Impaired Fetal Growth Research Articles

Effects of Prenatal Exposure to Bisphenol A Substitutes, Bisphenol S and Bisphenol F, on Offspring's Health: Evidence from Epidemiological and Experimental Studies.

Pregnancy and lactation are critical periods for human well-being and are sensitive windows for pollutant exposure. Bisphenol A (BPA) is well demonstrated as a toxicant and has been replaced in the plastic industry with other bisphenol analogs that share similarities in structure and characteristics, most commonly Bisphenol S (BPS) and Bisphenol F (BPF). Maternal exposure to BPS or BPF can result in their accumulation in the fetal compartment, leading to chronic exposure and potentially limiting normal fetal growth and development. This review summarizes considerable findings of epidemiological or experimental studies reporting associations between BPS or BPF and impaired fetal growth and development. Briefly, the available findings indicate that exposure to the two bisphenol analogs during pregnancy and lactation can result in multiple disturbances in the offspring, including fetal growth restrictions, neurological dysfunctions, and metabolic disorders with the potential to persist throughout childhood. The occurrence of premature births may also be attributed to exposure to the two bisphenols. The possible mechanisms of actions by which the two bisphenols can induce such effects can be attributed to a complex of interactions between the physiological mechanisms, including impaired placental functioning and development, dysregulation of gene expression, altered hormonal balance, and disturbances in immune responses as well as induced inflammations and oxidative stress. In conclusion, the available evidence suggests that BPS and BPF have a toxic potential in a compartment level to BPA. Future research is needed to provide more intensive information; long-term studies and epidemiological research, including a wide scale of populations with different settings, are recommended. Public awareness regarding the safety of BPA-free products should also be enhanced, with particular emphasis on educating individuals responsible for the well-being of children.

Assessment of Crown-Heel length, Head Circumference, and Mid-Arm Circumference for Estimation of Small for Gestational Age in Rural Area

Background: The burden of having small for gestational age (SGA) children is high in low- and middle-income countries, mainly in South Asia. Identifying these low birth weight and SGA infants and referring them to higher centers for effective intervention will help reduce neonatal mortality and morbidity. Anthropometric measurements of the neonatal population, especially birth weight measurements, constitute an important scientific research tool for studying the determinants and consequences of impaired or excessive fetal growth. Objective: To find an alternative anthropometric procedure, the present study was done to measure and compare birth weight with crown heel length (CHL), head circumference (HC), and mid-upper arm circumference (MUAC) as predictors of birth weight in small for gestational age (SGA). Methods: This cross-sectional, analytical study was done in the Department of Anatomy, Rangpur Medical College, Rangpur from July 2020 to June 2021 on 200 newborns of both sexes with gestational age between 37 and 42 weeks. The newborn was selected and measured within 24 hours of birth. 100 term newborns weighted <2.5 kg regarded as SGA were the subjects of the study. Another 100-term newborns weighted >2.5 kg regarded as AGA served as control. The birth weight, head circumference, mid-upper arm circumference, and crown heel length were measured and a comparison of all the variables was done between AGA and SGA newborns. Data was analyzed by using a statistical package for social sciences (SPSS version 26). Result: The mean± SD of birth weight in AGA and SGA groups was 2.99 ±0.31 and 2.10±0.24 respectively; it was observed that the mean± SD of crown heel length, head circumference, and mid-upper arm circumference and Ponderal index in AGA group was significantly higher than SGA group; however the MAC/HC ratio was almost similar between AGA and SGA groups. All the above variables were significantly correlated with birth weight in both AGA and SGA groups. Conclusion: Some simple and inexpensive measurements of newborns especially the head circumference of SGA newborns are as effective as birth weight measurement; crown heel length, and mid-upper arm circumference could also be used to predict birth weight in SGA newborns. J Rang Med Col. September 2023; Vol. 8, No. 2: 14-19

Adverse outcomes in SARS-CoV-2-infected pregnant mice are gestational age-dependent and resolve with antiviral treatment.

SARS-CoV-2 infection during pregnancy is associated with severe COVID-19 and adverse fetal outcomes, but the underlying mechanisms remain poorly understood. Moreover, clinical studies assessing therapeutics against SARS-CoV-2 in pregnancy are limited. To address these gaps, we developed a mouse model of SARS-CoV-2 infection during pregnancy. Outbred CD1 mice were infected at E6, E10, or E16 with a mouse-adapted SARS-CoV-2 (maSCV2) virus. Outcomes were gestational age-dependent, with greater morbidity, reduced antiviral immunity, greater viral titers, and impaired fetal growth and neurodevelopment occurring with infection at E16 (third trimester equivalent) than with infection at either E6 (first trimester equivalent) or E10 (second trimester equivalent). To assess the efficacy of ritonavir-boosted nirmatrelvir, which is recommended for individuals who are pregnant with COVID-19, we treated E16-infected dams with mouse-equivalent doses of nirmatrelvir and ritonavir. Treatment reduced pulmonary viral titers, decreased maternal morbidity, and prevented offspring growth restriction and neurodevelopmental impairments. Our results highlight that severe COVID-19 during pregnancy and fetal growth restriction is associated with heightened virus replication in maternal lungs. Ritonavir-boosted nirmatrelvir mitigated maternal morbidity along with fetal growth and neurodevelopment restriction after SARS-CoV-2 infection. These findings prompt the need for further consideration of pregnancy in preclinical and clinical studies of therapeutics against viral infections.

AI-Enhanced Analysis Reveals Impact of Maternal Diabetes on Subcutaneous Fat Mass in Fetuses without Growth Alterations.

Pregnant women with diabetes often present impaired fetal growth, which is less common if maternal diabetes is well-controlled. However, developing strategies to estimate fetal body composition beyond fetal growth that could better predict metabolic complications later in life is essential. This study aimed to evaluate subcutaneous fat tissue (femur and humerus) in fetuses with normal growth among pregnant women with well-controlled diabetes using a reproducible 3D-ultrasound tool and offline TUI (Tomographic Ultrasound Imaging) analysis. Additionally, three artificial intelligence classifier models were trained and validated to assess the clinical utility of the fetal subcutaneous fat measurement. A significantly larger subcutaneous fat area was found in three-femur and two-humerus selected segments of fetuses from women with diabetes compared to the healthy pregnant control group. The full classifier model that includes subcutaneous fat measure, gestational age, fetal weight, fetal abdominal circumference, maternal body mass index, and fetal weight percentile as variables, showed the best performance, with a detection rate of 70%, considering a false positive rate of 10%, and a positive predictive value of 82%. These findings provide valuable insights into the impact of maternal diabetes on fetal subcutaneous fat tissue as a variable independent of fetal growth.

Small-for-gestational-age fetus diagnosed in the second trimester: Possible etiologies and short-term neonataloutcomes.

The aim of our study was to investigate the causes of fetal growth <10th centile diagnosed <26 weeks' gestation in singleton pregnancies and compare pregnancy outcomes in relation to the identified etiology. Historical cohort study conducted in two Italian hospitals which included all small-for-gestational-age fetuses diagnosed between 18+0 and 26+0 weeks over a 10-year period. Fetuses were divided into three groups depending on the prenatally suspected etiology: chromosomal abnormalities (Group 1), malformations (Group 2) and isolated (Group 3). These groups were compared regarding pregnancy outcomes. Fetuses in Group 3 were divided into small-for-gestational-age and fetal growth restriction following the Delphi Consensus criteria and the outcomes were further compared. Fisher's Exact or Mann-Whitney test were used for comparison of groups. In all, 435 fetuses were included. Of these, 20 cases (4.6%) were associated with chromosomal abnormalities (Group 1), 98 (22.5%) with fetal malformations (Group 2) and 317 (72.9%) were isolated (Group 3). A higher percentage of live births was reported for Group 3 (P < 0.001). Termination of pregnancy was more common in Group 1 (P < 0.001). No differences in gestational age at delivery, birthweight, intrauterine death or neonatal death were detected within groups. Growth-restricted fetuses had lower gestational age at delivery, birthweight and number of live births (P < 0.001), higher rates of termination of pregnancy, intrauterine death (P < 0.001) and neonatal death <10 days (P = 0.002) compared to small-for-gestational-age. In 17 cases a chromosomal abnormality, genetic syndrome or adverse neurological outcome was diagnosed after birth: six from Group 2 (11.3% of live births in this group) and 11 from Group 3 (4.3%). We report that fetal growth <10th percentile diagnosed before 26 weeks is not isolated before birth in 27% of cases. Malformations and chromosomal abnormalities are common etiologies; therefore, detailed anomaly scans and invasive testing should be offered. In addition, there is a residual risk of neonatal death and postnatal diagnosis of a genetic syndrome or neurodevelopmental impairment despite normal prenatal tests. These results expand the small amount of information on the outcome of cases with very early diagnosis of impaired fetal growth currently available and highlight the importance of detailed counseling with couples.

Alcohol blunts pregnancy-mediated insulin resistance and reduces fetal brain glucose despite elevated fetal gluconeogenesis, and these changes associate with fetal weight outcomes.

Prenatal alcohol exposure (PAE) impairs fetal growth and neurodevelopment. Although alcohol is well known to alter metabolism, its impact on these processes during pregnancy is largely unexplored. Here, we investigate how alcohol affects maternal-fetal glucose metabolism using our established mouse binge model of PAE. In the dam, alcohol reduces the hepatic abundance of glucose and glycolytic intermediates, and the gluconeogenic enzymes glucose-6-phosphtase and phosphoenolpyruvate carboxykinase. Fasting blood glucose is also reduced. In a healthy pregnancy, elevated maternal gluconeogenesis and insulin resistance ensures glucose availability for the fetus. Glucose and insulin tolerance tests reveal that alcohol impairs the dam's ability to acquire insulin resistance. Alcohol-exposed dams have enhanced glucose clearance (p < .05) in early gestation, after just two days of alcohol, and this persists through late term when fetal glucose needs are maximal. However, maternal plasma insulin levels, hepatic insulin signaling, and the abundance of glucose transporter proteins remain unchanged. In the PAE fetus, the expression of hepatic gluconeogenic genes is elevated, and there is a trend for elevated blood and liver glucose levels. In contrast, fetal brain and placental glucose levels remain low. This reduced maternal fasting glucose, reduced hepatic glucose, and elevated glucose clearance inversely correlated with fetal body and brain weight. Taken together, these data suggest that alcohol blunts the adaptive changes in maternal glucose metabolism that otherwise enhance fetal glucose availability. Compensatory attempts by the fetus to increase glucose pools via gluconeogenesis do not normalize brain glucose. These metabolic changes may contribute to the impaired fetal growth and brain development that typifies PAE.

Sex-Specific Effects of Prenatal Hypoxia and a Placental Antioxidant Treatment on Cardiac Mitochondrial Function in the Young Adult Offspring.

Prenatal hypoxia is associated with placental oxidative stress, leading to impaired fetal growth and an increased risk of cardiovascular disease in the adult offspring; however, the mechanisms are unknown. Alterations in mitochondrial function may result in impaired cardiac function in offspring. In this study, we hypothesized that cardiac mitochondrial function is impaired in adult offspring exposed to intrauterine hypoxia, which can be prevented by placental treatment with a nanoparticle-encapsulated mitochondrial antioxidant (nMitoQ). Cardiac mitochondrial respiration was assessed in 4-month-old rat offspring exposed to prenatal hypoxia (11% O2) from gestational day (GD)15-21 receiving either saline or nMitoQ on GD 15. Prenatal hypoxia did not alter cardiac mitochondrial oxidative phosphorylation capacity in the male offspring. In females, the NADH + succinate pathway capacity decreased by prenatal hypoxia and tended to be increased by nMitoQ. Prenatal hypoxia also decreased the succinate pathway capacity in females. nMitoQ treatment increased respiratory coupling efficiency in prenatal hypoxia-exposed female offspring. In conclusion, prenatal hypoxia impaired cardiac mitochondrial function in adult female offspring only, which was improved with prenatal nMitoQ treatment. Therefore, treatment strategies targeting placental oxidative stress in prenatal hypoxia may reduce the risk of cardiovascular disease in adult offspring by improving cardiac mitochondrial function in a sex-specific manner.

Functional and Histological Changes in Umbilical Artery and Myometrium Isolated from IUGR Complicated Pregnancies

Objective: To investigate the relaxation responses mediated by L-type Ca2+ channels and big-conductance Ca2+-activated K+ (BKCa) channels and histological changes in the human umbilical artery (HUA) and myometrium smooth muscle isolated from pregnancies complicated with intrauterine growth restriction (IUGR).Methods: The muscle reactivity and the histology of the smooth muscle of the HUA and myometrium retrieved from 14 women with IUGR and 14 controls were investigated by the isolated tissue bath and immunohistochemical method.Results: In HUA, the maximum relaxation responses and pD2 values of nifedipine and NS11021 (BKCa channel opener) were significantly increased and significant histopathological changes are observed in the IUGR group.Conclusions: The pathogenesis of IUGR might be associated with the impairment in the functional responses of L-type Ca2+ channels and BKCa channels in HUA smooth muscle. The increased staining of myometrium and UC with HIF-1α in IUGR may indicate apoptosis, histological damage, and impaired fetal growth.

Maternal-derived galectin-1 shapes the placenta niche through Sda terminal glycosylation: Implication for preeclampsia.

Placental abnormalities cause impaired fetal growth and poor pregnancy outcome (e.g. preeclampsia [PE]) with long-lasting consequences for the mother and offspring. The molecular dialogue between the maternal niche and the developing placenta is critical for the function of this organ. Galectin-1 (gal-1), a highly expressed glycan-binding protein at the maternal-fetal interface, orchestrates the maternal adaptation to pregnancy and placenta development. Down-regulation or deficiency of gal-1 during pregnancy is associated with the development of PE; however, the maternal- and placental-derived gal-1 contributions to the disease onset are largely unknown. We demonstrate that lack of gal-1 imposes a risk for PE development in a niche-specific manner, and this is accompanied by a placental dysfunction highly influenced by the absence of maternal-derived gal-1. Notably, differential placental glycosylation through the Sda-capped N-glycans dominates the invasive trophoblast capacity triggered by maternal-derived gal-1. Our findings show that gal-1 derived from the maternal niche is essential for healthy placenta development and indicate that impairment of the gal-1 signaling pathway within the maternal niche could be a molecular cause for maternal cardiovascular maladaptation during pregnancy.

Two- and three-dimensional sonographic findings of harlequin ichthyosis: case report and literature review

BackgroundHarlequin ichthyosis (HI) is a rare skin disorder with extremely high lethality due to a mutation of the ABCA12 gene. Because of its rarity and the often-late onset, prenatal screening for HI is extremely difficult, and most pregnant women might easily miss the period for optimal examinations. ObjectiveTo summarize the sonographic features of HI for prenatal diagnostic purposes. MethodsThe authors describe a case of HI with no family history who was diagnosed by using prenatal ultrasound scanning. The sonographic features of HI and the clinical characteristics of pregnant women were summarized by searching relevant literature over nearly two decades. ResultsThe unique sonographic presentations including peeling skin, clenched hands and clubfeet, ectropion, flat nose, fetal growth impairment, polyhydramnios and echogenic amniotic fluid may be primarily related to skin disorders in HI fetuses. The authors also identified a novel pathogenic ABCA12 gene mutation and explained the possible pathogenic mechanisms. Study limitationsCaution should be exercised in summarizing disease characteristics because of the small number of cases, and the authors are faced with the possibility of incomplete case searching. ConclusionsHI has relatively unique sonographic features. Therefore, 2D-ultrasound combined with 3D-ultrasound may be an effective method for the prenatal diagnosis of HI. Moreover, a novel pathogenic ABCA12 gene mutation may provide important clues for future research on the etiology of HI. However, the authors consider that additional studies are needed to provide more evidence for prenatal diagnosis.

Obesity in Pregnant Women and Its Impact on Maternal and Neonatal Morbidity

Obesity in pregnancy is currently a health problem that is associated with increased maternal and neonatal morbidity. Along with the times and lifestyles that are more modern, the incidence of obesity is also increasing. Clinically, obesity is defined as the condition of having excess adipose tissue. Obesity is related to insulin resistance and chronic inflammation. This makes obesity a risk factor for various non-contagious diseases such as cardiovascular disease, hypertension, diabetes mellitus, and cancer. The health consequences of maternal obesity are based on low-grade, chronic (meta-inflammatory) inflammation that occurs as a result of changes in the immune system and proinflammatory cytokines in maternal obesity and pregnancy. Obesity can have a negative impact on maternal, neonatal and labor outcomes. Several maternal complications that can occur due to obesity (BMI 30-34.9) and morbid obesity (BMI ≥ 35) are hypertension during pregnancy (10.2-12.3%), preeclampsia (3-6.3%), gestational diabetes (6.3-9.5%). Risks that can occur to the fetus, such as the occurrence of macrosomia (15.4-17.2%), preterm birth (4-5.5%) and impaired fetal growth (1-0.8%). Maternal obesity is also associated with an increased risk of neural tube defects (NTD) in babies, as well as a higher risk of abortion (1.70-3.11%). Obesity also has an impact on the delivery process. Mothers with obesity have a higher rate of vaginal operative procedures (8.5-11.1%), labor induction and longer duration of labor. The increase in caesarean section deliveries is caused by the occurrence of complications due to maternal obesity, namely the occurrence of preeclampsia, fetal distress, macrosomia, and induction failure.

Birth weight and hypertension: nature or nurture?

Birth weight and hypertension: nature or nurture?

Association of C677T and A1298C genetic polymorphisms in MTHFR gene with fetal growth restriction, small for gestational age and low birth weight: A meta-analysis

Impaired fetal growth has a wide range of short-term and long-term effects on physical and mental health. Fetal Growth Restriction (FGR), Small for Gestational Age (SGA) and Low Birth Weight (LBW) are three diagnoses of impaired fetal growth/size, but differences between them are not fully understood. This meta-analysis aimed to investigate the association of two genetic variants C677T and A1298C in methylenetetrahydrofolate reductase (MTHFR) gene with the risk of impaired fetal growth and then confirm this association with specific diagnosis. According to PRISMA protocols, 24 articles were included after searching the following databases: PubMed, Google Scholar, Science Direct, Web of Science, Cochrane Library and Cyber-Lenics. Meta-analysis was conducted in dominant, recessive, and allelic models of inheritance. According to our data, MTHFR C677T is associated with higher risk of impaired fetal growth and especially with FGR susceptibility (OR = 1.93, 95% CI 1.27–2.95, P = 0.002). On the other hand, MTHFR A1298C can be suggested as a risk factor of SGA (OR = 1.61, 95% CI 1.16–2.24, P = 0.005). However, it has no significant association with FGR or LBW. Our findings help to better understand MTHFR impact on fetal growth and distinguish FGR and SGA as separated cases of fetal growth abnormality.

Ponderal Index: An Important Anthropometric Indicator for Physical Growth

The Ponderal Index (PI) is an essential measure to study physical growth of fetus, infants, newborn babies, adolescents, and adults. Lower PI is found among the malnourish infants and newborn babies and higher in obese ones. PI is also applied in maternity treatment to detect impaired fetal growth. Neonatal PI is essential to identify the effects of gestation age, sex, and maternal parity. In this study aspects of Ponderal Index (PI) are discussed to increase the measurement area for the reduction of risk factors of the infants and children morbidity and mortality.

Peningkatan Kemampuan Deteksi Dini Depresi pada Ibu Hamil di Kota Surabaya

The problems of pregnant women are not only physical health problems but also mental health problems. Mothers who experience mental and emotional health disorders are usually unable to carry out their daily functions properly and experience impaired fetal growth and development, social problems, and mental safety. So far, the examination of pregnant women and antenatal care efforts have focused more on efforts to maintain the physical health status of pregnant women and have not touched on the emotional health aspects, especially depression. So efforts to detect early and even prevent depression during pregnancy are significant. Increased knowledge and early detection of depression can help pregnant women prevent depression and provide solutions for appropriate treatment. This community service activity formed a class of pregnant women in RW 9, 13, and 14 as many as 28 people in Ujung Village, Semampir District, Surabaya City. The material was given directly by using a back sheet and leaflets. Pre-tests and post-tests are carried out before and after giving the material. The results of this community service activity showed that there was an increase in the ability to detect depression in pregnant women after attending classes for pregnant women on three materials (p=0,006; p=0.000; p=0,000; α=0.05). The ability to detect depression will prevent depression because pregnant women know the symptoms of depression that are visible or felt. So that pregnant women can make follow-up efforts and appropriate treatment if depression is detected.

Fetal factors disrupt placental and maternal iron homeostasis in murine β-thalassemia

AbstractPregnancy rates in β-thalassemia are increasing but the risk of complications is higher; thus, better understanding of maternal and fetal iron homeostasis in this disorder is needed. HbbTh3/+ (Th3/+) mice model human β-thalassemia. Both the murine and human diseases are characterized by low hepcidin, high iron absorption, and tissue iron overload, with concurrent anemia. We hypothesized that disordered iron metabolism in pregnant Th3/+ mice would negatively affect their unborn offspring. The experimental design included these groups: wild-type (WT) dams carrying WT fetuses (WT1); WT dams carrying WT and Th3/+ fetuses (WT2); Th3/+ dams carrying WT and Th3/+ fetuses (Th3/+); and age-matched, nonpregnant adult females. Serum hepcidin was low, and mobilization of splenic and hepatic storage iron was enhanced in all 3 groups of experimental dams. Intestinal 59Fe absorption was lower in Th3/+ dams (as compared with WT1/2 dams) but splenic 59Fe uptake was higher. Th3/+ dams had hyperferremia, which led to fetal and placenta iron loading, fetal growth restriction, and placentomegaly. Notably, Th3/+ dams loaded Th3/+ and WT fetuses, with the latter situation more closely mirroring human circumstances when mothers with thalassemia have relatively unaffected (thalassemia trait) offspring. Iron-related oxidative stress likely contributed to fetal growth impairment; enhanced placental erythropoiesis is a probable cause of placental enlargement. Moreover, high fetal liver iron transactivated Hamp; fetal hepcidin downregulated placental ferroportin expression, limiting placental iron flux and thus mitigating fetal iron loading. Whether gestational iron loading occurs in human thalassemic pregnancy, when blood transfusion can further elevate serum iron, is worth consideration.

The Proteome Landscape of Human Placentas for Monochorionic Twins with Selective Intrauterine Growth Restriction

In perinatal medicine, intrauterine growth restriction (IUGR) is one of the greatest challenges. The etiology of IUGR is multifactorial, but most cases are thought to arise from placental insufficiency. However, identifying the placental cause of IUGR can be difficult due to numerous confounding factors. Selective IUGR (sIUGR) would be a good model to investigate how impaired placentation affects fetal development, as the growth discordance between monochorionic twins cannot be explained by confounding genetic or maternal factors. Herein, we constructed and analyzed the placental proteomic profiles of IUGR twins and normal cotwins. Specifically, we identified a total of 5481 proteins, of which 233 were differentially expressed (57 up-regulated and 176 down-regulated) in IUGR twins. Bioinformatics analysis indicates that these differentially expressed proteins (DEPs) are mainly associated with cardiovascular system development and function, organismal survival, and organismal development. Notably, 34 DEPs are significantly enriched in angiogenesis, and diminished placental angiogenesis in IUGR twins has been further elaborately confirmed. Moreover, we found decreased expression of metadherin (MTDH) in the placentas of IUGR twins and demonstrated that MTDH contributes to placental angiogenesis and fetal growth in vitro. Collectively, our findings reveal the comprehensive proteomic signatures of placentas for sIUGR twins, and the DEPs identified may provide in-depth insights into the pathogenesis of placental dysfunction and subsequent impaired fetal growth.

SARS-CoV-2 Footprints in the Placenta: What We Know after Three Years of the Pandemic.

As the COVID-19 pandemic continues into its third year, there is accumulating evidence on the consequences of maternal infection. Emerging data indicate increased obstetrics risks, including maternal complications, preterm births, impaired intrauterine fetal growth, hypertensive disorders, stillbirth, gestational diabetes, and a risk of developmental defects in neonates. Overall, controversial concerns still exist regarding the potential for vertical transmission. Histopathological examination of the placenta can represent a useful instrument for investigation and can contribute significant information regarding the possible immunohistopathological mechanisms involved in developing unfavorable perinatal outcomes. Based on current evidence, SARS-CoV-2 infection can affect placental tissue by inducing several specific changes. The level of placental involvement is considered one of the determining factors for unfavorable outcomes during pregnancy due to inflammation and vascular injuries contributing to complex cascade immunological and biological events; however, available evidence does not indicate a strong and absolute correlation between maternal infection, placental lesions, and obstetric outcomes. As existing studies are still limited, we further explore the placenta at three different levels, using histology, immunohistochemistry, and molecular genetics to understand the epidemiological and virological changes observed in the ongoing pandemic.

Maternal biomarkers of endothelial dysfunction and pregnancy outcomes in women with and without HIV in Botswana.

Women living with HIV-1 (WLHIV) are at higher risk of having an adverse birth outcome, but the underlying mechanism(s) are unknown. We hypothesized that HIV-associated endothelial activation could adversely impact placental function and lead to impaired fetal growth or stillbirth. We used stored samples from WLHIV and HIV-negative women who had enrolled during pregnancy in the observational Botswana Tshipidi cohort. Written informed consent was obtained from the participants. We measured plasma levels of markers of endothelial activation (soluble vascular adhesion molecule 1 [VCAM-1], intercellular adhesion molecule 1 [ICAM-1] and E-selectin) from samples taken during pregnancy. We compared log10 biomarker levels by maternal HIV status and by the timing of ART initiation (ART prior to conception vs. during pregnancy; ART prior to sample collection vs. no ART prior to sampling) using t-tests and the Kruskal-Wallis rank test. We evaluated the association between these biomarkers and adverse birth outcomes (composite of stillbirth or small for gestational age [SGA]) using univariate and multivariate log-binomial regression controlling for maternal age (continuous) and timing of ART start. We also used generalized linear models (GLM) to evaluate the association between continuous birthweight (in grams) and gestational age (in weeks) and markers of endothelial dysfunction, adjusting for maternal age (continuous) and timing of ART relative to sample collection. Specimens collected before delivery were available for 414 women (372 WLHIV and 42 HIV-negative women), with a median age of 28 years and median gestational age at sample collection of 30 weeks (range 26, 35 weeks). WLHIV had significantly higher median VCAM1 (p = 0.002) than HIV-negative women, but HIV-negative women had higher median ICAM1 (p = 0.01); e-Selectin levels did not differ by maternal HIV status. Women starting ART during pregnancy had higher log10 VCAM1 levels than those on ART before conception, regardless of whether the sample was collected before (p = 0.02) or after (p = 0.03) ART initiation. However, ICAM1 and e-Selectin did not differ significantly by ART status or ART timing. Ninety-eight women (91 WLHIV and 7 HIV-negative), or 9 (2%) and 89 (22%) included in this study, had a stillborn or SGA baby respectively. Univariate and adjusted analyses did not show significant associations between levels of any of the biomarkers with these adverse birth outcomes. However, lower birthweight (p = 0.03) and lower gestational age at delivery were associated e-Selectin and ICAM (p = 0.008), respectively. Maternal HIV infection and lack of ART (or recent ART initiation) were associated with one marker of greater endothelial activation (VCAM-1), but not with other markers (ICAM-1 nor E-selectin) in pregnancy. e-Selectin was associated with lower birthweight and every unit increase in log ICAM-1 at delivery was associated with lower gestation age at delivery.

First-Trimester Maternal Serum Adiponectin/Leptin Ratio in Pre-Eclampsia and Fetal Growth.

The serum adiponectin/leptin ratio (A/L ratio) is a surrogate marker of insulin sensitivity. Pre-eclampsia (PE) is associated with maternal metabolic syndrome and occasionally impaired fetal growth. We assessed whether the A/L ratio in first-trimester maternal serum was associated with PE and/or birth weight. Adiponectin and leptin were quantitated in first-trimester blood samples (gestational week 10+3−13+6) from 126 women who later developed PE with proteinuria (98 mild PE; 21 severe PE; 7 HELLP syndrome), and 297 controls, recruited from the Copenhagen First-Trimester Screening Study. The A/L ratio was reduced in PE pregnancies, median 0.17 (IQR: 0.12−0.27) compared with controls, median 0.32 (IQR: 0.19−0.62) (p < 0.001). A multiple logistic regression showed that PE was negatively associated with log A/L ratio independent of maternal BMI (odds ratio = 0.315, 95% CI = 0.191 to 0.519). Adiponectin (AUC = 0.632) and PAPP-A (AUC = 0.605) were negatively associated with PE, and leptin (AUC = 0.712) was positively associated with PE. However, the A/L ratio was a better predictor of PE (AUC = 0.737), albeit not clinically relevant as a single marker. No significant association was found between A/L ratio and clinical severity of pre-eclampsia or preterm birth. PE was associated with a significantly lower relative birth weight (p < 0.001). A significant negative correlation was found between relative birth weight and A/L ratio in controls (β = −0.165, p < 0.05) but not in PE pregnancies), independent of maternal BMI. After correction for maternal BMI, leptin was significantly associated with relative birth weight (β = 2.98, p < 0.05), while adiponectin was not significantly associated. Our findings suggest that an impairment of the A/L ratio (as seen in metabolic syndrome) in the first trimester is characteristic of PE, while aberrant fetal growth in PE is not dependent on insulin sensitivity, but rather on leptin-associated pathways.