Neil Athayde

Vitamin D Supplementation and the Effects on Glucose Metabolism During Pregnancy: A Randomized Controlled Trial

OBJECTIVE Vitamin D deficiency in pregnancy is associated with an increased risk of gestational diabetes mellitus (GDM) and neonatal vitamin D deficiency. We conducted a double-blind, randomized controlled trial of low-dose (LD) versus high-dose (HD) vitamin D supplementation to investigate the effects of vitamin D supplementation on glucose metabolism during pregnancy. RESEARCH DESIGN AND METHODS Women with plasma 25-hydroxyvitamin D (25OHD) levels <32 ng/mL before 20 weeks’ gestation were randomized to oral vitamin D3 at 5,000 IU daily (HD) (n = 89) or the recommended pregnancy dose of 400 IU daily (LD) (n = 90) until delivery. The primary end point was maternal glucose levels on oral glucose tolerance test (OGTT) at 26–28 weeks’ gestation. Secondary end points included neonatal 25OHD, obstetric and other neonatal outcomes, and maternal homeostasis model assessment of insulin resistance. Analysis was by intention to treat. RESULTS There was no difference in maternal glucose levels on OGTT. Twelve LD women (13%) developed GDM versus seven (8%) HD women (P = 0.25). Neonatal cord 25OHD was higher in HD offspring (46 ± 11 vs. 29 ± 12 ng/mL, P < 0.001), and deficiency was more common in LD offspring (24 vs. 10%, P = 0.06). Post hoc analysis in LD women showed an inverse relationship between pretreatment 25OHD and both fasting and 2-h blood glucose level on OGTT (both P < 0.001). Baseline 25OHD remained an independent predictor after multiple regression analysis. CONCLUSIONS HD vitamin D supplementation commencing at a mean of 14 weeks’ gestation does not improve glucose levels in pregnancy. However, in women with baseline levels <32 ng/mL, 5,000 IU per day was well tolerated and highly effective at preventing neonatal vitamin D deficiency.

Association of umbilical placental Vascular disease with fetal acute inflammatory cytokine responses

Objective: We examined the hypothesis tha fetal proinflammatory cytokine release is a feature of placental vascular disease causing fetal compromise. We measured the concentrations of fetal proinflammaory cytokines interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and interleukin-8 (IL-8) in the presence of vascular disease in the umbilical placental villous circulation. Vascular disease was identified by high-resistance umbilical artery Doppler flow velocity waveform studies. Methods: We measured levels of the inflammatory cytokines IL-6 and TNF-α and the chemokine IL-8 in fetal blood. Blood was collected from the umbilical vein at delivery, and serumwas stored at -70C until assayed using chemiluminescent and enzyme-linked immunosorbent assay methods. We studied 36 normal pregnancies delivered by elective cesarean at term and 50 pregnancies with a high-resistance umbilical artery Doppler flow velocity waveform pattern indicative of feal placental vascular disease delivered by elective cesarean because of potential fetal compromise. Results: In the presence of umbilical placental vascular disease there were significantly higher levels of IL-6 (median 5.3 pg/mL, P < .05) and IL-8 (median 26.5 pg/mL, P < .01) compared with normal pregnanices (median value of IL-6 and IL-8 were below assay threshold). There was no difference for TNF-α,with the median results undetectable in both groups. Conclusion: We found higher concentrations of IL-6 and IL-8 in the fetal circulation in the presence of umbilical placental vascular disease.

Prospective ranking of the sonographic markers for aneuploidy: Data of 2143 prenatal cytogenetic diagnoses referred for abnormalities on ultrasound

Objective: To design a scheme to rank sonographic anomalies as indicators of aneuploidy and record the distribution of data from 2143 prenatal amniotic fluid/chorionic villous sample diagnoses referred for karyotyping because of fetal anomalies detected with ultrasound.

A new ultrasound technique to measure the isovolumetric contraction time as an index of cardiac contractility: fetal lamb validation.

Objective: We developed a noninvasive Doppler technique for measuring fetal cardiac isovolumetric contraction time (ICT). The purpose of this study was to determine how well our method real cardiac performance using fetal lamb as an instrumented model. Methods: The true ICT was measured by simultaneous recording of the pressure waves of the left ventricle and ascending aorta. The maximum first derivative of the left ventricular pressure wave (Max dp/dt) was calculated. The Doppler ICT was measured in the apporpriately filtered Doppler cardiac signals. Positive and negative inotropic agents were administered to change the cardiac contractility. Results: There was an inverse relationship between the Doppler ICT and the Max dp/dt. Excellent linear correlation was found an absolute value and changes from control value between the true ICT and the Doppler ICT (r = 0.959, r = 0.62). Conclusion: The Doppler ICT measurement provides useful information about changes in ventricular performance.

Fetuses Delivered Following Preterm Prelabor Rupture of the Membranes are Capable of Stimulating a Proinflammatory Response in Endothelial Cells

Objective: Preterm premature rupture of the membranes (PROM) has been attributed to ascending infection and a choriodecidual inflammatory response (ie, on the maternal side). However, on the fetal side those most at risk of morbidity have a systemic proinflammatory cytokine response. We have recently defined a similar proinflammatory response in pregnancies complicated by vascular disease on the fetal side of the placenta. A factor(s) present in fetal plasma from these pregnancies can stimulate human umbilical vein endothelial cells (HUVECs) to express mRNA for the proinflammatory cytokines, interleukin (IL)-6 and IL-8. The hypothesis of this study was that a similar factor(s) was present in preterm PROM. Methods: A standard culture of HUVECs was incubated with fetal plasma, obtained immediately following delivery, from normal pregnancies delivering vaginally at term (n = 16) and pregnancies delivering following preterm PROM (n = 19). Expression of mRNA for IL-6 and IL-8 was assessed by reverse transcription polymerase chain reaction (RT-PCR) and standardized to GAPDH mRNA expression. Results: Endothelial cell expression of IL-6 mRNA (median [25-75th centile] 0.295 [0.252-0.507] vs term vaginal delivery 0.208 [0.151-0.307]; P = .009) was enhanced in response to the fetal plasma from PROM cases compared to pregnancies delivering vaginally at term. In contrast, mRNA expression of IL-8 (median [25-75th centile] preterm PROM 0.41 [0.21-0.78] vs term vaginal delivery 0.49 [0.16-0.68]; P = .46) was not different in the two groups. Conclusions: We have demonstrated that in fetuses delivered following preterm PROM there is a factor(s) capable of stimulating a local endothelial cell proinflammatory cytokine (IL-6) response. This factor(s) that we have demonstrated may be responsible for the increased cytokine production seen in fetuses with the fetal inflammatory response syndrome.

Maternal Plasma From Pregnant Women With Umbilical Placental Vascular Disease Does Not Affect Endothelial Cell mRNA Expression of Nitric Oxide Synthase

Objective: In placental vascular disease identified by umbilical artery Doppler study we have shown the existence of a factor in fetal plasma that causes activation of endothelial cells in culture with expression of cell adhesion molecules and nitric oxide synthase, apoptosis, and proinflammatory cytokine production. The present work was carried out to investigate a maternal origin for this factor active in the fetal circulation. Methods: We collected maternal plasma from pregnant women with Doppler-defined umbilical placental vascular disease and examined its effect on endothelial cells in culture. Aliquots from a common culture of human umbilical vein endothelial cells (HUVEC) were incubated with maternal plasma from women with normal pregnancy (n = 23), umbilical placental vascular disease defined by abnormal umbilical artery Doppler (n = 30, with or without preeclampsia), and preeclampsia with normal umbilical artery Doppler (n = 14). The expression of mRNA for inducible and endothelial constitutive nitric oxide synthase (iNOS and ecNOS, respectively) was assessed by reverse transcriptase polymerase chain reaction. Results: There was no significant increase in either the iNOS or the ecNOS mRNA expression by HUVEC cultured with maternal plasma from pregnancies with umbilical placental vascular disease compared with normal pregnancy (iNOS 1.49 ± 0.35 versus 1.38 ± 0.25; ecNOS 1.51 ± 0.35 versus 1.25 ± 0.27; P > .05). In the placental vascular disease group the results were similar for the presence or absence of maternal preeclampsia. In the samples from women with preeclampsia with normal umbilical Doppler, both iNOS and ecNOS mRNA expression (iNOS 1.42 ± 0.53; ecNOS 1.46 ± 0.39; P > .05) did not differ from normal. Conclusion: Maternal plasma from pregnancies with umbilical placental vascular disease did not affect endothelial cell expression of nitric oxide synthase. This finding does not support a maternal origin for the factor demonstrated in fetal plasma. These results suggest separate pathogenic pathways for the endothelial cell activation seen in preeclampsia and fetal growth restriction associated with abnormal umbilical artery Doppler flow velocity waveforms. These findings are also consistent with the concept that the vascular pathology in the fetal placenta may be primary and that the uteroplacental circulation is reduced in response rather than acts as a constraint.

Congenital paraplegia. A complication of multifetal pregnancy reduction

A 31 year old woman was admitted to a tertiary level perinatal centre in preterm labour at 26 weeks of gestation. This was an in vitro fertilisation pregnancy following an eight-year history of infertility. At implantation there were four viable conceptuses. At ten weeks of gestation there had been an attempt at multifetal pregnancy reduction, with the aim of reducing the quadruplet pregnancy to a twin pregnancy. Both the in vitro fertilisation and selective reduction procedures had been performed overseas, and it was not possible to obtain further details of these. Her first local antenatal visit was at 14–15 weeks of gestation. Ultrasonography at that time recorded the presence of three viable fetuses and one non-viable fetus who appeared anencephalic. Ultrasound examinations at 22 and 25 weeks of gestation showed that one of the three viable fetuses had oedema and talipes of both feet. It is presumed the fourth fetus with anencephaly had been resorbed. Following the onset of spontaneous preterm labour at 26 weeks the mother was given antenatal steroids. At 28 weeks she had an emergency caesarean section for unsuppressed labour. Three live born infants were delivered, two girls and one boy. Their birthweights were appropriate for gestational age. Triplet one was found to have fixed flexion contractures of her hips, knees and ankles (Fig. 1). Her hips were widely abducted and her ankles were in the equinovarus position. There was no spontaneous movement of her lower limbs and no response to noxious stimuli. Her lower limbs were wasted and arreflexic; however, there was no abnormality of her upper limbs. Her buttocks were wasted and a sacral ‘dimple’ was evident, the anus was patulous, and there was constant dribbling of urine. A sensory level was approximated at T10. She was not dysmorphic, and her head circumference was on the 90th centile. The other two infants were normal. Her neonatal course was complicated by respiratory distress syndrome requiring exogenous surfactant, and she was intubated for two days. She had apnoea of prematurity and was on continuous positive airways pressure until day 35. A patent ductus arteriosus was closed with indomethacin and she was treated with phototherapy for hyperbilirubinaemia. Ultrasound examination of her head and kidneys was normal. Ultrasound examinations of her spine showed a 2 mm 3 mm 5 mm cystic lesion in the cord at thoracic vertebrae T10–11 level. There was no bony abnormality of the vertebrae and sacrum, thus excluding spina bifida and sacral agenesis. A skeletal survey showed a scoliosis, there being eleven ribs on the right with fusion of ribs five and six. There were no other bony abnormalities. Magnetic resonance imaging of the spine revealed a thin dysplastic cord caudally from T5–7. Cystic areas were confirmed at T10–11 and lumbar vertebrae L2–L3. The spinal cord was tethered at L5–S1. Her placental pathology showed a pale underperfused placental plate with focal amnionitis. The placenta was trichorionic and triamniotic. Serology for toxoplasmosis, rubella and cytomegalovirus and herpes simplex was negative.

Impact of the IADPSG criteria for gestational diabetes, and of obesity, on pregnancy outcomes

The adoption of the International Association of Diabetes Study Groups (IADPSG) criteria for gestational diabetes mellitus (GDM) in Australia has been controversial. Obesity in pregnancy is also a growing concern.

Erratum. Vitamin D Supplementation and the Effects on Glucose Metabolism During Pregnancy: A Randomized Controlled Trial. Diabetes Care 2014;37:1837–1844

In the print version of the article cited above, there are several minor errors in Tables 1 and 2. These errors do not affect the results or …