Madhavi Dhobale

Altered maternal micronutrients (folic acid, vitamin B 12 ) and omega 3 fatty acids through oxidative stress may reduce neurotrophic factors in preterm pregnancy

Abstract Preterm pregnancies account for approximately 10% of the total pregnancies and are associated with low birth weight (LBW) babies. Recent studies have shown that LBW babies are at an increased risk of developing brain disorders such as cognitive dysfunction and psychiatric disorders. Maternal nutrition, particularly, micronutrients involved in one-carbon metabolism (folic acid, vitamin B12, and docosahexaenoic acid (DHA)) have a major role during pregnancy for developing fetus and are important determinants of epigenesis. A series of our studies in pregnancy complications have well established the importance of omega 3 fatty acids especially DHA. DHA regulates levels of neurotrophins like brain-derived neurotrophic factor and nerve growth factor, which are required for normal neurological development. We have recently described that in one carbon metabolic pathway, membrane phospholipids are major methyl group acceptors and reduced DHA levels may result in diversion of methyl groups toward deoxyribonucleic acid (DNA) ultimately resulting in DNA methylation. In this review, we propose that altered maternal micronutrients (folic acid, vitamin B12), increased homocysteine, and oxidative stress levels that cause epigenetic modifications may be one of the mechanisms that contribute to preterm birth and poor fetal outcome, increasing risk for behavioural disorders in children.

Long chain polyunsaturated fatty acids in mothers and term babies

Abstract Aim: To establish the levels of docosahexaenoic acid (DHA) and arachidonic acid (AA) in both plasma and erythrocytes of maternal and cord blood as well as in breast milk of mothers delivering babies at term. Methods: A total of 148 mothers delivering babies at term were recruited from Bharati Medical Hospital, Pune, India. Results: Levels of DHA and AA in both plasma and erythrocyte were higher in cord blood compared to levels in maternal blood (P<0.001). Maternal plasma and erythrocyte DHA levels had a positive association with the respective levels in cord blood (P<0.001). However, such an association was not seen for AA levels. Maternal plasma omega 3 and omega 6 fatty acids were positively associated with the respective milk fatty acids (P<0.01). Conclusions: Our results indicate that milk long-chain polyunsaturated fatty acids (LCPUFA) status reflects the concentrations of maternal LCPUFA in women delivering babies at term. Improving the maternal LCPUFA status throughout pregnancy and lactation may improve the milk LCPUFA status and ultimately benefit the infant.

Reduced Folate, Increased Vitamin B12 and Homocysteine Concentrations in Women Delivering Preterm

Background and Aim: Maternal nutrition is an important determinant of the duration of pregnancy and fetal growth, and thereby influences pregnancy outcome. Folic acid and vitamin B12 are involved in one-carbon metabolism and are reported to underlie intrauterine programming of adult diseases. Methods: In the present study, the levels of folate, vitamin B12 and homocysteine were measured in mothers delivering preterm (PT; gestation <37 weeks; n = 67), those delivering preterm due to preeclampsia (PT-PE; n = 49) and women delivering at term (control group; n = 76). Results: Increased vitamin B12 and homocysteine levels (p < 0.05 for both) were seen in the PT-PE and PT groups as compared to the controls. In addition, reduced folate levels (p < 0.05) were observed in the PT group. A negative association of maternal plasma homocysteine with birth weight was seen in the idiopathic preterm group. Conclusions: Altered maternal micronutrients and resultant increased homocysteine concentrations exist in women delivering preterm. These alterations may also be partly associated with other factors such as undiagnosed inflammatory conditions or inadequate placentation in some women. Since these micronutrients play an important role in epigenetic regulation of vital genes involved in the fetal programming of adult diseases, further studies need to be undertaken to understand their role in preterm deliveries.

Reduced levels of placental long chain polyunsaturated fatty acids in preterm deliveries

Reports suggest that the placenta in preterm birth may provide clues to predicting the risk of individuals developing chronic diseases in later life. Placental delivery of long chain polyunsaturated fatty acids (LCPUFA) (constituents of the cell membrane and precursors of prostaglandins) is essential for the optimal development of the central nervous system of the fetus. The present study examines the levels of LCPUFA and their association with placental weight and birth outcome in 58 women delivering preterm and 44 women delivering at term. Docosahexaenoic acid (DHA) and arachidonic acid (ARA) levels were lower (p<0.01) in women delivering preterm. There was a positive association of placental DHA with placental weight (p=0.036) and nervonic acid with head circumference (p=0.040) in the preterm group. Altered placental LCPUFA status exists in Indian mothers delivering preterm, which may influence the birth outcome.

Differential expression of human placental neurotrophic factors in preterm and term deliveries

Neurotrophic factors such as brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are involved in development of the placenta and fetal brain. A series of human and animal studies in our department have shown that micronutrients (folic acid, vitamin B12) and omega 3 fatty acids like DHA are all interlinked in the one carbon cycle. Any alterations in one carbon components will lead to changes in methylation patterns that further affect the gene expression at critical periods of development resulting in complications during pregnancy. This may further contribute to risk for neurodevelopmental disorders in children born preterm. Therefore this study for the first time examines the mRNA levels from preterm and term placentae. A total number of 38 women delivering preterm (<37 weeks gestation) and 37 women delivering at term (=>37 weeks gestation) were recruited. The mRNA levels of BDNF and NGF were analyzed by real time quantitative polymerase chain reaction. Our results indicate that BDNF and NGF mRNA levels were lower in preterm group as compared to term group. There was a positive association of placental BDNF and NGF mRNA levels with cord plasma BDNF and NGF levels. The differential expression of BDNF and NGF gene in preterm placentae may also alter the vascular development in preterm deliveries. Our data suggests that the reduced mRNA levels of BDNF and NGF may possibly be a result of altered epigenetic mechanisms and may have an implication for altered fetal programming in children born preterm.

Association of brain-derived neurotrophic factor and tyrosine kinase B receptor in pregnancy.

Abnormal brain development in a compromised prenatal and/or early postnatal environment is thought to be a risk factor for several neurobehavioural disorders. However, the mechanisms underlying these are not well understood. We have earlier reported reduced placental docosahexaenoic acid (DHA) levels in preterm deliveries. We have hypothesized that increased oxidative stress and reduced DHA levels may lead to changes in the circulating levels of maternal and cord brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase B (TrkB) levels. A total number of 96 women delivering preterm and 95 women delivering at term were recruited. Plasma BDNF levels were measured in both mother and cord blood plasma using the BDNF Immuno Assay kit. Placental TrkB levels were analysed using sandwich enzyme-linked immunosorbent assay (ELISA). Maternal plasma BDNF levels and placental TrkB levels were higher (p<0.05) while cord plasma BDNF levels were lower (p<0.01) in women delivering preterm as compared to term. There was a negative association between levels of placental TrkB and DHA (p=0.034). A negative association between maternal plasma BDNF levels and placental weight (p=0.001) was observed while a positive association was seen between cord plasma BDNF levels and gestation (p=0.025). The reduction in cord BDNF levels may have implications for altered neurodevelopment in childhood and later life. Studies need to be undertaken to follow up children born preterm for risk of neurobehavioural disorders like attention deficit hyperactivity disorder (ADHD) to understand the effect of altered BDNF at birth on neurodevelopment.

Reduced maternal and cord nerve growth factor levels in preterm deliveries

Nerve growth factor (NGF) is a neurotrophin, which exerts an important role in the development and function of the central and peripheral nervous system. There is limited information regarding the levels of NGF during pregnancy and its role in fetal development. We have earlier reported increased oxidative stress in pregnancy complications. The present study examines the levels of NGF in maternal and cord samples in preterm deliveries and its association with oxidative stress marker. A total number of 96 women delivering preterm (<37 weeks gestation) and 94 women delivering at term (control group) (≥37 weeks gestation) were recruited. Plasma NGF levels were measured in both mother and cord plasma using the Emax Immuno Assay System Promega kit. Maternal and cord plasma NGF levels were significantly reduced (p < 0.05 for both) in women delivering preterm as compared to term. There was a positive association between maternal and cord plasma NGF levels (p = 0.022). Maternal NGF levels were negatively (p = 0.017) associated with maternal malondialdehyde (MDA) levels. Reduced cord NGF levels may affect fetal growth in preterm deliveries which may have implications for the neurodevelopmental pathologies in later life. Circulating maternal NGF levels in preterm pregnancies may be a useful marker to predict NGF levels in the neonate.

Neurotrophins: Role in adverse pregnancy outcome

Proper placental development is essential during pregnancy since it forms the interface between the maternal–foetal circulations and is critical for foetal nutrition and oxygenation. Neurotrophins such as nerve growth factor (NGF), brain derived neurotrophin (BDNF), neurotrophin‐3 (NT‐3) and neurotrophin‐4/5 (NT‐4/5) are naturally occurring molecules that regulate development of the placenta and brain. BDNF and NGF also involved in the regulation of angiogenesis. Recent studies suggest that the levels of BDNF and NGF are regulated by docosahexaenoic acid (DHA) which is an important omega‐3 fatty acid and is a structural component of the plasma membrane. Oxidative stress during pregnancy may lower the levels of DHA and affecting the fluidity of the membranes leading to the changes in the levels and expression of BDNF and NGF. Therefore altered levels and expression of NGF and BDNF may lead to abnormal foetal growth and brain development that may increase the risk for cardiovascular disease, metabolic syndromes and neurodevelopmental disorders in children born preterm. This review discuss about the neurotrophins and their role in the feto‐placental unit during critical period of pregnancy.

Differential oxidative stress levels in mothers with preeclampsia delivering male and female babies

Abstract Objectives: Increased oxidative stress is known to be associated with pregnancy complications like preeclampsia (PE). We hypothesize that increased maternal oxidative stress may differentially affect/program the pregnancy outcome during early postnatal periods in male and female babies. Materials and methods: One-hundred three healthy pregnant women (gestation ≥37 weeks) were recruited for the normotensive control (NC) group and 57 women with term-preeclampsia (T-PE; gestation ≥37 weeks) and 28 women with preterm-preeclampsia (PT-PE; gestation <37 weeks) were also recruited. All infants were followed for anthropometric measurements until six months of age. Results: Higher maternal plasma malondialdehyde (MDA) and erythrocyte superoxide dismutase and glutathione peroxidase (GPx) levels were observed in both T-PE and PT-PE groups. Higher maternal levels of MDA and GPx were seen in mothers delivering male babies in T-PE and PT-PE groups, respectively, as compared to mothers delivering female babies. Babies born to mothers with PT-PE showed poor growth and development on all the anthropometric parameters compared to those born to mothers with T-PE and NC. Conclusion: The altered levels of oxidative stress and antioxidant enzymes in mothers with PE delivering male babies suggest that they may be at higher risk for developing metabolic and neurodevelopmental disorders than female babies.

Differential levels of long chain polyunsaturated fatty acids in women with preeclampsia delivering male and female babies

Maternal long chain polyunsaturated fatty acids (LCPUFA) play a key role in fetal growth and development. This study for the first time examines the maternal and cord LCPUFA levels in preeclamptic mothers delivering male and female infants. In this study 122 normotensive control pregnant women (gestation≥37 weeks) and 90 women with preeclampsia were recruited. Results indicate lower maternal plasma docosahexaenoic acid (DHA) levels (p<0.05) in women with preeclampsia delivering male babies as compared to normotensive control women delivering male babies. Similarly, cord nervonic acid levels were lower (p<0.01) in women with preeclampsia delivering male babies as compared to normotensive control group. However, cord nervonic acid levels were comparable in women with preeclampsia and normotensive control women delivering female babies. This data suggests that male babies born to mothers with preeclampsia may be at an increased risk of developing neurodevelopmental disorders as compared to female babies. Future studies need to follow up both male and female children born to mothers with preeclampsia since altered levels of LCPUFA at birth may have differential implications for the growth and development.