Effects of antenatal melatonin therapy on lung structure in growth-restricted newborn lambs

Oxidative stress arising from suboptimal placental function contributes to a multitude of pathologies in infants compromised by fetal growth restriction (FGR). FGR infants are at high risk for respiratory dysfunction after birth and poor long-term lung function. Our objective was to investigate the contribution of oxidative stress to adverse lung development and the effects of melatonin administration, a powerful antioxidant, on lung structure in FGR lambs. Placental insufficiency and FGR was surgically induced in 13 fetal sheep at ∼105 days of gestation by ligation of a single umbilical artery. Maternal intravenous melatonin infusion was commenced in seven of the ewes 4 h after surgery and continued until birth. Lambs delivered normally at term and lungs were collected 24 h after birth for histological assessment of lung structure and injury and compared with appropriately grown control lambs ( n = 8). FGR fetuses were hypoxic and had lower glucose during gestation compared with controls. Melatonin administration prevented chronic hypoxia. Within the lung, FGR caused reduced secondary septal crest density and altered elastin deposition compared with controls. Melatonin administration had no effect on the changes to lung structure induced by FGR. We conclude that chronic FGR disrupts septation of the developing alveoli, which is not altered by melatonin administration. These findings suggest that oxidative stress is not the mechanism driving altered lung structure in FGR neonates. Melatonin administration did not prevent disrupted airway development but also had no apparent adverse effects on fetal lung development. NEW & NOTEWORTHY Fetal growth restriction (FGR) results in poor respiratory outcomes, which may be caused by oxidation in utero. We investigated the contribution of oxidative stress to adverse lung development and the effects of melatonin administration, a powerful antioxidant, on lung structure in FGR lambs. FGR disrupted septation of the developing alveoli, which is not altered by melatonin administration. Oxidative stress may not be the mechanism driving altered lung structure in FGR neonates.

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The role of melatonin in pregnancies complicated by placental insufficiency: a systematic review

10.22541/au.161790597.72492340/v1 ◽

2021 ◽

Author(s):

Ilaria Fantasia ◽

Sofia Bussolaro ◽

Tamara Stampalija ◽

Daniel Rolnik

Keyword(s):

Oxidative Stress ◽

Fetal Growth ◽

Fetal Growth Restriction ◽

Evidence Synthesis ◽

Placental Insufficiency ◽

Growth Restriction ◽

Melatonin Receptors ◽

Qualitative Evidence Synthesis ◽

Melatonin Administration

Background: Pregnancies complicated by placental insufficiency are characterised by increased oxidative stress. It has been suggested that melatonin has antioxidant properties and contributes to the maintenance of placental homeostasis. Objective: To systematically review the available literature about melatonin in pregnancies complicated by placental insufficiency, specifically preeclampsia and fetal growth restriction, exploring three different aspects: 1) maternal melatonin levels; 2) expression and activity of melatonin placental receptors; 3) effects of maternal melatonin administration. Search strategy: PubMed (Medline) and Scopus were searched until December 2020. Selection criteria: Published literature in English language describing the role of melatonin in pregnancies complicated by placental insufficiency, with a specific focus on preeclampsia and fetal growth restriction. Data collection and analysis: Identified studies were screened and assessed independently by two authors. Data were extracted and compiled in a qualitative evidence synthesis. Main results: Pregnancies complicated by placental insufficiency show a significant reduction in maternal systemic serum melatonin levels and a significant reduction in the expression of placental melatonin receptors. Melatonin administration in pregnancy seems safe and may reduce oxidative stress. Conclusion: The circadian pattern of melatonin secretion seems to be altered in pregnancies complicated by placental insufficiency. This is reflected by lower production of melatonin, with consequent lower systemic and placental concentrations, and lower expression of melatonin receptors, thus reducing the local release of the indole and its autocrine function. Funding: None Keywords: Melatonin, Preeclampsia, Fetal growth restriction, Placental insufficiency, Review.

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Effects of fetal growth restriction on lung development before and after birth: A morphometric analysis

Pediatric Pulmonology ◽

10.1002/ppul.1109 ◽

2001 ◽

Vol 32 (3) ◽

pp. 201-210 ◽

Cited By ~ 84

Author(s):

G.S. Maritz ◽

M.L. Cock ◽

S. Louey ◽

B.J. Joyce ◽

C.A. Albuquerque ◽

...

Keyword(s):

Fetal Growth ◽

Morphometric Analysis ◽

Fetal Growth Restriction ◽

Lung Development ◽

Growth Restriction ◽

Before And After

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Effect of Endogenic and Exogenic Oxidative Stress Triggers on Adverse Pregnancy Outcomes: Preeclampsia, Fetal Growth Restriction, Gestational Diabetes Mellitus and Preterm Birth

International Journal of Molecular Sciences ◽

10.3390/ijms221810122 ◽

2021 ◽

Vol 22 (18) ◽

pp. 10122

Author(s):

Eun Hui Joo ◽

Young Ran Kim ◽

Nari Kim ◽

Jae Eun Jung ◽

Seon Ha Han ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Preterm Birth ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Fetal Growth ◽

Pregnancy Outcomes ◽

Fetal Growth Restriction ◽

Growth Restriction ◽

Adverse Pregnancy

Oxidative stress is caused by an imbalance between the production of reactive oxygen species (ROS) in cells and tissues and the ability of a biological system to detoxify them. During a normal pregnancy, oxidative stress increases the normal systemic inflammatory response and is usually well-controlled by the balanced body mechanism of the detoxification of anti-oxidative products. However, pregnancy is also a condition in which this adaptation and balance can be easily disrupted. Excessive ROS is detrimental and associated with many pregnancy complications, such as preeclampsia (PE), fetal growth restriction (FGR), gestational diabetes mellitus (GDM), and preterm birth (PTB), by damaging placentation. The placenta is a tissue rich in mitochondria that produces the majority of ROS, so it is important to maintain normal placental function and properly develop its vascular network to ensure a safe and healthy pregnancy. Antioxidants may ameliorate these diseases, and related research is progressing. This review aimed to determine the association between oxidative stress and adverse pregnancy outcomes, especially PE, FGR, GDM, and PTB, and explore how to overcome this oxidative stress in these unfavorable conditions.

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Intrauterine Gardnerella vaginalis Infection Results in Fetal Growth Restriction and Alveolar Septal Hypertrophy in a Rabbit Model

Frontiers in Pediatrics ◽

10.3389/fped.2020.593802 ◽

2021 ◽

Vol 8 ◽

Author(s):

Fook-Choe Cheah ◽

Chee Hoe Lai ◽

Geok Chin Tan ◽

Anushia Swaminathan ◽

Kon Ken Wong ◽

...

Keyword(s):

Fetal Growth ◽

Fetal Growth Restriction ◽

Ureaplasma Urealyticum ◽

Rabbit Model ◽

Fetal Lung ◽

Growth Restriction ◽

Gardnerella Vaginalis ◽

Control Group ◽

Lung Weight ◽

Septal Hypertrophy

Background:Gardnerella vaginalis (GV) is most frequently associated with bacterial vaginosis and is the second most common etiology causing intrauterine infection after Ureaplasma urealyticum. Intrauterine GV infection adversely affects pregnancy outcomes, resulting in preterm birth, fetal growth restriction, and neonatal pneumonia. The knowledge of how GV exerts its effects is limited. We developed an in vivo animal model to study its effects on fetal development.Materials and Methods: A survival mini-laparotomy was conducted on New Zealand rabbits on gestational day 21 (28 weeks of human pregnancy). In each dam, fetuses in the right uterine horn received intra-amniotic 0.5 × 102 colony-forming units of GV injections each, while their littermate controls in the left horn received sterile saline injections. A second laparotomy was performed seven days later. Assessment of the fetal pups, histopathology of the placenta and histomorphometric examination of the fetal lung tissues was done.Results: Three dams with a combined total of 12 fetuses were exposed to intra-amniotic GV, and 9 fetuses were unexposed. The weights of fetuses, placenta, and fetal lung were significantly lower in the GV group than the saline-inoculated control group [mean gross weight, GV (19.8 ± 3.8 g) vs. control (27.9 ± 1.7 g), p < 0.001; mean placenta weight, GV (5.5 ± 1.0 g) vs. control (6.5 ± 0.7 g), p = 0.027; mean fetal lung weight, GV (0.59 ± 0.11 g) vs. control (0.91 ± 0.08 g), p = 0.002. There was a two-fold increase in the multinucleated syncytiotrophoblasts in the placenta of the GV group than their littermate controls (82.9 ± 14.9 vs. 41.6 ± 13.4, p < 0.001). The mean alveolar septae of GV fetuses was significantly thicker than the control (14.8 ± 2.8 μm vs. 12.4 ± 3.8 μm, p = 0.007). Correspondingly, the proliferative index in the interalveolar septum was 1.8-fold higher in the GV group than controls (24.9 ± 6.6% vs. 14.2 ± 2.9%, p = 0.011). The number of alveoli and alveolar surface area did not vary between groups.Discussion: Low-dose intra-amniotic GV injection induces fetal growth restriction, increased placental multinucleated syncytiotrophoblasts and fetal lung re-modeling characterized by alveolar septal hypertrophy with cellular proliferative changes.Conclusion: This intra-amniotic model could be utilized in future studies to elucidate the acute and chronic effects of GV intrauterine infections.

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Oxidative stress in the fetus of preeclamptic women with fetal growth restriction

Hypertension Research in Pregnancy ◽

10.14390/jsshp.1.98 ◽

2013 ◽

Vol 1 (2) ◽

pp. 98-102

Author(s):

Kazushi Watanabe ◽

Ai Iwasaki ◽

Toshitaka Mori ◽

Chiharu Kimura ◽

Hiroshi Matsushita ◽

...

Keyword(s):

Oxidative Stress ◽

Fetal Growth ◽

Fetal Growth Restriction ◽

Growth Restriction

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Changes in surfactant-associated protein mRNA profile in growth-restricted fetal sheep

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1999.276.3.l459 ◽

1999 ◽

Vol 276 (3) ◽

pp. L459-L465 ◽

Cited By ~ 16

Author(s):

Robert Gagnon ◽

Johnathan Langridge ◽

Kevin Inchley ◽

Jun Murotsuki ◽

Fred Possmayer

Keyword(s):

Fetal Growth ◽

Fetal Growth Restriction ◽

Plasma Cortisol ◽

Fold Increase ◽

Fetal Lung ◽

Placental Insufficiency ◽

Control Group ◽

Fetal Sheep ◽

Tissue Levels ◽

Fetal Plasma

To test the hypothesis that chronic placental insufficiency resulting in fetal growth restriction causes an increase in fetal lung surfactant-associated protein (SP) gene expression, we embolized chronically catheterized fetal sheep ( n = 6) daily using nonradioactive microspheres in the abdominal aorta for 21 days (between 0.74 and 0.88 of gestation) until fetal arterial oxygen content was reduced by ∼40–50%. Control animals ( n = 7) received saline only. Basal fetal plasma cortisol concentration was monitored. At the end of the experiment, fetal lung tissues were collected, and ratios of tissue levels of SP-A, SP-B, and SP-C mRNA to 18S rRNA were determined by standard Northern blot analysis. Total DNA content of fetal lungs was reduced by 30% in the embolized group compared with control group ( P = 0.01). There was a 2.7-fold increase in fetal lung SP-A mRNA ( P< 0.05) and a 3.2-fold increase in SP-B mRNA ( P < 0.01) in the chronically embolized group compared with those in the control group. SP-A and SP-B mRNA tissue levels were highly correlated with the mean fetal plasma cortisol levels on days 20–21( r = 0.90, P < 0.01 for SP-A mRNA and r = 0.94, P < 0.01 for SP-B mRNA). SP-C mRNA tissue levels were not significantly affected by placental insufficiency. We conclude that fetal growth restriction due to placental insufficiency is associated with alterations in fetal lung SP, suggesting enhanced lung maturation that was highly dependent on the degree of increase in fetal plasma cortisol levels.

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The expression profile of placental microRNAs as regulators of oxidative stress in fetal growth restriction

Akusherstvo i ginekologiia ◽

10.18565/aig.2019.1.74-80 ◽

2019 ◽

Vol 1_2019 ◽

pp. 74-80 ◽

Cited By ~ 2

Author(s):

Gusar V.A. Gusar ◽

Timofeeva A.V. Timofeeva ◽

Kan N.E. Kan ◽

Chagovets V.V. Chagovets ◽

Ganichkina M.B. Ganichkina ◽

...

Keyword(s):

Oxidative Stress ◽

Expression Profile ◽

Fetal Growth ◽

Fetal Growth Restriction ◽

Growth Restriction

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The Role of NFκB in Healthy and Preeclamptic Placenta: Trophoblasts in the Spotlight

International Journal of Molecular Sciences ◽

10.3390/ijms21051775 ◽

2020 ◽

Vol 21 (5) ◽

pp. 1775 ◽

Cited By ~ 8

Author(s):

Brooke Armistead ◽

Leena Kadam ◽

Sascha Drewlo ◽

Hamid-Reza Kohan-Ghadr

Keyword(s):

Oxidative Stress ◽

Fetal Growth ◽

Fetal Growth Restriction ◽

Growth And Development ◽

Protein Family ◽

Growth Restriction ◽

Placental Development ◽

Critical Organ ◽

And Oxidative Stress

The NFκB protein family regulates numerous pathways within the cell—including inflammation, hypoxia, angiogenesis and oxidative stress—all of which are implicated in placental development. The placenta is a critical organ that develops during pregnancy that primarily functions to supply and transport the nutrients required for fetal growth and development. Abnormal placental development can be observed in numerous disorders during pregnancy, including fetal growth restriction, miscarriage, and preeclampsia (PE). NFκB is highly expressed in the placentas of women with PE, however its contributions to the syndrome are not fully understood. In this review we discuss the molecular actions and related pathways of NFκB in the placenta and highlight areas of research that need attention

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