as individualized clinical assessment are essential to ensure good management and timely delivery.

Comparative effects of estrogens plus androgens and tibolone on bone, lipid pattern and sexuality in postmenopausal women.

BACKGROUND The main goals of estrogen replacement therapy (ERT) are the prevention of osteoporosis and cardioprotection and the improvement of quality of life (QL). Androgens and tibolone therapy may increase bone mineral density (BMD) to a greater extent than ERT and offer an increase in QL. Lipid and cardiovascular effects, however, are still a major concern. AIM To evaluate whether the addition of a weak androgen to ERT may improve postmenopausal bone loss and sexual activity without adverse effects on lipid pattern and to compare these effects with those observed after tibolone therapy. SUBJECTS AND METHODS This prospective study enrolled 120 surgical postmenopausal women; of these, 96 completed the 1-year follow-up. Patients were allocated to one of four groups. The first group (A; n = 23) received 4 mg of estradiol valerate plus 200 mg of enanthate of dihydroandrosterone im monthly. The second group (E; n = 26) received 50 microg/day of transdermal 17-b-estradiol continuously; the third (T; n = 23) received 2.5 mg of tibolone every day; and finally, the fourth group (C; n = 24) constituted a treatment-free control group. Bone mass (dual X-ray absorptiometry), serum total cholesterol, HDL, LDL, triglycerides, apolipoproteins A1 and B and sexual activity were evaluated before starting therapy and at the end of follow-up. RESULTS All active treatment groups showed an increase in BMD. This increase was higher in the A treatment group (4.08% P < 0.01). Sexuality improved significantly with therapy; however, tibolone and androgens increased scores to a greater extent than ERT. Androgen therapy was associated with significant increases in total cholesterol, LDL and triglycerides. Cholesterol and LDL fall into groups E and T, HDL into groups A and T and triglycerides in group T only. CONCLUSION The combined regimen of androgens and ERT increased vertebral bone mass and enhance sexual activity in postmenopausal women equal to that of tibolone and to a greater extent than ERT alone; its effects on lipids, however, are clearly adverse.

Green space, health inequality and pregnancy

Green spaces have been suggested to improve physical and mental health and well-being by increasing physical activity, reducing air pollution, noise, and ambient temperature, increasing social contacts and relieving psychophysiological stress. Although these mechanisms also suggest potential beneficial effects of green spaces on pregnancy outcomes, to our knowledge there is no available epidemiological evidence on this impact. We investigated the effects of surrounding greenness and proximity to major green spaces on birth weight and gestational age at delivery and described the effect of socioeconomic position (SEP) on these relationships. This study was based on a cohort of births (N=8246) that occurred in a major university hospital in Barcelona, Spain, during 2001-2005. We determined surrounding greenness from satellite retrievals as the average of Normalized Difference Vegetation Index (NDVI) in a buffer of 100 m around each maternal place of residence. To address proximity to major green spaces, a binary variable was used to indicate whether maternal residential address is situated within a buffer of 500 m from boundaries of a major green space. For each indicator of green exposure, linear regression models were constructed to estimate change in outcomes adjusted for relevant covariates including individual and area level SEP. None of the indicators of green exposure was associated with birth weight and gestational age. After assessing effect modification based on the level of maternal education, we detected an increase in birth weight (grams) among the lowest education level group (N=164) who had higher surrounding NDVI (Regression coefficient (95% confidence interval (CI) of 436.3 (43.1, 829.5)) or lived close to a major green space (Regression coefficient (95% CI)) of 189.8 (23.9, 355.7)). Our findings suggest a beneficial effect of exposure to green spaces on birth weight only in the lowest SEP group.

Fetal brain Doppler to predict cesarean delivery for nonreassuring fetal status in term small-for-gestational-age fetuses.

OBJECTIVE: To estimate the value of fetal brain Doppler in predicting the risk of cesarean delivery for nonreassuring fetal status and neonatal acidosis after labor induction in small-for-gestational-age fetuses with normal umbilical artery Doppler. METHODS: Fetal brain Doppler parameters, including cerebral tissue perfusion measured by fractional moving blood volume, cerebroplacental ratio, and middle cerebral artery pulsatility index, were evaluated before labor induction in a cohort of 210 term small-for-gestational-age fetuses with normal umbilical artery Doppler and 210 control participants matched by gestational age. The value of the cerebral Doppler indices to predict the risk of cesarean delivery, cesarean delivery for nonreassuring fetal status, and neonatal acidosis was analyzed. RESULTS: Overall, small-for-gestational-age fetuses showed a significant higher incidence of cesarean delivery (37.6% compared with 19.5%, P<.001), cesarean delivery for nonreassuring fetal status (29% compared with 4.8%, P<.001), and neonatal acidosis (7.6% compared with 2.4%, P=.03) than control participants. Within the small-for-gestational-age group, middle cerebral artery vasodilation was associated with the highest risk of cesarean delivery (67.7% compared with 32.4%, P<.001) and cesarean delivery for nonreassuring fetal status (58.1% compared with 24%, P<.001). In the subgroup of normal middle cerebral artery, incorporation of cerebroplacental ratio further distinguished two groups with different risks of cesarean delivery (51.4% compared with 27.5%, P<.01) and cesarean delivery for nonreassuring fetal status (37.8% compared with 20.4%, P=.01). Middle cerebral artery vasodilation was associated with increased risk of neonatal acidosis (odds ratio, 9.0). Fractional moving blood volume was not associated with the risk of cesarean delivery for nonreassuring fetal status or neonatal acidosis. CONCLUSION: Evaluation of brain Doppler indices before labor induction discriminates small-for-gestational-age fetuses at high risk of cesarean delivery for nonreassuring fetal status and neonatal acidosis. LEVEL OF EVIDENCE: II

Customised birthweight standards accurately predict perinatal morbidity

Objective: Fetal growth restriction is associated with adverse perinatal outcome but is often not recognised antenatally, and low birthweight centiles based on population norms are used as a proxy instead. This study compared the association between neonatal morbidity and fetal growth status at birth as determined by customised birthweight centiles and currently used centiles based on population standards. Design: Retrospective cohort study. Setting: Referral hospital, Barcelona, Spain. Patients: A cohort of 13 661 non-malformed singleton deliveries. Interventions: Both population-based and customised standards for birth weight were applied to the study cohort. Customised weight centiles were calculated by adjusting for maternal height, booking weight, parity, ethnic origin, gestational age at delivery and fetal sex. Main outcome measures: Newborn morbidity and perinatal death. Results: The association between smallness for gestational age (SGA) and perinatal morbidity was stronger when birthweight limits were customised, and resulted in an additional 4.1% (n = 565) neonates being classified as SGA. Compared with non-SGA neonates, this newly identified group had an increased risk of perinatal mortality (OR 3.2; 95% CI 1.6 to 6.2), neurological morbidity (OR 3.2; 95% CI 1.7 to 6.1) and non-neurological morbidity (OR 8; 95% CI 4.8 to 13.6). Conclusion: Customised standards improve the prediction of adverse neonatal outcome. The association between SGA and adverse outcome is independent of the gestational age at delivery.

Neurobehavior in Term, Small-for-Gestational Age Infants With Normal Placental Function

OBJECTIVE: The goal was to evaluate the neurobehavioral outcomes of term, small-for-gestational age (SGA) newborns with normal placental function. METHODS: A cohort of consecutive term SGA newborns with normal prenatal umbilical artery Doppler ultrasound findings was created and compared with a group of term infants with size appropriate for gestational age, who were sampled from our general neonatal population. Neonatal behavior was evaluated at corrected age of 40 ± 1 weeks with the Neonatal Behavioral Assessment Scale. The effect of the study group on each Neonatal Behavioral Assessment Scale area was adjusted, through multivariate analysis of covariance, for smoking during pregnancy, maternal BMI, socioeconomic level, onset of labor, mode of delivery, use of epidural anesthetic medication, gestational age at delivery, postnatal age (in days) at evaluation, and gender. RESULTS: A total of 202 newborns (102 SGA and 100 appropriate for gestational age) were included. All of the neurobehavioral areas studied were poorer in the SGA group, with significance for attention, habituation, motor, social-interactive, and regulation of state. The average mean differences in scores between the study groups were 0.77 (95% confidence interval: 0.38–1. 14) for attention, 0.64 (95% confidence interval: 0.13–1.14) for habituation, 0.52 (95% confidence interval: 0.31–0.74) for motor, 0.95 (95% confidence interval: 0.54–1.37) for social-interactive, and 0.68 (95% confidence interval: 0.23–1.13) for regulation of state. These differences remained significant after adjustment for potential confounders. CONCLUSION: Term SGA newborns with no signs of placental insufficiency had poorer neurobehavioral competencies, which suggests delayed neurologic maturation.

Altered small-world topology of structural brain networks in infants with intrauterine growth restriction and its association with later neurodevelopmental outcome.

Intrauterine growth restriction (IUGR) due to placental insufficiency affects 5-10% of all pregnancies and it is associated with a wide range of short- and long-term neurodevelopmental disorders. Prediction of neurodevelopmental outcomes in IUGR is among the clinical challenges of modern fetal medicine and pediatrics. In recent years several studies have used magnetic resonance imaging (MRI) to demonstrate differences in brain structure in IUGR subjects, but the ability to use MRI for individual predictive purposes in IUGR is limited. Recent research suggests that MRI in vivo access to brain connectivity might have the potential to help understanding cognitive and neurodevelopment processes. Specifically, MRI based connectomics is an emerging approach to extract information from MRI data that exhaustively maps inter-regional connectivity within the brain to build a graph model of its neural circuitry known as brain network. In the present study we used diffusion MRI based connectomics to obtain structural brain networks of a prospective cohort of one year old infants (32 controls and 24 IUGR) and analyze the existence of quantifiable brain reorganization of white matter circuitry in IUGR group by means of global and regional graph theory features of brain networks. Based on global and regional analyses of the brain network topology we demonstrated brain reorganization in IUGR infants at one year of age. Specifically, IUGR infants presented decreased global and local weighted efficiency, and a pattern of altered regional graph theory features. By means of binomial logistic regression, we also demonstrated that connectivity measures were associated with abnormal performance in later neurodevelopmental outcome as measured by Bayley Scale for Infant and Toddler Development, Third edition (BSID-III) at two years of age. These findings show the potential of diffusion MRI based connectomics and graph theory based network characteristics for estimating differences in the architecture of neural circuitry and developing imaging biomarkers of poor neurodevelopment outcome in infants with prenatal diseases.

Cardiovascular programming in children born small for gestational age and relationship with prenatal signs of severity

OBJECTIVE The objective of the study was to evaluate cardiovascular function in children who were small-for-gestational-age (SGA) fetuses. STUDY DESIGN This was a prospective study including 100 controls and 50 children diagnosed in utero as SGA after 34 weeks subdivided into the following categories: SGA and intrauterine growth restriction (IUGR) according to the absence or presence, respectively, of weight centile less than 3 or abnormal cerebroplacental Doppler. Postnatal cardiovascular outcome was evaluated at 3-6 years of age by echocardiography, blood pressure, and carotid ultrasound. RESULTS Both SGA and IUGR presented in childhood more globular hearts, reduced longitudinal motion, and impaired relaxation with an increase in radial function. Both groups showed increased blood pressure and carotid intima-media thickness. There was a linear tendency to worse cardiovascular results in IUGR as compared with SGA. CONCLUSION Fetal cardiovascular programming occurs in SGA, regardless of Doppler and weight centile. These findings challenge the concept of constitutionally small and warrant further investigation to identify predictors of cardiovascular outcome in SGA.

Performance of a first-trimester screening of preeclampsia in a routine care low-risk setting

OBJECTIVE We sought to evaluate the effectiveness of an integrated first-trimester screening test to predict preeclampsia (PE). STUDY DESIGN A prospective cohort of singleton pregnancies underwent routine first-trimester screening from 2009 through 2011 (n = 5759). A logistic regression-based predictive model for early- and late-onset PE was constructed based on: maternal characteristics; levels of pregnancy-associated plasma protein-A and free β-human chorionic gonadotropin at 8-12 weeks; and blood pressure and uterine artery Doppler at 11.0-13.6 weeks. RESULTS Of the 5170 enrolled participants, 136 (2.6%) developed PE (early PE: 26 [0.5%]; late PE: 110 [2.1%]). At 5% and 10% false-positive rates, detection rates were 69.2% and 80.8% for early PE (area under the curve, 0.95; 95% confidence interval, 0.94-0.98) and 29.4% and 39.6% for late PE (area under the curve, 0.71; 95% confidence interval, 0.66-0.76), respectively. CONCLUSION First-trimester screening combining maternal factors with uterine artery Doppler, blood pressure, and pregnancy-associated plasma protein-A is useful to predict PE in a routine care setting.