The Impact of Maternal Preeclampsia and Hyperglycemia on the Cardiovascular Health of the Offspring: A Systematic Review and Meta-analysis.

OBJECTIVES: The objective of this review was to assess the impact of maternal preeclampsia or hyperglycemia on the body composition and cardiovascular health in the offspring. STUDY DESIGN: We conducted a systematic review utilizing PubMed, EBSCO, CINAHLPlus, Cochrane Library, and Web of Science to include all studies assessing the impact of preeclampsia/eclampsia and/or gestational/pregestational diabetes mellitus on the health of the offspring (children <10 years of age). The health measures included anthropometry, cardiac dimensions and function, and vascular function. We performed a meta-analysis using Review Manager software and computed net risk ratio (RR) with 95% confidence interval (CI) for dichotomous data and mean difference (MD) with 95% CI for continuous data. RESULTS: There were 6,376 studies in total, of which 45 were included in the review and 40 in the meta-analysis. The results demonstrated higher birth weight (MD: 0.12 kg; 95% CI: 0.06-0.18) and systolic and diastolic blood pressure (BP; MD: 5.98 mm Hg; 95% CI: 5.64-6.32 and MD: 3.27 mm Hg; 95% CI: 0.65-5.89, respectively) in the offspring of mothers with gestational diabetes compared to controls. In contrast, the offspring of mothers with preeclampsia had lower birth weight (MD: -0.41 kg; 95% CI: -0.7 to -0.11); however, they had increased systolic (MD: 2.2 mm Hg; 95% CI: 1.28-3.12) and diastolic BP (MD: 1.41 mm Hg; 95% CI: 0.3-2.52) compared to controls. There is lack of data to conduct a meta-analysis of cardiac morphology, functional, and vascular imaging parameters. CONCLUSION: These findings suggest that the in-utero milieu can have a permanent impact on the body composition and vascular health of the offspring. Future work warrants multicenter prospective studies to understand the mechanism and the actual effect of exposure to maternal hyperglycemia and high BP on the cardiovascular health of the offspring and long-term outcomes. KEY POINTS: · Adverse in-utero exposures may have an impact on cardiovascular risk in children.. · Maternal hyperglycemia/preeclampsia lead to changes in birthweight and BP.. · Limited echocardiographic and vascular imaging data in these cohorts necessitates future work..

Comparative analysis of dental pulp stem cells and stem cells from human exfoliated teeth in terms of growth kinetics, immunophenotype, self-renewal and multi lineage differentiation potential for future perspective of calcified tissue regeneration.

Background and Objectives: Owing to high proliferation rate, multipotency and self-renewal capability, dental pulp stem cells (DPSC) and stem cells from human exfoliated teeth (SHED) have become stem cell source of choice for cell based regenerative therapies. We aimed to compare DPSC and SHED as stem cell sources with a future use in regeneration of calcified tissue. Methods: Explant derived human DPSC (n=9) and SHED (n=1) were cryopreserved, thawed and expanded for analysis of population doubling time, colony forming unit assay and efficiency. A growth curve was plotted to determine population doubling time, while colony forming numbers and efficiency was determined at plating cell densities of 5.6, 11.1 and 22.2 / cm2. The isolated cells were characterized for the presence of stem cell markers by immunophenotyping and immunofluorescence staining, and tri-lineage differentiation. Statistical analysis was performed by Pearson correlation, Exponential regression and two way Anova with Tukey test at p<0.05. Results: DPSC and SHED exhibited spindle shaped fibroblast like morphology. SHED was found superior than DPSC in terms of proliferation and colony forming efficiency. Immunophenotypes showed that DPSC contain 62.6±26.3 %, 90.9±14.8% and 19.8±0.1%, while SHED contain 90.5%, 97.7% and 0.1% positive cells for CD90, CD73 and CD105. DPSC were strongly positive for vimentin, CD29, CD73, while reactivity was moderate to weak against CD44 and CD90. SHED expressed vimentin, CD29, CD105, CD90 and CD44. Both were negative for CD45. Upon induction, both cell types differentiated into bone, fat and cartilage like cells. Conclusion: Cultured DPSC and SHED were proliferative and exhibited self-renewal property. Both DPSC and SHED expressed stem cell markers and were able to differentiate into bone, fat and cartilage like cells. Thus, these could be a suitable stem cell sources for cell based regenerative therapies.

Association of chemerin gene promoter methylation in maternal blood and breast milk during gestational diabetes.

The intrauterine environment and early-life nutrition are regulated by maternal biomarkers in the blood and breast milk. We aimed to explore epigenetic modifications that may contribute to differential chemerin expression in maternal plasma, colostrum, and breast milk and find its association with fetal cord blood and infant weight at 6 weeks postpartum. Thirty-three gestational diabetes mellitus (GDM) mothers and 33 normoglycemic mothers (NGT) were recruited. Two maternal blood samples (28th week of gestation and 6 weeks postpartum), cord blood, colostrum, and mature milk were collected. Methylation-specific polymerase chain reaction and enzyme-linked immunosorbent assay were conducted. The weight of the babies was measured at birth and 6 weeks postpartum. Serum chemerin levels at the 28th gestational week and 6 weeks postpartum were significantly lower for the NGT group as compared to the GDM group; (P < 0.05). Higher colostrum chemerin concentrations were observed in the GDM group and remained elevated in mature milk as compared to NGT (P < 0.05). Colostrum and breast milk chemerin levels showed an independent association with infant weight at 6 weeks postpartum (r = 0.270; P = 0.034) (r = 0.464; P < 0.001). Forty percent GDM mothers expressed unmethylated chemerin reflecting increased chemerin concentration in the maternal blood. This pattern was also observed in newborn cord blood where 52% of samples showed unmethylated chemerin in contrast to none in babies born to normoglycemic mothers. The results of this study highlight the critical importance of altered chemerin regulation in gestational diabetic mothers and its effect during early life period and suggest a possible role in contributing to childhood obesity.

Influence of intrauterine growth status on aortic intima-media thickness and aortic diameter in near-term fetuses: a comparative cross-sectional study.

Intrauterine undernutrition may lead to fetal vascular programming. We compared abdominal aortic intima-media thickness (aIMT) and aortic diameter (aD) between appropriate for gestational age (AGA) and growth-restricted fetuses (GRF). We recruited 136 singleton fetuses at 34-37 weeks of gestation from Fetal Medicine Unit of Aga Khan University Hospital, Karachi (January-November 2017). Subjects were classified as AGA (n = 102) and GRF (n = 34) using INTER-GROWTH 21st growth reference and standard ultrasound protocol. Their far- and near-wall aIMT and aD were compared after adjustment of maternal age, first-trimester body mass index, fetal gender, hypertension and hyperglycemia in pregnancy. As the severity of growth restriction increased in GRF, aIMT and aD showed an increasing and a decreasing trend, respectively. Both far- and near-wall aIMT in GRF [(adj. ß = 0.082, 95% confidence interval [CI] 0.042-0.123) and (adj. ß = 0.049, 95% CI 0.010-0.089)] were significantly greater with reference to AGA fetuses. GRF subgroup analysis into small for gestational age (SGA) fetuses and intrauterine growth restricted (IUGR) revealed highly significant difference between AGA and IUGR for far (0.142 mm, P-value < 0.001) and near-wall aIMT (0.115 mm, P-value < 0.001) and marginally significant aD difference (0.51 mm, P-value 0.05). These findings suggest that the extent of fetal aortic remodelling is influenced by the severity of growth restriction. Hence, the targeted interventions for the cardiovascular health promotion of IUGR and SGA born neonates are desirable during early childhood, particularly in set ups with high prevalence of low birth weight babies.

The Efficacy of a Personalized mHealth Coaching Program During Pregnancy on Maternal Diet, Supplement Use, and Physical Activity: Protocol for a Parallel-Group Randomized Controlled Trial.

BACKGROUND: Adequate intake of macro- and micronutrients and adoption of an active lifestyle during pregnancy are essential for optimum maternal and fetal health and offspring development. Dietary counseling and advice regarding adequate physical activity are integral components of antenatal care. Personalized coaching through the use of mobile health (mHealth) that supports behavior modification is an innovative approach that needs exploration. OBJECTIVE: Our primary aim is to assess the efficacy of an mHealth program in improving diet, supplement use, and physical activity during pregnancy. Secondary objectives include evaluation of the program's effect on maternal and offspring health outcomes and assessment of its compliance and usability. METHODS: A randomized controlled trial was initiated at the Aga Khan University Hospital in Karachi, Pakistan, in January 2020. We aim to recruit 300 pregnant women in their first trimester who have smartphones, do not have comorbidities, and are not taking medications. The intervention group will be trained to use an mHealth app called PurUmeed Aaghaz. Through this app, the subjects will report information about their diet, supplement use, and physical activity and will receive personalized advice and three push messages as weekly reminders. The research assistant will obtain similar information from the control group via a paperless questionnaire; this group will receive standard face-to-face counseling regarding diet, supplement use, and physical activity. Data will be collected at enrollment and during four follow-up sessions scheduled 6 weeks apart. Primary study outcomes include improvements in diet (ie, change in mean dietary risk score from baseline to each follow-up), supplement use (ie, changes in mean supplement use score and biochemical levels of folic acid, iron, calcium, and vitamin D on a study subset), and mean duration of reported physical activity (minutes). Secondary study outcomes relate to maternal health (ie, gestational diabetes mellitus, gestational hypertension, pre-eclampsia, and gestational weight gain), newborn health (ie, birth weight and length and gestational age at delivery), and infant health (ie, BMI and blood pressure at 1 year of age). Compliance will be determined by the proportion of participants who complete the 6-month coaching program. Usability will be assessed based on features related to design, interface, content, coaching, perception, and personal benefit. RESULTS: The study was approved by the Ethics Review Committee of the Aga Khan University in 2017. The recruitment of study participants was completed in September 2021. All follow-ups and outcome assessments are expected to be completed by March 2023 and analysis is expected to be completed by June 2023. We expect the results to be published by the end of 2023. CONCLUSIONS: This study will be an important step toward evaluating the role of mHealth in improving behaviors related to a healthy diet, supplement use, and promotion of physical activity during pregnancy, as well as in influencing maternal and offspring outcomes. If proven effective, mHealth interventions can be scaled up and included in antenatal care packages at tertiary care hospitals of low- and middle-income countries. TRIAL REGISTRATION: ClinicalTrials.gov NCT04216446; https://clinicaltrials.gov/ct2/show/NCT04216446. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/31611.

Cardiovascular Dysfunction in Children Exposed to Preeclampsia During Fetal Life.

BACKGROUND: Keeping in view the developmental origin of health and disease hypothesis, the aim of this study was to assess differences in cardiac and vascular structure and function in children exposed to preeclampsia in utero compared with those of normotensive mothers. The hypothesis under investigation was that children exposed to preeclampsia would have altered cardiac and vascular structure and function compared with the unexposed group. METHODS: This was a retrospective cohort study that included children 2 to 10 years of age born to mothers with and without exposure to preeclampsia in utero (n = 80 in each group). Myocardial morphology and function using echocardiography and carotid intima-media thickness and pulse-wave velocity were determined. Multivariate linear regression was used to compare preeclampsia-exposed and nonexposed groups. Subgroup analysis to assess differences between early- and late-onset preeclampsia was also performed. RESULTS: Forty-one percent of mothers (n = 33) had early-onset preeclampsia. Children in the exposed group had a significantly higher prevalence of stage 1 systolic and diastolic hypertension (22% [n = 18] and 35% [n = 18], respectively) compared with the unexposed group (9% [n = 7] and 19% [n = 15], respectively; P = .01). Children in the exposed group also had higher pulse-wave velocity compared with those in the unexposed group (0.42 ± 0.1 vs 0.39 ± 0.1, P = .03). Subgroup analysis revealed that changes in blood pressure and pulse-wave velocity were determined primarily by early-onset preeclampsia. There was no significant difference in cardiac morphology or systolic and diastolic function between the exposed and unexposed groups. CONCLUSION: In utero exposure to preeclampsia has an effect on vascular function in children aged 2 to 10 years, related primarily to early-onset disease. Routine blood pressure screening should be recommended for such children.

Seeing the fetus from a DOHaD perspective: discussion paper from the advanced imaging techniques of DOHaD applications workshop held at the 2019 DOHaD World Congress.

Advanced imaging techniques are enhancing research capacity focussed on the developmental origins of adult health and disease (DOHaD) hypothesis, and consequently increasing awareness of future health risks across various subareas of DOHaD research themes. Understanding how these advanced imaging techniques in animal models and human population studies can be both additively and synergistically used alongside traditional techniques in DOHaD-focussed laboratories is therefore of great interest. Global experts in advanced imaging techniques congregated at the advanced imaging workshop at the 2019 DOHaD World Congress in Melbourne, Australia. This review summarizes the presentations of new imaging modalities and novel applications to DOHaD research and discussions had by DOHaD researchers that are currently utilizing advanced imaging techniques including MRI, hyperpolarized MRI, ultrasound, and synchrotron-based techniques to aid their DOHaD research focus.

Follicular Sensitivity Index: A Tool To Predict Successful Conception After Intra-cytoplasmic Sperm Injection.

Follicular sensitivity index (FSI) is used for estimation of follicular responsiveness to controlled ovarian hyperstimulation (COH) during intra-cytoplasmic sperm injection (ICSI). In a retrospective study, FSI of 1,385 females was calculated as [pre-ovulatory follicle count (PFC) × 100,000]/ [antral follicle count (AFC) × total received stimulation doses]. Females were then categorised into low, middle and high FSI groups according to FSI tertile values. FSI was 8.65 ±2.82 in non-pregnant as compared to 12.02 ±2.04 (p <0.01) in pregnant cohort. FSI turned out to be a strong predictor of successful conception on the receiver operating curve with cutoff value 10.36 at 76% specificity, sensitivity of 86% and area under the curve (AUC; 0.83). Calculation of FSI can thus predict the chances of successful conception in females with different causes of infertility. Key Words: Follicular sensitivity index, Infertility, Intra-cytoplasmic sperm injection, Ovarian response, Follicular output rate.

Pregnancy outcomes amongst adolescents/young adults at tertiary-care hospital in a low-middle-income country: Ten-year retrospective record review.

OBJECTIVE: Adolescent pregnancies are known to be associated with adverse outcomes. Our objective was to compare pregnancy outcomes amongst adolescents (young adolescents YA: 15-17 years; older adolescents OA: 18- 19 years) and young adults (20 to 25 years). METHODS: Study was conducted at the Aga Khan University Hospital, Karachi. Ten-year retrospective record review was done through convenience sampling. Data was collected on predesigned proforma. Participants were 396 primiparous adolescents (15-19 years) with singleton low-risk pregnancy. Reference-group included 410 primiparous, low-risk, young adults. Pregnancies complicated with preexisting diabetes mellitus, chronic hypertension, renal disorders or cardiac diseases were excluded. Maternal /neonatal outcomes were compared amongst groups. RESULTS: Out of 806 charts reviewed, 75 (9.3%) were YA, 321 (39.8%) were OA and 410 (50.9%) were 20-25 years old young adults. Most of the un-booked cases were in young adolescents; 17 (22.7% YA), 41 (12.8% OA) and 33 (8.0% reference -group) (p-value 0.001). This group also booked at a later gestational age; YA (19.6±10.4 weeks), OA (17.2±9.3 weeks) and controls (15.5n±8.8 weeks) (p-value 0.002). Gestational age at delivery was not significantly different among the groups. Adolescents had a decreased likelihood of Caesarian section with youngest group having 29% less chance of Caesarian delivery (OR 95% CI 0.41, 0.2) compared to women of 20-25 years of age. Difference in maternal/neonatal outcomes remained insignificant between groups at univariate and multivariate analysis. CONCLUSIONS: Maternal/neonatal outcomes in adolescents were comparable to young adults. Good antenatal care, evidence-based protocols and strong family backing may reduce risks to mothers/babies in adolescent pregnancies.

Isolation and culture of dental pulp stem cells from permanent and deciduous teeth.

OBJECTIVE: To isolate dental pulp mesenchymal stem cells (MSCs) from non-infected human permanent and deciduous teeth. METHODS: It was an in-vitro experimental study. Human teeth were collected from 13 apparently healthy subjects including nine adults and four children. After decoronation dental pulps were extirpated from teeth and cultured via explant method in a stem cell defined media. Data was analyzed by descriptive statistics. RESULTS: As above MSCs emerged exhibiting fibroblast-like morphology. In vitro culture was positive for 100% (9/9) and 75% (3/4) of the permanent and deciduous teeth respectively. First cell appeared from deciduous teeth pulp in 10±6.2 days while permanent teeth pulp took 12.4±3.7 days. Together, 26.6±3.6 and 24.5±3.5 days were required for permanent and deciduous tooth pulp stem cells to be ready for further assays. CONCLUSIONS: The protocol we developed is easy and consistent and can be used to generate reliable source of MScs for engineering of calcified and non-calcified tissue for regenerative medicine approaches.

Is the child at risk? Cardiovascular remodelling in children born to diabetic mothers.

OBJECTIVE: The objective of this study was to assess differences in myocardial systolic and diastolic function and vascular function in children 2-5 years of age born to diabetic as compared to non-diabetic mothers. METHODS: This study was a retrospective cohort conducted in 2016 at The Aga Khan University Hospital, Karachi, Pakistan. It included children between 2 and 5 years of age born to mothers with and without exposure to diabetes in utero (n = 68 in each group) and who were appropriate for gestational age. Myocardial morphology and function using echocardiogram and carotid intima media thickness (cIMT) and pulse wave velocity was performed to evaluate cardiac function as well as macrovascular remodelling in these children. Multiple linear regression was used to compare the groups. RESULTS: There was no significant difference in cardiac morphology, myocardial systolic and diastolic function, and macrovascular assessment between the exposed and unexposed groups of AGA children. Subgroup analysis demonstrated a significantly decreased mitral E/A ratio in children whose mothers were on medications as compared to those on dietary control (median [IQR] = 1.7 [1.6-1.9] and 1.56 [1.4-1.7], respectively, p = 0.02), and a higher cIMT in children whose mothers were on medication as compared to controls (0.48 [0.44-0.52] and 0.46 [0.44-0.50], respectively, p = 0.03). CONCLUSION: In utero exposure to uncontrolled maternal diabetes has an effect on the cardiovascular structure and function in children aged 2-5 years. However, future work requires long-term follow-up from fetal to adult life to assess these changes over the life course.

Impact of pre-eclampsia on the cardiovascular health of the offspring: a cohort study protocol.

INTRODUCTION: Pre-eclampsia is a common disorder associated with serious maternal and fetal complications. It is associated with abnormal placentation, which significantly reduces flow, resulting in a relative hypoxic state. These pathophysiological changes lead to subtle macrovascular and cardiac structural and functional changes in the fetus. This can predispose the child with maternal history of pre-eclampsia to risk of premature cardiovascular disease. METHODS AND ANALYSIS: The children will be identified from a cohort of women with pre-eclampsia. The study will be conducted at The Aga Khan University Hospital, Karachi. Inclusion criteria will be children who are between 2 and 5 years of age and have a maternal history of pre-eclampsia. The child's current weight, height and blood pressure will be recorded. A two-dimensional functional echocardiogram and vascular assessment will be performed to evaluate alterations in cardiac function as well as macrovascular remodelling in these children. Data will be presented as mean±SD, median (IQR) or percentages as appropriate. Independent t-test or Mann-Whitney U test will be used for testing of continuous variables (based on the assumption of normality). A p<0.05 will be used to determine statistical significance. ETHICS AND DISSEMINATION: Ethical approval has been obtained from AKUH Ethics Review Committee. Findings will be disseminated through scientific publications and project summaries for the participants.

Online versus offline spatiotemporal image correlation (STIC) M-mode for the evaluation of cardiac longitudinal annular displacement in fetal growth restriction.

PURPOSE: Our first aim was to compare online M-mode with offline spatiotemporal image correlation (STIC) M-mode for assessing longitudinal annular displacement (LAD) in growth-restricted fetuses (FGR). Our second aim was to compare LAD measures of FGR cases with controls. MATERIALS AND METHODS: Prospective study including 40 FGR cases (defined estimated fetal weight and birth weight <10th centile) and 72 normally grown fetuses matched to cases by gestational age at scan. LAD was measured with online M-mode and offline STIC M-mode at the left and right ventricular free walls and septum in all fetuses. RESULTS: FGR cases had a significant decrease in LAD by STIC in all sites as compared to controls (e.g. right LAD in FGR mean 6.7 mm (SD 1.2) versus controls 7.2 mm (1.2), p = .033). There was a non-significant trend for lower values in FGR when using online M-mode (e.g. right LAD in FGR 6.9 mm (1.5) versus controls 7.4 mm (1.5), p = .084). CONCLUSIONS: STIC M-mode seems a better method than online M-mode for detecting subtle changes in myocardial motion. STIC presents more precise results and allows an ideal placement of the M-mode arrow. These results confirm previous data suggesting decreased longitudinal motion in FGR.

Evolution of foetal echocardiography as a screening tool for prenatal diagnosis of congenital heart disease.

Congenital cardiac anomalies are the most common anomalies, with an estimated incidence of about 4-13 per 1000 live births. Proper perinatal and neonatal management is dependent upon accurate prenatal diagnosis. Approximately 10% of foetuses with cardiac abnormalities have identified risk factors; hence, most of the anomalies occur in pregnancies without prenatal risk factors. Foetal echocardiography allows for prenatal diagnosis of congenital heart disease and serves as a routine screening tool for congenital heart defects. Advanced technology, has not only allowed more accurate and early detection of cardiac abnormalities but has also improved the care and outcome of selected foetuses with severe cardiac malformations or arrhythmias. It can also identify patients for in-utero cardiac interventions. Prenatal diagnosis of congenital heart disease has allowed for better counseling and preparation of families regarding the expected prenatal development of the foetus as well as the anticipated postnatal management strategy and prognosis.

Non-invasive prenatal determination of fetal RhD genotyping from maternal plasma: a preliminary study in Pakistan.

OBJECTIVE: To determine the accuracy of the non-invasive pre-natal real-time polymerase chain reaction based fetal RhD genotyping from maternal plasma. STUDY DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: Juma Health Sciences Research Laboratory, The Aga Khan University Hospital, Karachi, from July to December 2008. METHODOLOGY: Cell-free plasma DNA from 21 D-negative women with D-positive spouse between 20-39 weeks of gestation was tested for the presence of exon 5 region of RhD gene using real-time polymerase chain reaction. b-globin was employed as the house-keeping gene. Sensitivity and specificity of the real-time PCR-based non-invasive fetal RhD genotyping was obtained by calculating proportion of the D-positive fetuses that were D-positive at birth as well. RESULTS: Of the 21 D-negative women 13 and 8 neonates were determined to be D-positive and D-negative, respectively, by serologic studies on cord blood samples at birth. RhD status was correctly determined in 17 of 21 cases. There were three false-positive and one false-negative results. The sensitivity and specificity of the assay was 92.3% (95% CI: 62.1, 99.6) and 62.5% (95% CI: 25.9, 89.8), respectively. The positive and negative predictive value of the assay was 80% (95% CI: 51.4, 94.7) and 83.3% (36.5, 99.1), respectively. CONCLUSION: These preliminary results demonstrate the feasibility of non-invasive pre-natal diagnosis of fetal RhD status of D-negative mothers in Pakistan.