David Mundy

A Randomized Trial of Docosahexaenoic Acid Supplementation During the Third Trimester of Pregnancy

OBJECTIVE To hypothesize that higher intake of docosahexaenoic acid, an n-3 long chain polyunsaturated fatty acid, would increase duration of gestation and birth weight in US women. METHODS This was a randomized, double-blind, controlled, clinical trial. Subjects were enrolled in an ambulatory clinic where they received prenatal care. This was a population-based sample. Most subjects received government assistance for medical care and most were black (73%). Subjects were enrolled between the 24th and 28th week of pregnancy and consumed docosahexaenoic acid (33 or 133 mg) from eggs until parturition. Gestational age and birth weight were the main study outcomes. Infant length and head circumference, preterm birth, and low birth weight were secondary outcomes. RESULTS Eighty-three percent of subjects completed the study (291 of 350 enrolled). No subject was discontinued for an adverse event. After controlling for important predefined risk factors and confounding variables, gestation increased by 6.0 ± 2.3 days (P = .009) in the higher docosahexaenoic acid group. Birth weight, length, and head circumference increased, but did not reach statistical significance (P = .06–.18), although the increases could be clinically important indications of enhanced intrauterine growth. No safety concerns were raised by the study. CONCLUSION Duration of gestation increased significantly when docosahexaenoic acid intake was increased during the last trimester of pregnancy. The increase in gestation was similar to that reported for interventions with much larger amounts of n-3 long chain polyunsaturated fatty acids

The DIAMOND (DHA Intake And Measurement Of Neural Development) Study: a double-masked, randomized controlled clinical trial of the maturation of infant visual acuity as a function of the dietary level of docosahexaenoic acid

BACKGROUND The range of human milk docosahexaenoic acid (DHA) concentrations worldwide is much broader than the range explored in randomized clinical trials to date. OBJECTIVE The primary objective was to determine the effect of 4 amounts of DHA supplementation on the visual acuity of formula-fed infants at 12 mo of age. Secondary objectives were to evaluate visual acuity maturation, red blood cell fatty acids, tolerance, anthropometric measures, and adverse events. DESIGN This double-masked, randomized trial was conducted at 2 sites (Dallas and Kansas City). Three hundred forty-three healthy, term, formula-fed infants were enrolled at 1-9 d of age and were randomly assigned to be fed 1 of the following 4 infant formulas containing equivalent nutrient amounts, except for long-chain polyunsaturated fatty acids: control (0% DHA), 0.32% DHA, 0.64% DHA, or 0.96% DHA; DHA-supplemented formulas also provided 0.64% arachidonic acid. Visual acuity was measured by visual evoked potentials in 244 infants who completed the 12-mo primary outcome examination. RESULTS Infants fed control formula had significantly poorer visual evoked potential visual acuity at 12 mo of age than did infants who received any of the DHA-supplemented formulas (P < 0.001). There were no significant differences in visual evoked potential visual acuity between the 3 amounts of DHA supplementation for either site at any age tested. CONCLUSIONS DHA supplementation of infant formula at 0.32% of total fatty acids improves visual acuity. Higher amounts of DHA supplementation were not associated with additional improvement of visual acuity. This trial was registered at clinicaltrials.gov as NCT00753818.

DHA supplementation and pregnancy outcomes

BACKGROUND Observational studies associate higher intakes of n-3 (omega-3) long-chain polyunsaturated fatty acids (LCPUFAs) during pregnancy with higher gestation duration and birth size. The results of randomized supplementation trials using various n-3 LCPUFA sources and amounts are mixed. OBJECTIVE We tested the hypothesis that 600 mg/d of the n-3 LCPUFA docosahexaenoic acid (DHA) can increase maternal and newborn DHA status, gestation duration, birth weight, and length. Safety was assessed. DESIGN This phase III, double-blind, randomized controlled trial was conducted between January 2006 and October 2011. Women (n = 350) consumed capsules (placebo, DHA) from <20 wk of gestation to birth. Blood (enrollment, birth, and cord) was analyzed for red blood cell (RBC) phospholipid DHA. The statistical analysis was intent-to-treat. RESULTS Most of the capsules were consumed (76% placebo; 78% DHA); the mean DHA intake for the treated group was 469 mg/d. In comparison with placebo, DHA supplementation resulted in higher maternal and cord RBC-phospholipid-DHA (2.6%; P < 0.001), longer gestation duration (2.9 d; P = 0.041), and greater birth weight (172 g; P = 0.004), length (0.7 cm; P = 0.022), and head circumference (0.5 cm; P = 0.012). In addition, the DHA group had fewer infants born at <34 wk of gestation (P = 0.025) and shorter hospital stays for infants born preterm (40.8 compared with 8.9 d; P = 0.026) than did the placebo group. No safety concerns were identified. CONCLUSIONS A supplement of 600 mg DHA/d in the last half of gestation resulted in overall greater gestation duration and infant size. A reduction in early preterm and very-low birth weight could be important clinical and public health outcomes of DHA supplementation. This trial was registered at clinicaltrials.gov as NCT00266825.

Evidence-based approach to umbilical artery Doppler fetal surveillance in high-risk pregnancies: an update.

Antepartum fetal surveillance with Doppler ultrasound of umbilical artery has shown significant diagnostic efficacy in identifying fetal compromise in pregnancies complicated with fetal growth restriction and preeclampsia. Moreover, randomized clinical trials and their meta-analyses have shown its effectiveness in decreasing perinatal mortality (level I evidence). This is the only antepartum fetal test that has shown this level of effectiveness. There is no evidence that routine Doppler in low-risk pregnancies improves the outcome. It is recommended that umbilical artery Doppler should be the standard of practice in managing high-risk pregnancies complicated with fetal growth restriction and preeclampsia (level A recommendation). However, its use should be integrated with other current fetal monitoring tests (levels B and C recommendation). The overall management should also be guided by additional clinical considerations such as the gestational age, fetal and maternal status, and obstetrical conditions.

Umbilical artery Doppler in the assessment of fetal growth restriction.

Antepartum fetal surveillance with Doppler ultrasound of umbilical artery has shown significant diagnostic efficacy in identifying fetal compromise in pregnancies complicated with fetal growth restriction (FGR). Its effectiveness in decreasing perinatal mortality has been shown by randomized clinical trials (Level I evidence). This test is the only antepartum fetal test that has shown this level of effectiveness and should be the standard of practice in managing FGR (Level A recommendation). The overall management considerations should encompass other standard fetal monitoring tests (Level B and C recommendations).

Down-regulation of placental neuropilin-1 in fetal growth restriction.

BACKGROUND Fetal growth restriction (FGR) is associated with adverse outcomes extending from fetal to adult life, and thus, constitutes a major health care challenge. Fetuses with progressive growth restriction show increasing impedance in the umbilical artery flow, which may become absent during end-diastole. Absent end-diastolic flow (AEDF) is associated with adverse perinatal outcomes including stillbirths and perinatal asphyxia. Placentas from such pregnancies demonstrate deficient fetoplacental vascular branching. Current evidence, moreover, indicates an antiangiogenic state in maternal circulation in several pregnancy complications including preeclampsia, small-for-gestational-age births, fetal death, and preterm labor. The angiogenic mediators in maternal circulation are predominantly of placental origin. Information, however, on the role of specific proangiogenic and antiangiogenic mechanisms operating at the placental level remains limited. Elucidation of these placenta-specific angiogenic mechanisms will not only extend our understanding of the causal pathway for restricted fetal growth but may also lead to the development of biomarkers that may allow early recognition of FGR. OBJECTIVE We sought to test the hypothesis that fetoplacental angiogenic gene expression is altered in pregnancies complicated with FGR and umbilical artery Doppler AEDF. STUDY DESIGN Placental samples were collected from FGR pregnancies complicated with umbilical artery Doppler AEDF (study group, n = 7), and from uncomplicated pregnancies (control group, n = 7), all delivered by cesarean during the last trimester of pregnancy. Angiogenic oligonucleotide microarray analysis was performed and was corroborated by quantitative real-time polymerase chain reaction, Western blot analysis, and immunohistochemistry. The Student t test with Bonferroni correction was used with P < .05 considered statistically significant. Independent groups t test was used to analyze the immunostain intensity scores with a P < .05 considered statistically significant. RESULTS Our microarray results showed that among several differentially expressed angiogenic genes in the growth-restricted group, only the down-regulation of neuropilin (NRP)-1 was most significant (P < .0007). Quantitative real-time polymerase chain reaction confirmed a significantly lower NRP-1 gene expression in the FGR group than in the control group (mean ± SD (ˆ)cycle threshold: 0.624 ± 0.55 and 1.325 ± 0.84, respectively, P = .04). Western blot validated significantly lower NRP-1 protein expression in the FGR group than in the control group (mean ± SD NRP-1/β-actin ratio: 0.13 ± 0.04 and 0.34 ± 0.05, respectively, P < .001). Finally, immunohistochemistry of placental villi further corroborated a significantly decreased expression of NRP-1 in the FGR group (P = .006). CONCLUSION The study demonstrated significant down-regulation of placental NRP-1 expression in FGR pregnancies complicated with AEDF in umbilical artery. As NRP-1 is known to promote sprouting angiogenesis, its down-regulation may be involved in the deficient vascular branching observed in FGR placentas suggesting the presence of an antiangiogenic state. Further studies may elucidate such a causal role and may lead to the development of novel diagnostic and therapeutic tools.

4D Fetal Echocardiography

Congenital heart defects (CHD) are the most frequent malformation in the human fetus and are the leading cause of mortality due to malformations in the first year of life. Despite its clinical importance screening performed by ultrasonographic examination during the second trimester of pregnancy has shown disappointingly low detection rates mainly due to the difficulties in obtaining an adequate examination of the fetal heart. Four-dimensional (4D) ultrasound of the fetal heart has been recently suggested as a tool to improve the detection rate of CHD by decreasing the dependency on operator skills required in two-dimensional ultrasound scans but up to now no practical manuals are available in describing its application in clinical practice for the study of fetal heart. The objective of this Ebook is to explain the role of 4D during second trimester examination and in fetuses with CHD. The technique of obtaining 4D volume of the fetal heart, how to navigate in the volume to obtain diagnostic planes and how to use semiautomatic and automatic software of analysis are described. We believe that after reading this book the standard fetal cardiac anatomy survey can be performed in the second trimester fetus by 4D in both normal and abnormal hearts. This approach may reduce the operator dependency in diagnosis CHD. This Ebook should prove to be a valuable resource for obstetricians, sonographers and pediatric cardiologists.

Racial/ethnic disparities in magnesium sulphate neuroprotection: A subgroup analysis of a multicenter randomized controlled trial

Abstract Objective: Despite known racial disparities in obstetrics, as well as differences in magnesium pharmacodynamics according to race, the effect of race/ethnicity in magnesium sulfate (MgSO4) use during pregnancy has not been studied. Whether some mothers are at increased risk of side effects, or infants at decreased neuroprotective effects is unknown. We analyze the effect of race/ethnicity in maternal/infant outcomes after MgSO4 neuroprotection. Study design: Subgroup analysis of a multicenter clinical trial (BEAM trial) where pregnant women at risk of preterm birth were randomized to either MgSO4 or placebo. For this study, nonanomalous singleton pregnancies were studied. The effect of race in maternal/neonatal outcomes after MgSO4 was analyzed with Breslow–Day and multifactorial ANOVA. Logistic regression was used to calculate odds ratios (OR) of complications according to race. Results: 922 MgSO4 and 972 placebo cases were included (45.0% African-American, 36.2% Caucasian, 17.8% Hispanics, and 1.0% Asians). Interaction analysis showed a significant effect of race/ethnicity (p = .043). Hispanics presented the highest frequency (88.3%, p < .001), as well as the highest odds of MgSO4 side effects [OR(95%CI) = 6.6 (1.3–33.8)]. Conclusion: Hispanics present increased risk of magnesium toxicity compared to other racial/ethnic groups. Whether specific racial/ethnic groups require closer surveillance for early signs of magnesium toxicity needs to be further explored.

Fetoplacental regional variations in the expression of angiopoietin-1, angiopoietin-2, and Tie2 in normal-term and near-term pregnancies.

Abstract Background: Angiopoietin-1 (Ang1), angiopoietin-2 (Ang2), and the receptor tyrosine kinase with immunoglobulin-like and EGF-like domains 2 (Tie2) are known to be involved in fetoplacental angiogenesis adequacy, which is a primary determinant of fetal growth. Regional variations in Ang1, Ang2, and Tie2 remain unknown, although fetoplacental vascularity and gene expressions differ between the placental center and the periphery. Objective: The aim of this study was to test the hypothesis that there are regional variations in the expression of these angiopoietins in human placentas from uncomplicated term and near term pregnancies. Study design: In this prospective study, central and peripheral samples were collected from fresh placentas from normal-term and near-term pregnancies delivered by Cesarean section (n = 7, 36–41 week gestation) prior to the onset of labor. Regional differences in Ang1, Ang2, and Tie2 protein expressions were measured by Western blot and densitometric analyses with b-actin normalization, and their fetoplacental regional localization assessed by immunohistochemistry. The Ang1 and Ang2 ratios at central and peripheral sites were determined. Statistical analysis was performed using Student’s t-test. Results: Ang1 protein expression was higher in the placental periphery than in the center (2.48 ± 0.42 versus 1.74 ± 0.27, p = 0.01). In contrast, Ang2 protein expression was greater in the placental center than in the periphery (10.10 ± 1.82 versus 7.15 ± 1.12, respectively, p = 0.03). The Ang1–Ang2 ratio reflected these differential expressions. Tie2 protein expression was higher in the placental periphery than in the center (0.21 ± 0.02 versus 0.16 ± 0.02, p = 0.003). The immunoreactivity of Ang1 and Tie2 was stronger in the periphery than in the center, and that of Ang2 was stronger in the center than in the periphery. Conclusions: Ang1, Ang2, and Tie2 are differentially expressed in placental center and periphery. Ang1/Ang2 ratio reflects this regional variation in the angiogenic balance that has implications for fetoplacental villous angiogenesis. The results also demonstrate the importance of considering the location of placental sampling sites for any future investigations of fetoplacental villous angiogenesis.

Overview of the Normal Development of the Human Embryo and Fetus

Human antenatal development is a very complex process that still is not fully understood. Continuous technological advancement provides new methods to achieve a better understanding of this process. Gestational development starts with the fertilization of the oocyte by the spermatozoon and ends at the moment of delivery. During this process, a myriad of cellular events occur, including cellular division, migration, differentiation, rearrangement, transportation, growth, and apoptosis. This process is divided in two important periods: The first period is called embryonic development, which starts with fertilization and ends on day 56. This period is characterized by formation of organs and systems. The second period is called fetal development, which begins on day 57 of fetal development and concludes at birth. This period is characterized by growth and differentiation. In this chapter, we review the most important events during the embryonic and fetal development periods, and emphasize important aspects of the formation of specific organs and systems.