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Maternal Omega-3 Nutrition, Placental Transfer and Fetal Brain Development in Gestational Diabetes and Preeclampsia.
Devarshi, PP, Grant, RW, Ikonte, CJ, Hazels Mitmesser, S
Nutrients. 2019;(5)
Abstract
Omega-3 fatty acids, particularly docosahexaenoic fatty acid (DHA), are widely recognized to impact fetal and infant neurodevelopment. The impact of DHA on brain development, and its inefficient synthesis from the essential alpha-linolenic acid (ALA), has led to recommended DHA intakes of 250-375 mg eicosapentaenoic acid + DHA/day for pregnant and lactating women by the Dietary Guidelines for Americans. Despite these recommendations, the intake of omega-3s in women of child-bearing age in the US remains very low. The low maternal status of DHA prior to pregnancy could impair fetal neurodevelopment. This review focuses on maternal omega-3 status in conditions of gestational diabetes mellitus (GDM) and preeclampsia, and the subsequent impact on placental transfer and cord blood concentration of omega-3s. Both GDM and preeclampsia are associated with altered maternal omega-3 status, altered placental omega-3 metabolism, reduced cord blood omega-3 levels and have an impact on neurodevelopment in the infant and on brain health later in life. These findings indicate lower DHA exposure of the developing baby may be driven by lower placental transfer in both conditions. Thus, determining approaches which facilitate increased delivery of DHA during pregnancy and early development might positively impact brain development in infants born to mothers with these diseases.
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Association of vitamin D level and vitamin D deficiency with risk of preeclampsia: A systematic review and updated meta-analysis.
Akbari, S, Khodadadi, B, Ahmadi, SAY, Abbaszadeh, S, Shahsavar, F
Taiwanese journal of obstetrics & gynecology. 2018;(2):241-247
Abstract
OBJECTIVES Because of the immune modulatory effects of vitamin D3 in preeclampsia, we intend to have a systematic review and meta-analysis on association of both 25-hydroxy vitamin D (25-OHD) level (parametric approach) and 25-OHD deficiency (non-parametric approach) with preeclampsia. As well, for the parametric part, we used receiver operating characteristic (ROC) curve model. MATERIALS AND METHODS We used Web of Science, PubMed and Science Direct data bases through searching in titles. Google Scholar search engine was used in order to find missing papers. Finally 23 studies were imported. Both random and fixed models were reported. RESULTS Based on the forest plot, lower levels of 25-OHD were significantly associated with risk of preeclampsia (fixed and random P < 0.001). Based on the forest plot, vitamin D deficiency (25-OHD < 20 ng/ml) was significantly associated with risk of preeclampsia (fixed P < 0.0001; random P = 0.0029; fixed OR = 1.33; random OR = 1.54). Based on ROC curve results, we found 2 cutoffs of 10.60 and 20.05 ng/ml. CONCLUSION Women with vitamin D deficiency at cutoff 20 ng/ml are more at risk of preeclampsia. This association can be specific up to 90% at 10.60 ng/ml cutoff. Treatment of vitamin D deficiency is necessary before pregnancy.
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Genetic and non-genetic risk factors for pre-eclampsia: umbrella review of systematic reviews and meta-analyses of observational studies.
Giannakou, K, Evangelou, E, Papatheodorou, SI
Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology. 2018;(6):720-730
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OBJECTIVE To summarize evidence from the literature on genetic and non-genetic risk factors associated with pre-eclampsia (PE), assess the presence of statistical bias in the studies and identify risk factors for which there is robust evidence supporting their association with PE. METHODS PubMed and ISI Web of Science were searched from inception to October 2016, to identify systematic reviews and meta-analyses of observational studies examining associations between genetic or non-genetic risk factors and PE. For each meta-analysis, the summary-effect size was estimated using random-effects and fixed-effects models, along with 95% CIs and the 95% prediction interval. Between-study heterogeneity was expressed using the I2 statistic, and evidence of small-study effects (large studies had significantly more conservative results than smaller studies) and evidence of excess significance bias (too many studies with statistically significant results) were estimated. RESULTS Fifty-eight eligible meta-analyses were identified, which included 1466 primary studies and provided data on 130 comparisons of risk factors associated with PE, covering a wide range of comorbid diseases, genetic factors, exposure to environmental agents and biomarkers. Sixty-five (50%) associations had nominally statistically significant findings at P < 0.05, while 16 (12%) were significant at P < 10-6 . Sixty-five (50%) associations had large or very large heterogeneity. Evidence for small-study effects and excess significance bias was found in 10 (8%) and 26 (20%) associations, respectively. The only non-genetic risk factor with convincing evidence for an association with PE was oocyte donation vs spontaneous conception, which had a summary odds ratio of 4.33 (95% CI, 3.11-6.03), was supported by 2712 cases with small heterogeneity (I2 = 26%) and 95% prediction intervals excluding the null value, and without hints of small-study effects (P for Egger's test > 0.10) or excess of significance (P > 0.05). Of the statistically significant (P < 0.05) genetic risk factors for PE, only PAI-1 4G/5G (recessive model) polymorphism was supported by strong evidence for a contribution to the pathogenesis of PE. Eleven factors (serum iron level, pregnancy-associated plasma protein-A, chronic kidney disease, polycystic ovary syndrome, mental stress, bacterial and viral infections, cigarette smoking, oocyte donation vs assisted reproductive technology, obesity vs normal weight, severe obesity vs normal weight and primiparity) presented highly suggestive evidence for an association with PE. CONCLUSIONS A large proportion of meta-analyses of genetic and non-genetic risk factors for PE have caveats that threaten their validity. Oocyte donation vs spontaneous conception and PAI-1 4G/5G polymorphism (recessive model) showed the strongest consistent evidence for an association with risk for PE. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.
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Epidural therapy for the treatment of severe pre-eclampsia in non labouring women.
Ray, A, Ray, S
The Cochrane database of systematic reviews. 2017;(11):CD009540
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BACKGROUND Pre-eclampsia is a pregnancy-specific multi-organ disorder, which is characterised by hypertension and multisystem organ involvement and which has significant maternal and fetal morbidity and mortality. Failure of the placental vascular remodelling and reduced uteroplacental flow form the etiopathological basis of pre-eclampsia. There are several established therapies for pre-eclampsia including antihypertensives and anticonvulsants. Most of these therapies aim at controlling the blood pressure or preventing complications of elevated blood pressure, or both. Epidural therapy aims at blocking the vasomotor tone of the arteries, thereby increasing uteroplacental blood flow. This review was aimed at evaluating the available evidence about the possible benefits and risks of epidural therapy in the management of severe pre-eclampsia, to define the current evidence level of this therapy, and to determine what (if any) further evidence is required. OBJECTIVES To assess the effectiveness, safety and cost of the extended use of epidural therapy for treating severe pre-eclampsia in non-labouring women. This review aims to compare the use of extended epidural therapy with other methods, which include intravenous magnesium sulphate, anticonvulsants other than magnesium sulphate, with or without use of the antihypertensive drugs and adjuncts in the treatment of severe pre-eclampsia.This review only considered the use of epidural anaesthesia in the management of severe pre-eclampsia in the antepartum period and not as pain relief in labour. SEARCH METHODS We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) (13 July 2017) and reference lists of retrieved studies. SELECTION CRITERIA Randomised controlled trials (RCTs) or quasi-RCTs comparing epidural therapy versus traditional therapy for pre-eclampsia in the form of antihypertensives, anticonvulsants, magnesium sulphate, low-dose dopamine, corticosteroids or a combination of these, were eligible for inclusion. Trials using a cluster design, and studies published in abstract form only are also eligible for inclusion in this review. Cross-over trials were not eligible for inclusion in this review. DATA COLLECTION AND ANALYSIS The two review authors independently assessed trials for inclusion and trial quality. There were no relevant data available for extraction. MAIN RESULTS We included one small study (involving 24 women). The study was a single-centre randomised trial conducted in Mexico. This study compared a control group who received antihypertensive therapy, anticonvulsant therapy, plasma expanders, corticosteroids and dypyridamole with an intervention group that received epidural block instead of the antihypertensives, as well as all the other four drugs. Lumbar epidural block was given using 0.25% bupivacaine, 10 mg bolus and 5 mg each hour on continuous epidural infusion for six hours. This study was at low risk of bias in three domains but was assessed to be high risk of bias in two domains due to lack of allocation concealment and blinding of women and staff, and unclear for random sequence generation and outcome assessor blinding.The included study did not report on any of this review's important outcomes. Meta-analysis was not possible.For the mother, these were: maternal death (death during pregnancy or up to 42 days after the end of the pregnancy, or death more than 42 days after the end of the pregnancy); development of eclampsia or recurrence of seizures; stroke; any serious morbidity: defined as at least one of stroke, kidney failure, liver failure, HELLP syndrome (haemolysis, elevated liver enzymes and low platelets), disseminated intravascular coagulation, pulmonary oedema.For the baby, these were: death: stillbirths (death in utero at or after 20 weeks' gestation), perinatal deaths (stillbirths plus deaths in the first week of life), death before discharge from the hospital, neonatal deaths (death within the first 28 days after birth), deaths after the first 28 days; preterm birth (defined as the birth before 37 completed weeks' gestation); and side effects of the intervention. Reported outcomesThe included study only reported on a single secondary outcome of interest to this review: the Apgar score of the baby at birth and after five minutes and there was no clear difference between the intervention and control groups.The included study also reported a reduction in maternal diastolic arterial pressure. However, the change in maternal mean arterial pressure and systolic arterial pressure, which were the other reported outcomes of this trial, were not significantly different between the two groups. AUTHORS' CONCLUSIONS Currently, there is insufficient evidence from randomised controlled trials to evaluate the effectiveness, safety or cost of using epidural therapy for treating severe pre-eclampsia in non-labouring women.High-quality randomised controlled trials are needed to evaluate the use of epidural agents as therapy for treatment of severe pre-eclampsia. The rationale for the use of epidural is well-founded. However there is insufficient evidence from randomised controlled trials to show that the effect of epidural translates into improved maternal and fetal outcomes. Thus, there is a need for larger, well-designed studies to come to an evidence-based conclusion as to whether the lowering of vasomotor tone by epidural therapy results in better maternal and fetal outcomes and for how long that could be maintained. Another important question that needs to be answered is how long should extended epidural be used to ensure any potential clinical benefits and what could be the associated side effects and costs. Interactions with other modalities of treatment and women's satisfaction could represent other avenues of research.
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Periconceptional folic acid fortification for the risk of gestational hypertension and pre-eclampsia: a meta-analysis of prospective studies.
Yang, X, Chen, H, Du, Y, Wang, S, Wang, Z
Maternal & child nutrition. 2016;(4):669-79
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Published literatures report controversial results about the association of folic acid-containing multivitamins with gestational hypertension and pre-eclampsia. A comprehensive search was performed to identify related prospective studies to assess the effect of folic acid fortification on gestational hypertension and pre-eclampsia. The Q test and I(2) statistic were used to examine between-study heterogeneity. Fixed or random effects models were selected based on study heterogeneity. A funnel plot and modified Egger linear regression test were used to estimate publication bias. Eleven studies conformed to the criteria. Pooled results indicated that folic acid fortification alone was not associated with the occurrence of gestational hypertension [relative risk (RR) = 1.03, 95% confidence interval (CI): 0.98-1.09, P = 0.267] and pre-eclampsia (RR = 0.99, 95% CI: 0.90-1.08, P = 0.738). However, supplementation of multivitamins containing folic acid could prevent gestational hypertension (RR = 0.57, 95% CI: 0.43-0.76, P < 0.001) and pre-eclampsia (RR = 0.64, 95% CI: 0.48-0.84, P = 0.001). The difference between folic acid fortification alone and multivitamins containing folic acid was significant. This meta-analysis suggests that periconceptional multivitamin supplementation with appropriate dose, not folic acid alone, is an appropriate recommendation for pregnant women. The effect should be further confirmed by conducting large-scale randomised controlled trials.
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Nitric oxide and reactive oxygen species in the pathogenesis of preeclampsia.
Matsubara, K, Higaki, T, Matsubara, Y, Nawa, A
International journal of molecular sciences. 2015;(3):4600-14
Abstract
Preeclampsia (PE) is characterized by disturbed extravillous trophoblast migration toward uterine spiral arteries leading to increased uteroplacental vascular resistance and by vascular dysfunction resulting in reduced systemic vasodilatory properties. Its pathogenesis is mediated by an altered bioavailability of nitric oxide (NO) and tissue damage caused by increased levels of reactive oxygen species (ROS). Furthermore, superoxide (O2-) rapidly inactivates NO and forms peroxynitrite (ONOO-). It is known that ONOO- accumulates in the placental tissues and injures the placental function in PE. In addition, ROS could stimulate platelet adhesion and aggregation leading to intravascular coagulopathy. ROS-induced coagulopathy causes placental infarction and impairs the uteroplacental blood flow in PE. The disorders could lead to the reduction of oxygen and nutrients required for normal fetal development resulting in fetal growth restriction. On the other hand, several antioxidants scavenge ROS and protect tissues against oxidative damage. Placental antioxidants including catalase, superoxide dismutase (SOD), and glutathione peroxidase (GPx) protect the vasculature from ROS and maintain the vascular function. However, placental ischemia in PE decreases the antioxidant activity resulting in further elevated oxidative stress, which leads to the appearance of the pathological conditions of PE including hypertension and proteinuria. Oxidative stress is defined as an imbalance between ROS and antioxidant activity. This review provides new insights about roles of oxidative stress in the pathophysiology of PE.
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Preeclampsia and diabetes.
Weissgerber, TL, Mudd, LM
Current diabetes reports. 2015;(3):9
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Preeclampsia is diagnosed in women presenting with new onset hypertension accompanied by proteinuria or other signs of severe organ dysfunction in the second half of pregnancy. Preeclampsia risk is increased 2- to 4-fold among women with type 1 or type 2 diabetes. The limited number of pregnant women with preexisting diabetes and the difficulties associated with diagnosing preeclampsia in women with proteinuria prior to pregnancy are significant barriers to research in this high-risk population. Gestational diabetes mellitus (GDM) also increases preeclampsia risk, although it is unclear whether these two conditions share a common pathophysiological pathway. Nondiabetic women who have had preeclampsia are more likely to develop type 2 diabetes later in life. Among women with type 1 diabetes, a history of preeclampsia is associated with an increased risk of retinopathy and nephropathy. More research examining the pathophysiology, treatment, and the long-term health implications of preeclampsia among women with preexisting and gestational diabetes is needed.
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Vitamin E supplementation in pregnancy.
Rumbold, A, Ota, E, Hori, H, Miyazaki, C, Crowther, CA
The Cochrane database of systematic reviews. 2015;(9):CD004069
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BACKGROUND Vitamin E supplementation may help reduce the risk of pregnancy complications involving oxidative stress, such as pre-eclampsia. There is a need to evaluate the efficacy and safety of vitamin E supplementation in pregnancy. OBJECTIVES To assess the effects of vitamin E supplementation, alone or in combination with other separate supplements, on pregnancy outcomes, adverse events, side effects and use of health services. SEARCH METHODS We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 March 2015) and reference lists of retrieved studies. SELECTION CRITERIA All randomised or quasi-randomised controlled trials evaluating vitamin E supplementation in pregnant women. We excluded interventions using a multivitamin supplement that contained vitamin E. DATA COLLECTION AND ANALYSIS Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. MAIN RESULTS Twenty-one trials, involving 22,129 women were eligible for this review. Four trials did not contribute data. All of the remaining 17 trials assessed vitamin E in combination with vitamin C and/or other agents. Overall the risk of bias ranged from low to unclear to high; 10 trials were judged to be at low risk of bias, six trials to be at unclear risk of bias and five trials to be at high risk of bias. No clear difference was found between women supplemented with vitamin E in combination with other supplements during pregnancy compared with placebo for the risk of stillbirth (risk ratio (RR) 1.17, 95% confidence interval (CI) 0.88 to 1.56, nine studies, 19,023 participants, I² = 0%; moderate quality evidence), neonatal death (RR 0.81, 95% CI 0.58 to 1.13, nine trials, 18,617 participants, I² = 0%), pre-eclampsia (average RR 0.91, 95% CI 0.79 to 1.06; 14 trials, 20,878 participants; I² = 48%; moderate quality evidence), preterm birth (average RR 0.98, 95% CI 0.88 to 1.09, 11 trials, 20,565 participants, I² = 52%; high quality evidence) or intrauterine growth restriction (RR 0.98, 95% CI 0.91 to 1.06, 11 trials, 20,202 participants, I² = 17%; high quality evidence). Women supplemented with vitamin E in combination with other supplements compared with placebo were at decreased risk of having a placental abruption (RR 0.64, 95% CI 0.44 to 0.93, seven trials, 14,922 participants, I² = 0%; high quality evidence). Conversely, supplementation with vitamin E was associated with an increased risk of self-reported abdominal pain (RR 1.66, 95% CI 1.16 to 2.37, one trial, 1877 participants) and term prelabour rupture of membranes (PROM) (average RR 1.77, 95% CI 1.37 to 2.28, two trials, 2504 participants, I² = 0%); however, there was no corresponding increased risk for preterm PROM (average RR 1.27, 95% CI 0.93 to 1.75, five trials, 1999 participants, I² = 66%; low quality evidence). There were no clear differences between the vitamin E and placebo or control groups for any other maternal or infant outcomes. There were no clear differing patterns in subgroups of women based on the timing of commencement of supplementation or baseline risk of adverse pregnancy outcomes. The GRADE quality of the evidence was high for preterm birth, intrauterine growth restriction and placental abruption, moderate for stillbirth and clinical pre-eclampsia, and low for preterm PROM. AUTHORS' CONCLUSIONS The data do not support routine vitamin E supplementation in combination with other supplements for the prevention of stillbirth, neonatal death, preterm birth, pre-eclampsia, preterm or term PROM or poor fetal growth. Further research is required to elucidate the possible role of vitamin E in the prevention of placental abruption. There was no convincing evidence that vitamin E supplementation in combination with other supplements results in other important benefits or harms.
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Vitamin D and Inflammatory Cytokines in Healthy and Preeclamptic Pregnancies.
Barrera, D, Díaz, L, Noyola-Martínez, N, Halhali, A
Nutrients. 2015;(8):6465-90
Abstract
Preeclampsia is a pregnancy disease characterized by hypertension and proteinuria. Among several disorders, the imbalance of inflammatory cytokines and the alteration of vitamin D metabolism have been reported in preeclampsia. The effects of calcitriol upon inflammatory cytokines has been demonstrated. In healthy pregnant women there is a shift toward a Th2 cytokine profile, which is necessary for an adequate pregnancy outcome. As compared with normal pregnancy, high pro-inflammatory and low anti-inflammatory cytokine levels have been observed in preeclamptic women. Preeclampsia has been associated with low calcitriol levels and vitamin D deficiency is correlated with a higher risk of the development of this disease. It has been demonstrated that placenta is a source as well as the target of calcitriol and cytokines and placental dysfunction has been associated with preeclampsia. Therefore, the present manuscript includes a review about serum calcitriol levels in non-pregnant, pregnant, and preeclamptic women as well as a review on the fetoplacental vitamin D metabolism in healthy and preeclamptic pregnancies. In addition, circulating and fetoplacental inflammatory cytokines in healthy and preeclamptic pregnancies are reviewed. Finally, the effects of calcitriol upon placental pro-inflammatory cytokines are also explored. In conclusion, maternal and placental calcitriol levels are low in preeclampsia which may explain, at least in part, high pro-inflammatory cytokine levels in this disease.
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The association between dietary factors and gestational hypertension and pre-eclampsia: a systematic review and meta-analysis of observational studies.
Schoenaker, DA, Soedamah-Muthu, SS, Mishra, GD
BMC medicine. 2014;:157
Abstract
BACKGROUND Dietary factors have been suggested to play a role in the prevention of hypertensive disorders of pregnancy (HDP), including gestational hypertension and pre-eclampsia, but inconsistent findings have been reported. A systematic review and meta-analyses were performed to synthesize evidence from observational studies of reproductive-aged women on the association between dietary factors and HDP. METHODS MEDLINE and EMBASE were searched to identify studies published until the end of May 2014. Studies were included if they were observational studies of reproductive-age women and reported results on dietary factors (energy, nutrients, foods or overall dietary patterns, alone or in combination with dietary supplements) and gestational hypertension and/or pre-eclampsia. Studies were excluded if they reported on supplements not in combination with dietary intake, or examined a biomarker of dietary intake. Random effects meta-analyses were performed on calculated weighted mean differences (WMD) of dietary intake between cases and non-cases, and effect estimates were pooled. RESULTS In total, 23 cohort and 15 case-control studies were identified for systematic review, of which 16 could be included in the meta-analyses. Based on meta-analyses of cohort studies, unadjusted energy intake was higher for pre-eclampsia cases (WMD 46 kcal/day, 95% confidence interval (CI) -13.80 to 106.23; I 2 = 23.9%, P = 0.26), although this was not statistically significant. Unadjusted intakes of magnesium (WMD 8 mg/day, 95% CI -13.99 to -1.38; I 2 = 0.0%, P = 0.41) and calcium (WMD 44 mg/day, 95% CI -84.31 to -3.62, I 2 = 51.1%, P = 0.03) were lower for the HDP cases, compared with pregnant women without HDP. Higher calcium intake consistently showed lower odds for HDP after adjustment for confounding factors (OR = 0.76, 95% CI 0.57 to 1.01, I 2 = 0.0%, P = 0.79). A few studies examining foods and dietary patterns suggested a beneficial effect of a diet rich in fruit and vegetables on pre-eclampsia, although not all the results were statistically significant. CONCLUSIONS Based on a limited number of studies, higher total energy and lower magnesium and calcium intake measured during pregnancy were identified as related to HDP. Further prospective studies are required to provide an evidence base for development of preventive health strategies, particularly focusing on dietary factors during pre-pregnancy and early pregnancy.