Maternal angiogenic factor disruptions prior to clinical diagnosis of preeclampsia: insights from the REVAMP study.

Preeclampsia is characterized by impaired angiogenesis and assessment of angiogenic factors can play a crucial role in the early diagnosis of preeclampsia. The current study reports the levels of angiogenic factors longitudinally from early pregnancy in women with preeclampsia and in the subtypes of preeclampsia, to identify their role in early prediction of preeclampsia. A total of 1154 women with singleton pregnancies were recruited in early pregnancy from 2 hospitals. Blood samples were collected, plasma samples were separated and stored at four time points across gestation: V1 = 11-14 weeks, V2 = 18-22 weeks, V3 = 26-28 weeks, and V4 = at delivery. The current study includes a total of 108 women developed preeclampsia (PE), and 216 matched controls. Angiogenic factors were estimated using commercially available ELISA kits. Receiver operating characteristic (ROC) curves were used to evaluate the potential diagnostic value in the prediction of PE. Lower levels of VEGF, PlGF, and higher levels of sEng and sEng/PlGF ratio (p < 0.05 for all) predate clinical diagnosis in women with preeclampsia. sEng levels and sEng/PlGF ratio showed significant correlation with odds of preeclampsia at all the timepoints. This study identifies a cut off of 33.5 for sFlt-1/PlGF and 25.9 for sEng/PlGF for prediction of early onset preeclampsia. This study reports various angiogenic factors serially across gestation in a general population to identify women at risk of developing preeclampsia and its subtypes. The study also reports a potential biomarker and a pragmatic window for estimation of angiogenic markers to identify women at risk.

The ethics and practice of perinatal care at the limit of viability: FIGO recommendations.

An arbitrary gestational age limit of viability cannot be set, and in clinical practice the focus should be on a periviability interval-the so-called "gray zone" of prognostic uncertainty. For cases within this interval, the most appropriate decision-making process remains debatable and periviability has emerged as one of the greatest challenges in bioethics. Universally recognized ethical principles may be interpreted differently due to socioeconomic, cultural, and religious aspects. In the case of periviability, there is considerable uncertainty over whether interventions result in a greater balance of clinical good over harm. Furthermore, the fetus or neonate is unable to exercise autonomy and the physicians and parents will act as patient surrogates. When parents and physicians disagree about the infant's best interest, a dialogue without paternalistic attitudes is essential, whereby physicians should only offer, but not recommend, perinatal interventions. Parental choice, based on thorough information, should be respected within the limits of what is medically feasible and appropriate. When disagreements between parents and physicians occur, how is consensus to be achieved? Professional guidelines can be helpful as a framework and starting point for discussion. In reality, however, guidelines only rarely draw categorical lines and in many cases remain vague and ambiguously worded. Local ethics committees can provide counseling and function as moderators during discussions, but ethics committees do not have decision precedence. Counseling assumes the most significant role in periviability discussions, taking into consideration the particular fetal and maternal characteristics, as well as parental values. Several caveats should be observed relative to counseling: message fragmentation or inconsistence should be minimized, prognosis should preferably be presented in a positive framing, and overreliance on statistics should be avoided. It is recommended that decisions regarding neonatal resuscitation in the periviability interval be made before birth and not conditional on the newborn's appearance at birth. Regardless of decision, it is important to assure pre- and postnatal coherence. The present article describes how individual physicians, centers, and countries differ in the approach to the decision to initiate or forgo intensive care in the periviability interval. It is impossible to provide a global consensus view and there can be no unifying ethical, moral, or practical strategy. Nevertheless, ethically justified, quality care comprises early involvement of the obstetric and neonatal team to enable a coherent, comprehensible, nonpaternalistic, and balanced plan of care. Ultimately, physicians will need to adjust the expectations to the local standards, local outcome data, and local neonatal support availability.

Longitudinal Assessment of Oxidative Stress Markers in Women with Preeclampsia.

Preeclampsia (PE) is a pregnancy-specific disorder and a major contributor to maternal and fetal morbidity and mortality. Role of oxidative stress in early pregnancy with the pathophysiology of the disorder is unclear. The current study aims to analyse maternal levels of oxidative stress markers (MDA and protein carbonyl) longitudinally across gestation and placental levels of oxidative stress markers (MDA, protein carbonyl and 8-oxo-2'-deoxyguanosine) in women with PE and compare them with non-PE women. 324 pregnant women (216 non-PE and 108 PE women) were longitudinally followed during pregnancy. Women with preeclampsia were stratified as early onset preeclampsia (EOP) and late onset preeclampsia (LOP) Maternal blood at four time points across gestation (11-14 weeks, 18-22 weeks, 26-28 weeks, and at delivery) and placenta were collected. Maternal and placental levels of oxidative stress markers were assessed using commercially available kits. Maternal plasma MDA and protein carbonyl levels were comparable between the PE and non-PE group at all timepoints across gestation. Maternal plasma MDA were significantly higher levels at 26-28 weeks in EOP women when compared to non-PE women (p < 0.05). Placental 8-oxo-dG levels were lower in the EOP group as compared to non-PE (p < 0.05). Elevated plasma MDA levels were positively associated with birth length at 18-22 weeks and 26-28 weeks in the PE group (p < 0.05 for both). Maternal plasma MDA levels were positively associated with systolic blood pressure at 18-22 weeks. Oxidative stress in early pregnancy is not associated with risk of PE.

A meta-analysis of ferric carboxymaltose versus other intravenous iron preparations for the management of iron deficiency anemia during pregnancy.

Objective: We conducted a meta-analysis of randomized clinical trials evaluating the clinical effects of ferric carboxymaltose therapy compared to other intravenous iron in improving hemoglobin and serum ferritin in pregnant women. We also assessed the safety of ferric carboxymaltose vs. other intravenous iron. Data source: EMBASE, PubMed, and Web of Science were searched for trials related to ferric carboxymaltose in pregnant women, published between 2005 and 2021. We also reviewed articles from google scholar. The keywords "ferric carboxymaltose," "FCM," "intravenous," "randomized," "pregnancy," "quality of life," and "neonatal outcomes" were used to search the literature. The search was limited to pregnant women. Selection of studies: Studies related to ferric carboxymaltose in pregnancy were scanned. Observational studies, review articles, and case reports were excluded. Randomized studies in pregnant women involving ferric carboxymaltose and other intravenous iron formulations were shortlisted. Of 256 studies, nine randomized control trials were selected. Data collection: Two reviewers independently extracted data from nine selected trials. Data synthesis: The final effect size for increase in hemoglobin after treatment was significant for ferric carboxymaltose vs. iron sucrose/iron polymaltose (standard mean difference 0.89g/dl [95% confidence interval 0.27,1.51]). The final effect size for the increase in ferritin after treatment was more for ferric carboxymaltose vs. iron sucrose/iron polymaltose (standard mean difference 22.53µg/L [-7.26, 52.33]). No serious adverse events were reported with ferric carboxymaltose or other intravenous iron. Conclusion: Ferric carboxymaltose demonstrated better efficacy than other intravenous iron in increasing hemoglobin and ferritin levels in treating iron deficiency anemia in pregnant women.

Real-world utilization pattern of dydrogesterone in 7287 Indian women with obstetric and gynecological conditions: data from multicentric, retrospective study.

Objective: Despite the literature on dydrogesterone, studies on dydrogesterone utilization patterns are largely lacking in Indian patients. Methods: This was a multi-center, retrospective, observational, cross-sectional, and descriptive study across 817 centers in India. Data of patients who received dydrogesterone in past and provided consent for future use of their medical record for research purpose was were retrieved and analyzed. Results: Data of 7287 subjects (aged 29.55±4.84 years) was analyzed. Threatened abortion was the most common indication for which the subjects received dydrogesterone (46.9%) followed by recurrent pregnancy loss. Polycystic ovary syndrome (PCOS), thyroid disorders and anemia were the most common comorbid conditions and prior pregnancy loss, advanced maternal age and obesity were the most common risk factors seen in subjects who received dydrogesterone. Total 27.5% of subjects received a loading dose of dydrogesterone, and majority (64%) received 40 mg as loading dose. 10 mg dose was used as maintenance or regular dose in 81.4% of the subjects. Twice daily (BID) was the most common dosing frequency (66.6%). The most common concomitant medications being taken by the subjects on dydrogesterone included folic acid (45.1%), iron supplements (30.3%) and calcium and vitamin D3 supplements (25.5%). Another progesterone preparation (oral, injection, vaginal, tubal) other than dydrogesterone was used concurrently in 7.8% of subjects. Conclusion: The study helped to identify the patient population that is benefitted by dydrogesterone and the preferred indications, risk factors, comorbid conditions and concomitant medication used in this patient population at real-life scenario.

Fatty acids and their metabolites (resolvins) are altered in women with gestational diabetes mellitus (GDM).

The maternal fatty acid status plays a key role in influencing pregnancy outcomes. Omega-3 fatty acids are the precursors for E-series (RvE) and D-series resolvins (RvD) and possess anti-inflammatory properties. Pregnancy complications like gestational diabetes mellitus (GDM) are associated with excess maternal inflammation. This study reports the levels of maternal fatty acids across gestation in GDM and non-GDM women, placental fatty acids, resolvins and their association with the maternal fatty acid status. Pregnant women were recruited at 11-14 (V1) weeks and followed at 18-22 (V2) and 26-28 (V3) weeks and at delivery (V4). A total of 209 women who were diagnosed as GDM and 207 non-GDM women were included in this study. Fatty acids were estimated using gas chromatography. The protein levels of resolvins (RvE1, RvE2, RvD1 and RvD2) were measured using ELISA kits. Total PUFAs, eicosapentaenoic acid (EPA), omega-6 fatty acids, linoleic acid (LA) and arachidonic acid (AA) were lower, while saturated fatty acid (SFA) and alpha-linolenic acid (ALA) levels were higher in GDM women at 18-22 weeks. Placental AA was lower (p < 0.05) in women with GDM. Placental protein levels of RvE1, RvD1 and RvD2 were lower (p < 0.001 for all) in the GDM group. The maternal delta 5 desaturase index was positively associated, while erythrocyte omega-3 and omega-6 fatty acids were negatively associated with RvE2 at 11-14 weeks. Placental LA and ALA were positively associated with RvD1 and RvD2 (p < 0.05, for both), respectively. Our findings suggest that the maternal fatty acid status influences pro-resolving mediators which may lead to increased inflammation in GDM.

A meta-analysis of ferric carboxymaltose versus other intravenous iron preparations for the management of iron deficiency anemia during pregnancy

Abstract Objective: We conducted a meta-analysis of randomized clinical trials evaluating the clinical effects of ferric carboxymaltose therapy compared to other intravenous iron in improving hemoglobin and serum ferritin in pregnant women. We also assessed the safety of ferric carboxymaltose vs. other intravenous iron. Data source: EMBASE, PubMed, and Web of Science were searched for trials related to ferric carboxymaltose in pregnant women, published between 2005 and 2021. We also reviewed articles from google scholar. The keywords "ferric carboxymaltose," "FCM," "intravenous," "randomized," "pregnancy," "quality of life," and "neonatal outcomes" were used to search the literature. The search was limited to pregnant women. Selection of studies: Studies related to ferric carboxymaltose in pregnancy were scanned. Observational studies, review articles, and case reports were excluded. Randomized studies in pregnant women involving ferric carboxymaltose and other intravenous iron formulations were shortlisted. Of 256 studies, nine randomized control trials were selected. Data collection: Two reviewers independently extracted data from nine selected trials Data synthesis: The final effect size for increase in hemoglobin after treatment was significant for ferric carboxymaltose vs. iron sucrose/iron polymaltose (standard mean difference 0.89g/dl [95% confidence interval 0.27,1.51]). The final effect size for the increase in ferritin after treatment was more for ferric carboxymaltose vs. iron sucrose/iron polymaltose (standard mean difference 22.53µg/L [-7.26, 52.33]). No serious adverse events were reported with ferric carboxymaltose or other intravenous iron. Conclusion: Ferric carboxymaltose demonstrated better efficacy than other intravenous iron in increasing hemoglobin and ferritin levels in treating iron deficiency anemia in pregnant women.

Real-world utilization pattern of dydrogesterone in 7287 Indian women with obstetric and gynecological conditions: data from multicentric, retrospective study

Abstract Objective: Despite the literature on dydrogesterone, studies on dydrogesterone utilization patterns are largely lacking in Indian patients. Methods: This was a multi-center, retrospective, observational, cross-sectional, and descriptive study across 817 centers in India. Data of patients who received dydrogesterone in past and provided consent for future use of their medical record for research purpose was were retrieved and analyzed. Results: Data of 7287 subjects (aged 29.55±4.84 years) was analyzed. Threatened abortion was the most common indication for which the subjects received dydrogesterone (46.9%) followed by recurrent pregnancy loss. Polycystic ovary syndrome (PCOS), thyroid disorders and anemia were the most common comorbid conditions and prior pregnancy loss, advanced maternal age and obesity were the most common risk factors seen in subjects who received dydrogesterone. Total 27.5% of subjects received a loading dose of dydrogesterone, and majority (64%) received 40 mg as loading dose. 10 mg dose was used as maintenance or regular dose in 81.4% of the subjects. Twice daily (BID) was the most common dosing frequency (66.6%). The most common concomitant medications being taken by the subjects on dydrogesterone included folic acid (45.1%), iron supplements (30.3%) and calcium and vitamin D3 supplements (25.5%). Another progesterone preparation (oral, injection, vaginal, tubal) other than dydrogesterone was used concurrently in 7.8% of subjects. Conclusion: The study helped to identify the patient population that is benefitted by dydrogesterone and the preferred indications, risk factors, comorbid conditions and concomitant medication used in this patient population at real-life scenario.

A Rapid, Sensitive and Type-Specific Detection of High-Risk HPV-16 and HPV-18.

Human papillomavirus (HPV) infection, particularly infection with HPVs 16 and 18, is a major cause of cervical cancer. The current high-risk HPV screening or diagnosis tests use cytological or molecular techniques that are primarily based on qualitative HPV DNA detection. Comparative studies, however, revealed that different assays have varying sensitivities for detecting specific HPV types. Here, we developed and optimized a sensitive PCR (Polymerase Chain Reaction) assay for detection of high-risk HPV-16 and HPV-18. The PCR parameters were optimized, and analytical specificities were validated. Performance of developed PCR assay was evaluated in clinical samples (n = 100) which showed 100% specificity for both the assays and 96.97% and 94.12% sensitivity for HPV-16 and HPV-18, respectively. The developed assay demonstrated high sensitivity and specificity for detection of high-risk HPV-16 and HPV-18, making it applicable to routine HPV detection practices.

Longitudinal profile of high-sensitivity C-reactive protein in women with pre-eclampsia.

PROBLEM: C-reactive protein (CRP) is a marker for inflammation and its role as a possible biomarker for an early prediction of pre-eclampsia (PE) is unclear. The present study investigates the levels of high-sensitivity CRP (hs-CRP) longitudinally across pregnancy in women with PE and compares them to women without PE (non-PE). METHOD OF STUDY: A total of 324 pregnant women [216 non-PE and 108 PE women] were included in this study. Maternal blood was taken at four different intervals (V1 = 11-14 weeks, V2 = 18-22 weeks, V3 = 26-28 weeks, and V4 = at delivery). RESULTS: Maternal serum hs-CRP levels were higher at V1, V2, and V3 (p < .05 for all) in the PE group compared to the non-PE group. The hs-CRP levels were associated with maternal blood pressure throughout pregnancy. Maternal hs-CRP levels did not differ among early and late onset PE. Higher maternal hs-CRP levels were associated with the increased risk of PE in unadjusted model in early pregnancy. However, there was no significance after adjusting for confounding factors. CONCLUSIONS: Our findings suggest although the levels of hs-CRP were higher in PE in early pregnancy, they are not associated with an increased risk of PE.

Association of maternal vitamin D status with the risk of preeclampsia.

The aim of this study was to examine serum vitamin D concentrations from early pregnancy until delivery in women who did and did not develop preeclampsia. This longitudinal study was carried out in Pune, India. A total of 1154 women with singleton pregnancies were recruited in early pregnancy from two hospitals. Blood samples were collected and stored at four time points across gestation: V1 = 11-14 weeks, V2 = 18-22 weeks, V3 = 26-28 weeks and V4 = at delivery. 108 women who developed preeclampsia (PE) and 216 who did not develop PE (Non-PE) were randomly selected from the remainder. Serum 25-hydroxy vitamin D concentrations (25(OH)D) were estimated in their samples using commercially available ELISA kits. Independent t-tests were used to compare 25(OH)D between PE and non-PE groups. Logistic and linear regressions were used to examine associations of 25(OH)D with the risk of preeclampsia and birth outcomes, respectively, after adjusting for confounders. The mean (SD) 25(OH)D at V1 was 21.95 (19.64) in the Non-PE group and 17.76 (13.21) in the PE group. A decrease in the concentrations of vitamin D (ng ml-1) in mid-pregnancy (V2) and at delivery was associated with an increased risk of preeclampsia (0.31 [95% CI 0.11, 0.86], p = 0.024 and 0.24 [95% CI 0.08, 0.77], p = 0.016), respectively. Our finding of lower vitamin D concentrations in mid-pregnancy, before women developed clinical preeclampsia, suggests that vitamin D may have a role in its pathophysiology.

Longitudinal Assessment of Calcium and Magnesium Levels in Women with Preeclampsia.

The present study reports the levels of maternal serum calcium and magnesium from early pregnancy until delivery, along with cord levels, in women who developed preeclampsia (PE) and compares them with those without PE. A total of 324 pregnant women (216 non-PE and 108 PE women) were included in this retrospective case-control study of prospectively collected data nested in an observational cohort study. Maternal blood was collected at 4 time points during pregnancy (V1 = 11-14 weeks, V2 = 18-22 weeks, V3 = 26-28 weeks, and V4 = at delivery) and umbilical cord blood at delivery. Independent t tests were used to compare calcium, magnesium, and their ratio between two groups, and their associations with PE were studied using regression models. Calcium levels were similar between groups at all time points. Magnesium levels were lower (p = 0.021) at V2 in PE group as compared with non-PE group. Maternal calcium and magnesium levels were negatively associated, with blood pressure in early pregnancy. In fully adjusted logistic regression analysis, lower magnesium levels were associated with an increased risk of PE at V2 (OR 0.25 [95% CI 0.07, 0.94] p = 0.04). Lower magnesium in mid-pregnancy was associated with higher risk of PE. These changes were observed before the diagnosis of PE, thereby suggesting that they may have a role in the etiology of PE.

Gestational weight gain in the REVAMP pregnancy cohort in Western India: Comparison with international and national references.

Objective: To determine the trimester specific gestational weight gain (GWG) in a population of pregnant women from Western India and compare it with the Intergrowth-21st international and an Indian reference (GARBH-Ini cohort-Group for Advanced Research on BirtH outcomes). Study design: A prospective longitudinal observational study was undertaken in Pune, West India and data for gestational weight gain was collected [the REVAMP study (Research Exploring Various Aspects and Mechanisms in Preeclampsia)]. Generalized Additive Models for Location, Scale and Shape method (GAMLSS model) were used to create GWG centile curves according to gestational age, stratified by BMI at recruitment (n = 640) and compared with Intergrowth-21st reference and GARBH-Ini cohort. Multivariable regression analysis was used to evaluate the relationship between GWG and antenatal risk factors. Results: The median GWG was 1.68, 5.80, 7.06, and 11.56 kg at gestational ages 18, 26, 30, and 40 weeks, respectively. In our study, pregnant women gained less weight throughout pregnancy compared to Intergrowth-21st study, but more weight compared to the GARBH-Ini cohort centile curves in all the BMI categories. GWG in overweight/obese women (BMI ≥ 25) was significantly lower (<0.001) as compared to underweight (BMI < 18.5), or normal weight women (BMI ≥ 18.5 and <25). The median GWG at 40 weeks in underweight, normal and overweight/obese women was 13.18, 11.74, and 10.48 kg, respectively. Higher maternal BMI, older maternal age, higher parity and higher hemoglobin concentrations were associated with lower GWG, while taller maternal height was associated with greater GWG. Conclusion: GWG of Indian women is lower than the prescriptive standards of the Intergrowth charts.

The 2021 International Society for the Study of Hypertension in Pregnancy classification, diagnosis & management recommendations for international practice.

All units managing hypertensive pregnant women should maintain and review uniform departmental management protocols and conduct regular audits of maternal & fetal outcomes. The cause(s) of pre-eclampsia and the optimal clinical management of the hypertensive disorders of pregnancy remain uncertain; therefore, we recommend that every hypertensive pregnant woman be offered an opportunity to participate in research, clinical trials and follow-up studies.

Clinical effects and safety of ferric carboxymaltose in pregnancy: An Indian real-life experience.

BACKGROUND: There is limited clinical evidence of ferric carboxymaltose injection (FCM) usage in Indian pregnant women. We assessed the efficacy and safety of FCM in Indian pregnant women with moderate-to-severe anemia. METHODS: Single-center, retrospective, observational data collection was conducted at a tertiary care research institute. Data of pregnant women with anemia who received FCM in their second and third trimester was retrieved and analyzed for hematological parameters at baseline and at 4 ± 2 weeks. Neonatal outcomes were also assessed. Adverse events and other safety parameters were noted. RESULTS: Data of 271 patients was retrieved and analyzed for safety and data for 168 patients analyzed for efficacy. A significant increase in hemoglobin was noted with FCM in 4 weeks (1.25 g/dL; p < 0.001). Patients with severe anemia reported an increase in hemoglobin of 4.23 g/dL (p = 0.01). Patients receiving FCM in the second trimester noted a significant increase in hemoglobin of 1.74 g/dL (p < 0.001). A significant increase in hemoglobin was noted as early as 20 days (p < 0.001) and also in patients receiving FCM after 34 weeks (p = 0.002). No adverse fetal or neonatal outcomes were observed. Adverse events noted in 4% of patients with itching and rash being most common. Continuous monitoring of blood pressure, heart rate, and oxygen saturation for 40 min during and after FCM administration reported no deterioration or negative safety signal. CONCLUSION: FCM corrects anemia in all subsets of Indian pregnant women and supports evidence of efficacy and safety. Continuous monitoring of vital parameters during FCM infusions supports its excellent safety.

Unravelling the potential of angiogenic factors for the early prediction of preeclampsia.

Preeclampsia is a multisystem, multiorgan hypertensive disorder of pregnancy responsible for maternal and perinatal morbidity and mortality in low- and middle-income countries. The classic diagnostic features hold less specificity for preeclampsia and its associated adverse outcomes, suggesting a need for specific and reliable biomarkers for the early prediction of preeclampsia. The imbalance of pro- and antiangiogenic circulatory factors contributes to the pathophysiology of preeclampsia. Several studies have examined the profile of angiogenic factors in preeclampsia to search for a biomarker that will improve the diagnostic ability of preeclampsia and associated adverse outcomes. This may help in more efficient patient management and the reduction of associated health care costs. This article reviews the findings from previous studies published to date on angiogenic factors and suggests a need to apply a multivariable model from the beginning of pregnancy and continuing throughout gestation for the early and specific prediction of preeclampsia.

Placental neurotrophin levels in gestational diabetes mellitus.

OBJECTIVE: Neurotrophins are known to influence the development and maturation of the feto-placental unit and affect fetal growth trajectories. This study reports the levels of nerve growth factor (NGF) and brain-derived growth factor (BDNF) in the placenta of women with gestational diabetes mellitus (GDM). METHODS: A total number of 60 women with GDM and 70 women without GDM (non-GDM) were included in the study. Placental NGF and BDNF levels were measured using commercially available ELISA kits. RESULTS: Placental NGF levels were lower (p < .05) in women with GDM compared to non-GDM women. Maternal body mass index (BMI), mode of delivery, and the gender of the baby influenced the placental NGF levels. Placental BDNF levels were similar in GDM and non-GDM women. There was an influence of baby gender on the placental BDNF levels while maternal BMI and mode of delivery did not show any effect. In regression models adjusted for maternal age at delivery, gestational age, maternal BMI, mode of delivery, and baby gender, the placental NGF levels in the GDM group were lower (-0.144 pg/ml [95% CI -0.273, 22120.016] p = .028) as compared to the non-GDM group. However, there was no difference in the BDNF levels between the groups. CONCLUSION: This study for the first time demonstrates differential effects on neurotrophic factors such as BDNF and NGF in the placenta in pregnancies complicated by GDM. Alterations in the levels of placental neurotrophins in GDM deliveries may affect placental development and fetal brain growth. This has implications for increased risk for neurodevelopmental pathologies in later life.