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Background Fetal alcohol spectrum disorder (FASD) is a lifelong condition. Early interventions targeting core neurocognitive deficits have the potential to confer long-term neurodevelopmental benefits. Time-targeted choline supplementation is one such intervention that has been shown to provide neurodevelopmental benefits that emerge with age during childhood. We present a long-term follow-up study evaluating the neurodevelopmental effects of early choline supplementation in children with FASD approximately 7 years on average after an initial efficacy trial. Methods The initial study was a randomized, double-blind, placebo-controlled trial of choline vs. placebo in 2.5 to 5 year olds with FASD. Participants in this long-term follow-up study include 18 children (9 placebo; 9 choline) seen 7 years on average following initial trial completion. The mean age at follow-up was 11.0 years old. Diagnoses were 28% fetal alcohol syndrome (FAS), 28% partial FAS, and 44% alcohol-related neurodevelopmental disorder. The follow-up included measures of executive functioning and an MRI scan. Results Children who received choline had better performance on several tasks of lower-order executive function (e.g., processing speed) and showed higher white matter microstructure organization (i.e., greater axon coherence) in the splenium of the corpus callosum compared to the placebo group. Conclusions These preliminary findings, although exploratory at this stage, highlight potential long-term benefits of choline as a neurodevelopmental intervention for FASD and suggest that choline may affect white matter development, representing a potential target of choline in this population. Trial registration Prior to enrollment, this trial was registered with clinicaltrials.gov (NCT01149538) on June 23, 2010.

Fetal Alcohol Spectrum Disorder (FASD) affects 2–5% of children in the United States. In the preschool age-range, inhibitory deficits frequently manifest as impaired ability to delay gratification, which is associated with deficits in cognitive flexibility in these children. The goal of this longitudinal study was to determine whether the ability to delay gratification in preschool children with FASD is: 1) associated with broader manifestations in temperament and behavior; 2) predictive of later inhibitory control, cognitive flexibility and working memory in middle childhood; and 3) predictive of later parent-reported behavioral problems and school functioning in middle childhood. Forty-seven children with FASD, ages 2.5 to 5 were administered a delay of gratification task in which they chose between receiving two snacks immediately or ten snacks after waiting for ten minutes. Two groups were defined based on a median split of waiting time. Four years later, twenty-nine children completed measures of inhibitory control (Flanker task), cognitive flexibility (Dimensional Change Card Sort Test), and working memory (Stanford-Binet Intelligence Scales), and their parents completed the Child Behavior Checklist as a measure of the child’s behavioral problems and school functioning. Children with longer wait times on the delay of gratification task in preschool showed better inhibitory control on the Flanker task in middle childhood and better parent-reported school functioning in English. These findings indicate that early inhibitory capacity persists into middle childhood in those with FASD, and may be a promising target for early intervention to improve later cognitive outcomes in these children.

Background Prenatal alcohol exposure (PAE) is linked to a variety of neurodevelopmental challenges, including social functioning (SF) and executive functioning (EF) deficits. These deficits present differently across developmental stages from preschool age to adolescence. Methods The post hoc analyses described here were conducted on data from 83 preschool-age children with PAE (early childhood group; ages 2.5 to 5.0) and 95 adolescents (49 with PAE, 46 controls; ages 8 to 16). Each child completed EF tasks as part of several prior studies. Parents completed social and communication inventories about their child's abilities. Thirty-three participants from the early childhood group returned for a 4-year follow-up and completed both SF and EF measures. Results Both the early childhood and adolescent groups with PAE showed deficits in SF and EF. There was a relationship between SF and EF within the adolescent PAE group that was not present in the adolescent control group or the early childhood PAE group. However, at the 4-year follow-up (Mage = 8.45), participants originally in the early childhood PAE group also demonstrated this relationship. Conclusions These findings support previous research on EF/SF deficits in adolescents with PAE while also addressing a gap in the literature concerning early childhood research on this topic. Additionally, these findings suggest that the relationship between EF and SF deficits may strengthen throughout development. This line of research highlights potential sensitive periods for SF and EF training in children with PAE and suggests that fetal alcohol spectrum disorders programs consider targeting EF training as a component of social skill interventions.

Objectives: Cortical abnormalities in prenatal alcohol exposure (PAE) are known, including in gyrification (LGI), thickness (CT), volume (CV), and surface area (CS). This study provides longitudinal and developmental context to the PAE cortical development literature. Experimental design: Included: 58 children with PAE and 52 controls, ages 6–17 at enrollment, from four Collaborative Initiative on FASD (CIFASD) sites. Participants underwent a formal evaluation of physical anomalies and dysmorphic facial features associated with PAE. MRI data were collected on three platforms (Siemens, GE, and Philips) at four sites. Scans were spaced two years apart. Change in LGI, CT, CS, and CV were examined. Principal observations: Several significant regional age-by-diagnosis linear and quadratic interaction effects in LGI, CT, and CV were found, indicating atypical developmental trajectories in PAE. No significant correlations were observed between cortical measures and IQ. Conclusions: Regional differences were seen longitudinally in CT, CV, and LGI in those with PAE. The findings represent important insights into developmental trajectories and may have implications for the timing of assessments and interventions in this population. It is noteworthy that cortical metrics did not correlate with IQ, suggesting that more specific aspects of cognitive development may need to be explored to provide further context. Keywords: Cerebral cortex, Fetal alcohol spectrum disorder, Longitudinal MRI, Neuropsychology, Pediatric

Background This study was a randomized double-blind sham-controlled trial examining the effects of transcranial direct current stimulation (tDCS) augmented cognitive training (CT) in children with Fetal Alcohol Spectrum Disorders (FASD). Prenatal alcohol exposure has profound detrimental effects on brain development and individuals with FASD commonly present with deficits in executive functions including attention and working memory. The most commonly studied treatment for executive deficits is CT, which involves repeated drilling of exercises targeting the impaired functions. As currently implemented, CT requires many hours and the observed effect sizes are moderate. Neuromodulation via tDCS can enhance brain plasticity and prior studies demonstrate that combining tDCS with CT improves efficacy and functional outcomes. TDCS-augmented CT has not yet been tested in FASD, a condition in which there are known abnormalities in neuroplasticity and few interventions. Methods This study examined the feasibility and efficacy of this approach in 44 children with FASD. Participants were randomized to receive five sessions of CT with either active or sham tDCS targeting the dorsolateral prefrontal cortex, a region of the brain that is heavily involved in executive functioning. Results The intervention was feasible and well-tolerated in children with FASD. The tDCS group showed nominally significant improvement in attention on a continuous performance test compared to sham (p = .043). Group differences were observed at the third, fourth and fifth treatment sessions. There was no effect of tDCS on working memory (p = .911). Further, we found no group differences on a trail making task (p = .659) or on the verbal fluency test (p = .826). In the active tDCS group, a significant correlation was observed between improvement in attention scores and decrease in parent-reported attention deficits (p = .010). Conclusions These results demonstrate that tDCS-augmented CT is well tolerated in children with FASD and potentially offers benefits over and above CT alone.

Background Despite the high prevalence of fetal alcohol spectrum disorder (FASD), there are few interventions targeting its core neurocognitive and behavioral deficits. FASD is often conceptualized as static and permanent, but interventions that capitalize on brain plasticity and critical developmental windows are emerging. We present a long-term follow-up study evaluating the neurodevelopmental effects of choline supplementation in children with FASD 4 years after an initial efficacy trial. Methods The initial study was a randomized, double-blind, placebo-controlled trial of choline vs. placebo in 2–5-year-olds with FASD. Participants include 31 children (16 placebo; 15 choline) seen 4 years after trial completion. The mean age at follow-up was 8.6 years. Diagnoses were 12.9% fetal alcohol syndrome (FAS), 41.9% partial FAS, and 45.1% alcohol-related neurodevelopmental disorder. The follow-up included measures of intelligence, memory, executive functioning, and behavior. Results Children who received choline had higher non-verbal intelligence, higher visual-spatial skill, higher working memory ability, better verbal memory, and fewer behavioral symptoms of attention deficit hyperactivity disorder than the placebo group. No differences were seen for verbal intelligence, visual memory, or other executive functions. Conclusions These data support choline as a potential neurodevelopmental intervention for FASD and highlight the need for long-term follow-up to capture treatment effects on neurodevelopmental trajectories. Trial registration ClinicalTrials.Gov #NCT01149538; Registered: June 23, 2010; first enrollment July 2, 2010

The purpose of the current study was to evaluate the relationship between parent-report and objective measures of executive function in children diagnosed with Fetal Alcohol Spectrum Disorder (FASD). The participants were a clinical sample of 551 children who completed 597 evaluations, including initial and re-evaluations. Participants were 6-16 years old, with a mean age of 10. Pearson correlations were used to determine the relationship between performance-based measures and parent-report measures of executive functioning. Relationships among the same types of measures, that is, performance based or parent report, were also evaluated. The data largely demonstrate low nonsignificant correlations between performance-based measures and parental report of executive function. Parent-report measures were internally consistent as were objective measures. It is possible that a third variable, for example, parental frustration, significantly influences parent reports. It is also likely that objective measures, which are administered in a controlled environment, do not fully capture children's day-to-day functioning. That is, a child may have the executive function abilities (i.e., good performance on objective measures) but may be unable to deploy the appropriate skills in their daily lives, as evidenced by parental report. Children with FASD who have executive function abilities but not implementation skills likely require different interventions than children who lack abilities and skills.

There are no biological treatments for fetal alcohol spectrum disorders (FASDs), lifelong conditions associated with physical anomalies, brain damage, and neurocognitive abnormalities. In preclinical studies, choline partially ameliorates memory and learning deficits from prenatal alcohol exposure. This phase I pilot study evaluated the feasibility, tolerability, and potential adverse effects of choline supplementation in children with FASD. We hypothesized that choline would be well tolerated with minimal adverse events. The study design was a double-blind, randomized, placebo-controlled trial. Participants included 20 children aged 2.5 to 4.9 years with prenatal alcohol exposure and FASD diagnoses. Participants were randomly assigned to 500 mg choline or placebo daily for 9 months (10 active, 10 placebo). Primary outcome measures included feasibility, tolerability, adverse effects, and serum choline levels. Seventeen participants completed the study. Compliance was 82% to 87%, as evidenced by parent-completed log sheets and dose counts. Periodic 24-hour dietary recalls showed no evidence of dietary confounding. Adverse events were minimal and were equivalent in the active and placebo arms with the exception of fishy body odor, which occurred only in the active group. There were no serious adverse events to research participants. This phase I pilot study demonstrates that choline supplementation at 500 mg/d for 9 months in children aged 2 to 5 years is feasible and has high tolerability. Further examination of the efficacy of choline supplementation in FASD is currently underway.

To determine whether the postnatal growth rate of infants with intrauterine growth restriction (IUGR) is associated with later cognitive function and body mass index (BMI).Infants with IUGR (2211 g ator =37 weeks' gestation) were identified in data from the Collaborative Perinatal Project, excluding those with diagnoses affecting cognition or growth. Wechsler Scale of Children's Intelligence (WISC) scores at age 7 years and data on postnatal growth at 16 weeks were available for 463 infants with IUGR. Linear regression relating postnatal growth and WISC score, adjusting for potential confounders, was performed for these infants. BMI at 7 years also was examined.Weight gain at 16 postnatal weeks ranged from 1059 to 5119 g in the infants with IUGR, with lower achieved cognitive testing scores apparent at both extremes (ie, an inverted J-shape; P.001). Infants gaining 1200 and 5000 g scored 15.5 and 2.4 fewer points, respectively, on the full scale compared with infants with score-maximizing growth. In contrast, BMI at 7 years was linearly related to postnatal weight gain (P.001).Growth in the first 4 postnatal months is an independent risk factor for cognitive outcome at age 7 years, with both extremes associated with negative effects.

Because prenatal alcohol exposure is associated with growth deficiency, little attention has been paid to the potential for overweight and obesity in children with fetal alcohol spectrum disorders (FASD). This study examined the prevalence of overweight/obesity (body mass index [BMI]) in a large clinical sample of children with FASD.Children, aged 2 to 19 years, who were evaluated for FASD at University Clinics, included 445 with an FASD diagnosis and 171 with No-FASD diagnosis. Prevalence of overweight/obesity (BMI ≥ 85 percentile) was compared to national and state prevalence. BMI was examined in relation to FASD diagnosis, gender, and age. Dietary intake data were examined for a young subsample (n = 42).Thirty-four percent with any FASD diagnosis were overweight or obese, which did not differ from the No-FASD group or U.S. prevalence. Underweight was prevalent in those with fetal alcohol syndrome (FAS) (17%). However, increased rates of overweight/obesity were seen in those with partial FAS (40%). Among adolescents, those with any FASD diagnosis had increased overweight/obesity (42%), particularly among females (50%). The rate in adolescent females with FASD (50%) was nearly 3 times higher than state prevalence for adolescent females (17 to 18%), p0.001. In the young subsample, those who were overweight/obese consumed more calories, protein, and total fat per day than those who were not overweight or obese.Rates of overweight/obesity are increased in children with partial FAS. In adolescents, rates are increased for any FASD diagnosis (particularly in females). Results are suggestive of possible metabolic/endocrine disruption in FASD-a hypothesis for which there is evidence from animal models. These data suggest that clinicians may consider prenatal alcohol exposure as a risk factor for metabolic/endocrine disruption, should evaluate diet as a risk in this population, and may need to target interventions to females prior to puberty to effect changes in overweight-related outcomes.

Executive function (EF) deficit is a hallmark of Fetal Alcohol Spectrum Disorders (FASD), but the vast majority of available evidence comes from school-age children and adolescents. Very little is known about EF during the critical developmental period prior to 6 years of age in FASD. We evaluated EF in 39 children with FASD (3.0-5.5 years) and a comparison group of 50 age-matched, nonexposed controls. Measures included the EF Scale for Early Childhood and a Delay of Gratification task. Compared to age-matched controls, preschool children with FASD had impairments on the EF Scale and showed more impulsivity on the Delay of Gratification task. To confirm the EF Scale finding, FASD group performance was compared to a separate normative dataset (N = 1,400). Those with FASD performed below normal (M = -0.57, SD = 0.92). Within the FASD group, IQ was correlated with the EF Scale (partial r = .60, p = .001) and Delay of Gratification (partial r = .58, p = .005). EF Scale performance did not differ significantly across levels of FASD severity (fetal alcohol syndrome [FAS], partial FAS, or alcohol-related neurobehavioral disorder [ARND]). However, compared to normative data, those with FAS had the largest deficits (M = -0.91 SD from the mean, SE = 0.23), followed by partial FAS (M = -0.66 SD from the mean, SE = 0.26), then ARND (M = -0.36 SD from the mean, SE = 0.20). These novel data show that EF deficits manifest well before the age of 6 years in children with FASD, that they occur across the spectrum, and that EF may be most impaired in children with more severe forms of FASD and/or lower IQs.

Thirty-eight healthy women undergoing elective Caesarean section under spinal anaesthesia at term were allocated randomly to receive boluses of either phenylephrine 100 micrograms or ephedrine 5 mg for maintenance of maternal arterial pressure. The indication for administration of vasopressor was a reduction in systolic pressure to < or = 90% of baseline values. Maternal arterial pressure (BP) and heart rate (HR) were measured every minute by automated oscillometry. Cardiac output (CO) was measured by cross-sectional and Doppler echocardiography before and after preloading with 1500 ml Ringer lactate solution and then every 2 min after administration of bupivacaine. Umbilical artery pulsatility index (PI) was measured using Doppler before and after spinal anaesthesia. The median (range) number of boluses of phenylephrine and ephedrine was similar; 6 (1-10) vs 4 (1-8) respectively. Maternal systolic BP and CO changes were similar in both groups, but the mean [95% CI] maximum percentage change in maternal HR was larger in the phenylephrine group (-28.5 [-24.2, -32.9]%) than in the ephedrine group (-14.4 [-10.6, -18.2]%). As a consequence atropine was required in 11/19 women in the phenylephrine group compared with 2/19 in the ephedrine group (P < 0.01). Mean umbilical artery pH [95% CI] was higher in the phenylephrine group (7.29 [7.28-7.30]) than in the ephedrine group (7.27 [7.25-7.28]). The results of the present study support the use of phenylephrine for maintenance of maternal arterial pressure during spinal anaesthesia for elective Caesarean section.

Serial haemodynamic investigations were performed in 32 women who were allocated randomly to receive either spinal or extradural anaesthesia for elective Caesarean section. Cardiac output was measured by Doppler and cross-sectional echocardiography at the aortic valve. Doppler flow velocity waveforms were recorded also from the umbilical artery. Preloading with Ringer lactate solution 1 litre increased cardiac output in both groups. After injection of bupivacaine, cardiac output remained increased in the extradural group, but decreased in the spinal group. This was associated with an increase in umbilical artery pulsatility index in the spinal group. Umbilical artery pH was less in the spinal group (7.22 vs 7.27), although no neonate was depressed at birth. The maximum percentage change in cardiac output and umbilical artery pulsatility index correlated with umbilical artery pH (r = 0.54, r = 0.72, respectively). There was no significant correlation with change in arterial pressure.

The incidence of regurgitant flow velocities were determined using colour flow mapping and pulse Doppler in 107 pregnant women, 55 of whom were less than 28 weeks gestation. The results were compared with 51 non-pregnant controls. The incidence of tricuspid regurgitant velocities increased from 42% in the control group to 67% at greater than or equal to 28 weeks gestation with a median peak regurgitant velocity of 1.7 ms-1. The incidence of pulmonary regurgitant velocities increased from 50% in the control group to 96% at greater than or equal to 28 weeks gestation with a median peak regurgitant velocity of 1.1 m s-1. Mitral and aortic regurgitant velocities were recorded in 27% and 2% of non-pregnant controls respectively. No statistically significant increase in left sided regurgitant velocities was evident during pregnancy. The increase in incidence of right heart regurgitant velocities may be secondary to the dilatation of the respective value orifices due to the volume loading of pregnancy.

To determine the most appropriate ultrasonic measurement for the prediction of a small for gestational age (SGA) infant.A literature search of all English language journals over the last 15 years was undertaken. One hundred seventeen articles on the use of morphometric and Doppler ultrasonic measurements in the diagnosis of SGA were reviewed.Studies were included if antenatal and postnatal criteria for diagnosis were clearly defined and data for SGA and normal fetuses were reported, allowing the construction of a 2 x 2 table.Studies with the same criteria were grouped according to whether the population was high or low risk. The sensitivity, odds ratio (OR), and false-positive rate were calculated for each study; summary statistics were then calculated for each ultrasonic measurement provided the individual sensitivities, ORs, and false-positive rates were not significantly different (P.01).In high-risk subjects, abdominal circumference below the tenth percentile had the highest common sensitivity, and estimated fetal weight below the tenth percentile had the highest common OR. In studies in which morphometric and Doppler ultrasonic measurements were compared in the same subjects, the Doppler ORs tended to be lower than the ORs for morphometric measurements. In low-risk subjects, much lower ORs were found for all ultrasonic measurements. The heterogeneous nature of the studies reviewed may have contributed to the different results within each group.

1. Serial pulmonary haemodynamic investigations were performed in 13 women before conception, at monthly intervals throughout pregnancy, and then at 6 months after delivery. 2. Mean pulmonary artery pressure was calculated from pulsed Doppler pulmonary velocities. Pulmonary flow was measured by Doppler and cross-sectional echocardiography. These two measurements were used to calculate pulmonary vascular resistance. 3. Mean non-pregnant pulmonary artery pressure was 13.8 mmHg and no significant change was demonstrated during pregnancy. 4. Pulmonary flow increased from 4.88 to 7.19 litres/min during pregnancy. 5. Pulmonary vascular resistance decreased from 2.85 resistance units before pregnancy to 2.17 resistance units at 8 weeks gestation. Thereafter there was no further significant change, values returning to pre-pregnant levels by 6 months after delivery.

Serial measurements of apparent liver blood flow and cardiac output were performed in 12 women at 12-14, 24-26 and 36-38 weeks of pregnancy and then at 10-12 weeks after delivery. Apparent liver blood flow was calculated from indocyanine green clearance. Cardiac output was measured by Doppler and cross-sectional echocardiography at the aortic valve. Postnatal apparent liver blood flow was 1.81 l/min and no significant change was demonstrated during pregnancy. In contrast cardiac output decreased from 7.46 l/min at 36-38 weeks gestation to 4.90 l/min after delivery. Apparent liver blood flow accounted for 24% of cardiac output during pregnancy. This increased to 37% after delivery.

Serial hemodynamic investigations were performed in 10 women with twin pregnancies at 20, 24, 28, 32, and 36 weeks' gestation and at 6 months after delivery. Cardiac output was measured by Doppler and cross-sectional echocardiography at the aortic, pulmonary, and mitral valves. Cardiac chamber size and ventricular function were investigated by M-mode echocardiography. The hemodynamic results were compared with those of 13 women with singleton pregnancies. Mean Doppler cardiac output was increased at 20 weeks of twin pregnancy (7.63 L/min) and showed no significant change during the remainder of pregnancy, but fell to 5.07 L/min after delivery. This increase was significantly greater than that recorded during singleton pregnancy, because of a relatively greater increase in heart rate. Twin pregnancy was associated with a significantly greater increase in left atrial dimension, but the increases in left ventricular dimensions, wall thickness, and function were comparable to those recorded in singleton pregnancy.

Serial hemodynamic investigations were performed in 40 women at 38 weeks' gestation and then 1, 2, 6, 10, and 14 days after normal delivery. Cardiac output was measured by Doppler and cross-sectional echocardiography at the aortic valve. In 30 controls who received an average of 280 mL intravenous fluid during labor, the mean cardiac output remained elevated (7.15 L/minute) for 24 hours after delivery and then fell to 5.39 L/minute at 10 days as a result of decreases in both heart rate and stroke volume. Blood pressure fell during the first 2 days after delivery and thereafter increased to values not significantly different from those recorded at the end of pregnancy. In ten women who experienced postpartum hemorrhage, stroke volume decreased and heart rate increased, relative to the control group, during the first 48 hours after delivery. Blood pressure and cardiac output, however, were not significantly different from values in the control group.

The temporal variability of combined cross-sectional and Doppler echocardiographic estimates of cardiac output was studied in 14 normal subjects. In each subject cross-sectional echocardiographs and Doppler velocities were recorded from the aortic, pulmonary and mitral valves. Recordings were repeated after 30-60 min and after 1-3 months to allow estimation of short-term and long-term temporal variability. A components of variance analysis showed that between-subject variability was significantly larger than within-subject variability for all measured and calculated variables. Long-term variability was larger than short-term variability for all variables except the mitral valve area. Calculation of flows from the three measurement sites were equally reproducible and the mean percentage error for CO measurements performed 1-3 months apart ranged from 6.4% to 7.4%. The 95% confidence intervals for Doppler measurements of CO at the three sites ranged from +/- 0.49 l min-1 to +/- 0.56 l min-1, suggesting that the temporal variability of flow measurements using the non-invasive Doppler method is sufficiently small for the method to be useful in serial haemodynamic studies.

Serial hemodynamic investigations were performed in 10 women with twin pregnancies at 20, 24, 28, 32, and 36 weeks' gestation and at 6 months after delivery. Cardiac output was measured by Doppler and cross-sectional echocardiography at the aortic, pulmonary, and mitral valves. Cardiac chamber size and ventricular function were investigated by M-mode echocardiography. The hemodynamic results were compared with those of 13 women with singleton pregnancies. Mean Doppler cardiac output was increased at 20 weeks of twin pregnancy (7.63 L/min) and showed no significant change during the remainder of pregnancy, but fell to 5.07 L/min after delivery. This increase was significantly greater than that recorded during singleton pregnancy, because of a relatively greater increase in heart rate. Twin pregnancy was associated with a significantly greater increase in left atrial dimension, but the increases in left ventricular dimensions, wall thickness, and function were comparable to those recorded in singleton pregnancy.

Summary Serial haemodynamic investigations were performed in 20 women who had epidural anaesthesia before elective Caesarean section. Cardiac output was measured by Doppler and cross-sectional echocardiography at the aortic valve. Measurements were performed after preloading the circulation with Ringer lactate solution (mean volume 805 ml) and then 10, 20, 30 and 40 minutes after administration of 0.5% bupivacaine. Preloading increased mean stroke volume from 84 to 94 ml and mean cardiac output from 7.01 to 7.70 litres/minute. Relative to basal values, mean arterial pressure decreased in all subjects after administration of bupivacaine (mean –14%, range –1 to –33%). Five subjects were given ephedrine because of hypotension. In three of these subjects hypotension was associated with a marked decrease in cardiac output. No significant changes in arterial blood pressure or cardiac output were demonstrated relative to basal values in the remaining 15 subjects. Ephedrine induced consistent increases in blood pressure and cardiac output.

Serial hemodynamic investigations were performed in 10 women with twin pregnancies at 20, 24, 28, 32, and 36 weeks' gestation and at 6 months after delivery. Cardiac output was measured by Doppler and cross-sectional echocardiography at the aortic, pulmonary, and mitral valves. Cardiac chamber size and ventricular function were investigated by M-mode echocardiography. The hemodynamic results were compared with those of 13 women with singleton pregnancies. Mean Doppler cardiac output was increased at 20 weeks of twin pregnancy (7.63 L/min) and showed no significant change during the remainder of pregnancy, but fell to 5.07 L/min after delivery. This increase was significantly greater than that recorded during singleton pregnancy, because of a relatively greater increase in heart rate. Twin pregnancy was associated with a significantly greater increase in left atrial dimension, but the increases in left ventricular dimensions, wall thickness, and function were comparable to those recorded in singleton pregnancy.

Serial hemodynamic measurements were performed in 13 women on two occasions before conception and then at monthly intervals throughout pregnancy. Cardiac output (CO) was measured by Doppler and cross-sectional echocardiography at the aortic, pulmonary, and mitral valves. Cardiac chamber size and ventricular function were investigated by M-mode echocardiography. CO increased from a mean of 4.88 l/min before the conception to a maximum of 7.21 l/min at 32 wk, the increase being significant by 5 wk after the last menstrual period. Heart rate and left ventricular performance increased during the first trimester. Heart rate increased further during the second trimester, during which left atrial and left ventricular end-diastolic dimensions increased, suggesting an increase in venous return. Derived values of total peripheral vascular resistance fell during the first 20 wk. These changes were associated with a progressive increase in valve orifice area and left ventricular wall thickness during pregnancy.

Serial haemodynamic investigations were performed in 15 women delivered by elective caesarean section under epidural anaesthesia at 38-40 weeks gestation. Cardiac output was measured by Doppler and cross-sectional echocardiography at the aortic valve. No haemodynamic changes were demonstrable after attainment of surgical anaesthesia (T5 or above). Stroke volume increased 13% after delivery of the placenta and remained elevated until the end of the operation at which time cardiac output was 11% above pre-operative values. Stroke volume and cardiac output fell during the first postoperative day. Heart rate remained elevated at pre-operative values for 48 h after delivery. There was a fall in heart rate and cardiac output between the second and the sixth days after delivery. By 2 weeks after delivery cardiac output was 28% lower than pre-operative values. Compared with pre-operative values, diastolic blood pressure was lower on the first and second postnatal days.

Serial hemodynamic investigations were performed in 40 women at 38 weeks' gestation and then 1, 2, 6, 10, and 14 days after normal delivery. Cardiac output was measured by Doppler and cross-sectional echocardiography at the aortic valve. In 30 controls who received an average of 280 mL intravenous fluid during labor, the mean cardiac output remained elevated (7.15 L/minute) for 24 hours after delivery and then fell to 5.39 L/minute at 10 days as a result of decreases in both heart rate and stroke volume. Blood pressure fell during the first 2 days after delivery and thereafter increased to values not significantly different from those recorded at the end of pregnancy. In ten women who experienced postpartum hemorrhage, stroke volume decreased and heart rate increased, relative to the control group, during the first 48 hours after delivery. Blood pressure and cardiac output, however, were not significantly different from values in the control group.

We investigated the role of nitric oxide (NO) in the vascular resistance changes of normotensive and preeclamptic pregnancy. Forearm blood flow (FBF) responses to brachial artery infusion of N G-monomethyl-l-arginine (l-NMMA), an NO synthase inhibitor, and angiotensin II (ANG II), an NO-independent vasoconstrictor, were determined by plethysmography in 20 nonpregnant women, 20 normotensive primigravidae, and 15 primigravidae with untreated preeclampsia. In pregnant subjects, FBF was reduced to nonpregnancy levels by infusion of norepinephrine (NE), which was then coinfused with ANG II (2, 4, and 8 ng/min) and l-NMMA (200, 400, and 800 μg/min) each for 5 min. In separate studies, responses to NE (20, 50, and 100 ng/min) were determined in 8 nonpregnant women, with FBF elevated to pregnancy levels by concomitant infusion of glyceryl trinitrate, and 10 pregnant women. Vasoconstrictor responses tol-NMMA were increased in pregnant compared with nonpregnant subjects [mean ± SE summary measure (in arbitrary units): 60 ± 7 vs. 89 ± 8, respectively; P < 0.01], whereas responses to ANG II were blunted (125 ± 11 vs. 79 ± 7, respectively; P < 0.001). Compared with normotensive pregnant subjects, preeclamptic subjects had an enhanced response to ANG II (79 ± 7 vs. 103 ± 8, respectively; P < 0.05) but no difference in response to l-NMMA (89 ± 8 vs. 73 ± 10, respectively; P = 0.30). Responses to NE were similar in pregnant and nonpregnant subjects (110 ± 20 vs. 95 ± 33, respectively; P = 0.66). During the third trimester of pregnancy, forearm constrictor responses tol-NMMA are increased. The responses to NE are unchanged, whereas responses to ANG II are blunted. Increased NO activity contributes to the fall in peripheral resistance. In preeclampsia, forearm constrictor responses to ANG II but notl-NMMA are increased compared with those in normal pregnancy. Changes in vascular NO activity are unlikely to account for the increased vascular tone in this condition.

We sought to determine whether the enhanced forearm vascular activity of nitric oxide during pregnancy and preeclampsia is associated with altered smooth muscle sensitivity to nitric oxide or with stimulated nitric oxide release.Forearm blood flow responses to brachial artery infusion of glyceryl trinitrate (a nitric oxide donor), serotonin (an endothelium-dependent nitric oxide-mediated agonist), and ritodrine (a beta-adrenergic receptor agonist) were studied in 10 nonpregnant women, 12 pregnant women, and 7 women with preeclampsia by means of strain-gauge plethysmography. Responses to each drug (maximum dilator response and the sum of the percentage of dilator responses to each drug) were compared by analysis of variance.Compared with nonpregnant women, pregnant subjects showed reduced responses to serotonin (summary response, 117 +/- 19 vs 221 +/- 30; P.05). Responses to serotonin were reduced in the group with preeclampsia compared with those in the nonpregnant group (summary response, 71 +/- 28; P.05) but did not differ from the responses in pregnant women. There were no differences between responses to glyceryl trinitrate and responses to ritodrine in any of the groups.Vascular smooth muscle sensitivity to nitric oxide is not altered in normal pregnancy or preeclampsia, but dilator responses to serotonin appear blunted. Alterations in serotonin receptor coupling to nitric oxide synthase, or a limitation of availability of the substrate for nitric oxide synthase (L-arginine) during pregnancy, could account for the reduction in stimulated nitric oxide release.