National Institute for Health Research and Medical Research Council.

BACKGROUND Severe early-onset fetal growth restriction (FGR) predisposes to fetal death, neonatal death, neonatal morbidity and neurodisability. The use of placental biomarkers has been proposed for risk stratification in pre-eclampsia but they could be equally useful in FGR in order to aid management. METHODS This is a secondary analysis of the multicenter, placebo-controlled STRIDER trial of singleton pregnancies with severe early-onset FGR. Women with a pregnancy complicated by FGR between 22 +0 and 29 +6 weeks of gestation were randomly assigned to receive either sildenafil 25 mg three times daily or placebo until 32 +0 weeks' gestation or delivery. We developed prediction models for livebirth, gestation at birth, birth weight, overall survival and neonatal morbidity based upon maternal demographics (age, parity, blood pressure, preeclampsia, gestational hypertension), fetal biometric (estimated fetal weight) and Doppler measurements (Middle Cerebral Artery, Umbilical Artery) and maternal angiogenic biomarkers (PlGf, sEng, sFlt-1 and sFlt-1:PlGF ratio). RESULTS A complete data set was available for 105 out 135 randomised women. Multivariable analysis identified estimated fetal weight (EFW) and soluble fms-like tyrosine kinase 1: placental growth factor ratio (sFlt-1:PlGF) as independent predictors of livebirth and overall survival. EFW was a consistent predictor for all outcomes other than gestation at delivery. sFlt-1:PlGF ratio was a consistent predictor for all outcomes other than neonatal morbidity. CONCLUSIONS In severe early-onset FGR pregnancies livebirth and overall survival can be predicted using a model involving EFW and sFlt-1:PlGF ratio. This model will allow informed decision making about pregnancy management, especially in cases that may be considered previable.

SDQ Strengths and DifficultiesQuestionnaire SGA Small for gestational age AIM The functional polymorphism Val158Met in the catechol-O-methyltransferase (COMT) gene was analysed to determine its association with maternal stress and childhood total difficulties.METHOD Data were collected at birth from a group of infants who were born small for gestational age and a group who were born at an appropriate size for gestational age and had been enrolled in the Auckland Birthweight Collaborative Study. Children were followed up at the ages of 1 year, 3 years 6 months, 7 years, and 11 years. At the age of 11 years, DNA samples were collected from 546 children (270 females, 276 males): 227 children born small for gestational age and 319 children born at an appropriate size for gestational age. The main independent variable was perceived maternal stress at birth and at 7 and 11 years of age, assessed using the total difficulties scale of the Strength and Difficulties Questionnaire. IQ was assessed at the age of 7 years.RESULTS Met ⁄ Met homozygotes were at a significantly increased risk of behavioural and emotional problems at the ages of 7 (p=0.002) and 11 years (p=0.003), relative to either heterozygous or homozygous carriers of the Val158Met polymorphism, but only when they were exposed to maternal stress in utero. Met ⁄ Met homozygotes had, on average, IQ scores that were four points higher than those of Val ⁄ Val homozygotes (p=0.010).INTERPRETATION These findings emphasize the potential long-term consequences of prenatal stress for genetically susceptible individuals during neurodevelopment in utero. Our findings add to the general understanding of the aetiology and developmental nature of childhood emotional and behavioural problems.Exposure to maternal antenatal stress can have deleterious effects on the subsequent development of offspring. A number of recent studies have reported an increased risk of socioemotional and behavioural disturbances, 1,2 including attention-deficit-hyperactivity disorder (ADHD). 3 Exposure to stress during pregnancy can influence prenatal development and increase the risk of problems in childhood. Stress-induced activation of the sympathetic nervous system causes an increase in uterine artery resistance, reducing blood flow to the fetus and potentially altering brain structure and function. 4 Moreover, cortisol secreted by the mother in response to stress can reach the fetus, 5 which in turn can influence the functioning of the fetus's hypothalamo-pituitaryadrenal axis.6 Changes in the hypothalamo-pituitary-adrenal axis can increase the risk of later behavioural and emotional problems through an alteration of gene expression in developing brain cells. 7The catechol-O-methyltransferase (COMT) gene has received attention recently with regard to the role it plays in stress vulnerability. 8 It is considered to be a good candidate for studying the genetic basis of stress sensitivity because it encodes an enzyme that is involved in the breakdown of dopamine in the prefrontal cortex.9 COMT is ...

Objective: Because dopamine functioning varies by sex and age it might be expected that the effects of methylphenidate or amfetamine, the psychostimulants used for the treatment of Attention Deficit /Hyperactivity Disorder (ADHD), will also be moderated by these factors.Here we review the published literature on whether stimulant effects in ADHD symptoms vary by age and sex. Results: Randomised controlled trials confirm that stimulant medication is efficacious for, and well tolerated by, males and females and patients across the age range; although preschoolers appear to have a less beneficial response and more side effects. Few studies that specifically examined the moderating effect of age and/or sex were identified. For sex, no effects on overall response were found, although one study reported that sex moderated methylphenidate pharmacodynamics. The few effects found for age were small and inconsistent. Conclusions:The available evidence suggests that stimulant medication, when appropriately administered, has efficacy as an ADHD treatment for both sexes and across all ages. There are currently too few published papers examining the effects of sex and age to draw strong conclusions about moderation. Further studies of the pharmacodynamics of stimulants on ADHD MEDICATION MODERATORS 3 symptoms measured using objective tests in the laboratory or classroom setting need to be undertaken.

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