Preterm Fetuses Research Articles

Traditional female cervical cauterization and risk of preterm birth in Somalia: a single-center prospective observational study

Numerous traditional practices are both beneficial and harmful. Traditional harmful practices, such as female genital mutilation and traditional cervical cauterization, are carried out for a number of reasons but can have negative health and social effects. In addition to deeply held beliefs, a lack of knowledge and awareness of the consequences of these practices contributes to the persistence of these issues. The objective of this study is to examine whether traditional cervical cauterizations were associated with preterm births in Somalia. This prospective cohort study was conducted at our hospital over a one-year period. Seven hundred and two patients were included in this study; these patients were divided into two groups, cauterized and non-cauterized groups, and the two groups were compared on pregnancy outcomes. We examined whether traditional cervical cauterizations were associated with adverse pregnancy outcomes, including preterm births. According to the findings of this study, traditional cervical cauterization was prevalent among patients visiting MSTREH (n = 328, 46.7%). Infections of the uterine cervix and infertility were the two main indications for cauterization, 44.8%, and 34.8%, respectively.Being older, uneducated, and poverty were significantly associated with traditional cauterization (P < 0.001). There was a significant correlation between prior traditional cervical cauterization and the risk of preterm births. Women with prior cauterization were two and half times more likely to deliver a preterm fetus (OR: 2.64, 95% CI 2.15–3.33) compared to non-cauterized mothers. Our findings show that women who have previously undergone traditional cervical cauterization have a significantly higher risk of preterm birth and negative pregnancy outcomes than non-cauterized women. Health professionals, particularly those who are close to the community, are crucial in developing and putting into practice plans to end harmful traditions in Somalia.

Variations of cervical head entrapment in vaginal breech births: New insights on how to prevent, manage and resolve

This paper presents a novel, systematic way to understand the causes of cervical head entrapment in vaginal breech births, and new insights into management. Three different types of cervical head entrapment are described, with detailed illustrations: unpredictable and potentially catastrophic, manageable, and preventable. The first affects preterm and growth-restricted fetuses. The second involves some degree of uterine prolapse. The third may result from prolonged head entrapment at the pelvic inlet, leaving time for cervical contraction or oedematous entrapment. Traditional and innovative strategies to resolve and prevent this complication are described and illustrated, with suggestions for further research.

Echocardiographic assessment of cardiovascular physiology of preterm miniature piglets supported with a pumped artificial placenta system.

We evaluated fetal cardiovascular physiology and mode of cardiac failure in premature miniature piglets on a pumped artificial placenta (AP) circuit. Fetal pigs were cannulated via the umbilical vessels and transitioned to an AP circuit composed of a centrifugal pump and neonatal oxygenator and maintained in a fluid-filled biobag. Echocardiographic studies were conducted to measure ventricular function, umbilical blood flow, and fluid status. In utero scans were used as control data. AP fetuses (n=13; 102±4d gestational age [term 115d]; 616±139g [g]; survival 46.4±46.8h) were tachycardic and hypertensive with initially supraphysiologic circuit flows. Increased myocardial wall thickness was observed. Signs of fetal hydrops were present in all piglets. Global longitudinal strain (GLS) measurements increased in the left ventricle (LV) after transition to the circuit. Right ventricle (RV) and LV strain rate decreased early during AP support compared with in utero measurements but recovered toward the end of the experiment. Fetuses supported for >24h had similar RV GLS to in utero controls and significantly higher GLS compared to piglets surviving only up to 24h. Fetuses on a pump-supported AP circuit experienced an increase in afterload, and redistribution of blood flow between the AP and systemic circulations, associated with elevated end-diastolic filling pressures. This resulted in heart failure and hydrops. These preterm fetuses were unable to tolerate the hemodynamic changes associated with connection to the current AP circuit. To better mimic the physiology of the native placenta and preserve normal fetal cardiovascular physiology, further optimization of the circuit will be required.

Agenesis of the ductus venosus and fetal growth restriction: Is there a relation? A tertiary care center experience and systematic review of the literature.

An update on the antenatal diagnosis of agenesis of ductus venosus (ADV) by differentiating the various possible types of shunts, focusing on the associated fetal anomalies, and predicting neonatal outcomes. This study reviewed the experience of two tertiary referral centers and literature. An unfavorable outcome was detected in preterm fetuses (p = 0.017), fetuses with a genetic anomaly (p = 0.046) or other associated malformations (p < 0.001). 71% of ADVs with other anomalies had an extrahepatic ADV (p = 0.002). 76% of fetuses with Fetal Growth Restriction (FGR) had an extrahepatic ADV (p = 0.025). ADV may negatively influence fetal growth in cases with extrahepatic vein drainage.

Correlation of fetal lung area with MRI derived pulmonary volume

BackgroundNeonatal chest-Xray (CXR)s are commonly performed as a first line investigation for the evaluation of respiratory complications. Although lung area derived from CXRs correlates well with functional assessments of the neonatal lung, it is not currently utilised in clinical practice, partly due to the lack of reference ranges for CXR-derived lung area in healthy neonates. Advanced MR techniques now enable direct evaluation of both fetal pulmonary volume and area. This study therefore aims to generate reference ranges for pulmonary volume and area in uncomplicated pregnancies, evaluate the correlation between prenatal pulmonary volume and area, as well as to assess the agreement between antenatal MRI-derived and neonatal CXR-derived pulmonary area in a cohort of fetuses that delivered shortly after the antenatal MRI investigation. MethodsFetal MRI datasets were retrospectively analysed from uncomplicated term pregnancies and a preterm cohort that delivered within 72 h of the fetal MRI. All examinations included T2 weighted single-shot turbo spin echo images in multiple planes. In-house pipelines were applied to correct for fetal motion using deformable slice-to-volume reconstruction. An MRI-derived lung area was manually segmented from the average intensity projection (AIP) images generated. Postnatal lung area in the preterm cohort was measured from neonatal CXRs within 24 h of delivery. Pearson correlation coefficient was used to correlate MRI-derived lung volume and area. A two-way absolute agreement was performed between the MRI-derived AIP lung area and CXR-derived lung area. ResultsDatasets from 180 controls and 10 preterm fetuses were suitable for analysis. Mean gestational age at MRI was 28.6 ± 4.2 weeks for controls and 28.7 ± 2.7 weeks for preterm neonates. MRI-derived lung area correlated strongly with lung volumes (p < 0.001). MRI-derived lung area had good agreement with the neonatal CXR-derived lung area in the preterm cohort [both lungs = 0.982]. ConclusionMRI-derived pulmonary area correlates well with absolute pulmonary volume and there is good correlation between MRI-derived pulmonary area and postnatal CXR-derived lung area when delivery occurs within a few days of the MRI examination. This may indicate that fetal MRI derived lung area may prove to be useful reference ranges for pulmonary areas derived from CXRs obtained in the perinatal period.

Magnesium sulfate and risk of hypoxic ischemic encephalopathy in a high-risk cohort

Hypoxic ischemic encephalopathy contributes to morbidity and mortality among neonates ≥ 360 weeks' gestation. Evidence of preventative antenatal treatment is limited. Magnesium sulfate has neuroprotective properties among preterm fetuses. Hypertensive disorders of pregnancy are a risk factor for hypoxic ischemic encephalopathy and magnesium sulfate is recommended for maternal seizure prophylaxis among patients with pre-eclampsia with severe features. 1) Determine trends in incidence of hypertensive disorders of pregnancy, antenatal magnesium sulfate and hypoxic ischemic encephalopathy, 2) evaluate the association between hypertensive disorders of pregnancy and hypoxic ischemic encephalopathy and 3) evaluate if, among patients with hypertensive disorders of pregnancy, the odds of hypoxic ischemic encephalopathy is mitigated by receipt of antenatal magnesium sulfate. STUDY DESIGN: We conducted an analysis of a prospective cohort of live births ≥360 weeks' gestation between 2012-2018 within the California Perinatal Quality Care Collaborative registry, linked with the California Department of Health Care Access and Information files. We used Cochran-Armitage tests to assess trends in hypertensive disorders, encephalopathy diagnoses, and magnesium sulfate utilization, and compared demographic factors between patients with or without hypertensive disorders of pregnancy or treatment with magnesium sulfate. Hierarchical logistic regression models were built to explore if hypertensive disorders of pregnancy were associated with any severity and moderate/severe hypoxic ischemic encephalopathy. Separate hierarchical logistic regression models were built among those with hypertensive disorders of pregnancy to evaluate the association of magnesium sulfate with hypoxic ischemic encephalopathy. Among 44,314 unique infants, the diagnosis of hypoxic ischemic encephalopathy, maternal hypertensive disorders of pregnancy and the use of magnesium sulfate increased over time. Compared to patients with hypertensive disorders of pregnancy alone, patients with hypertensive disorders treated with magnesium sulfate represented a higher risk population. They were more likely to be publicly insured, born 36-38 weeks' gestation, be small for gestational age, have lower Apgar scores, require a higher level of resuscitation at delivery, have prolonged rupture of membranes, preterm labor, fetal distress, and undergo operative delivery (all p-values <0.002). Hypertensive disorders of pregnancy were associated with hypoxic ischemic encephalopathy (aOR 1.26, 95% CI 1.13-1.40, p-value <.001) and specifically moderate/severe hypoxic ischemic encephalopathy (aOR 1.26, 95% CI 1.11-1.42, p-value <.001). Among patients with hypertensive disorders of pregnancy, treatment with magnesium sulfate was associated with 29% reduction in the odds of neonatal hypoxic ischemic encephalopathy (aOR 0.71, 95% CI 0.52-0.97, p-value= 0.03) and a 37% reduction in the odds of moderate/severe neonatal hypoxic ischemic encephalopathy (aOR 0.63, 95% CI 0.42-0.94, p-value=0.03). Hypertensive disorders of pregnancy are associated with hypoxic ischemic encephalopathy and specifically, moderate/severe disease. Among people with hypertensive disorders, receipt of antenatal magnesium sulfate is associated with significant reduction in the odds of hypoxic ischemic encephalopathy and moderate/severe disease in a neonatal cohort admitted to the NICU ≥360 weeks' gestation. The findings of this observational study cannot prove causality and are intended to be hypothesis generating for future clinical trials on MgSO4 in term infants.

Leptin deficiency, a potential mechanism for impaired fetal lung development in uteroplacental insufficiency?

Uteroplacental insufficiency (UPI) is a major cause of fetal growth restriction (FGR). Leptin, an adipokine, has been shown to play a vital role in fetal organogenesis. There is evidence reporting leptin deficiency in preterm and growth-restricted fetuses. In this issue of Pediatric Research, Yuliana et al. report leptin expression and lung development in UPI-induced FGR rats. UPI-induced FGR rats expressed decreased lung leptin and had impaired lung development, as shown by decreased surface area and lung volume. They also found a significant association between lung radial alveolar count, serum leptin, von Willebrand factor, and specific metabolites on metabolomic analyses. Previous studies on leptin supplementation in vivo have been associated with improvement in lung maturation; supporting the evidence, that leptin improves lung growth and development in FGR and may have future therapeutic potential in the improvement of respiratory outcomes in these infants. Future studies to support evidence of this association in humans are warranted.

Upregulation of hepatic nuclear receptors in extremely preterm ovine fetuses undergoing artificial placenta therapy

Objective Extremely preterm infants have low Nuclear Receptor (NR) expression in their developing hepatobiliary systems, as they rely on the placenta and maternal liver for compensation. NRs play a crucial role in detoxification and the elimination of both endogenous and xenobiotic substances by regulating key genes encoding specific proteins. In this study, we utilized an Artificial Placenta Therapy (APT) platform to examine the liver tissue expression of NRs of extremely preterm ovine fetuses. This fetal model, resembling a “knockout placenta,” lacks placental and maternal support, while maintaining a healthy extrauterine survival. Methods Six ovine fetuses at 95 ± 1 d gestational age (GA; term = ∼150 d)/∼600 g delivery weight were maintained on an APT platform for a period of 120 h (APT Group). Six age-matched, in utero control fetuses were delivered at 99–100 d GA (Control Group). Fetal liver tissue samples and blood samples were collected at delivery from both groups and assessed mRNA expression of NRs and target transporters involved in the hepatobiliary transport system using quantitative PCR. Data were tested for group differences with ANOVA (p < .05 deemed significant). Results mRNA expression of NRs was identified in both the placenta and the extremely preterm ovine fetal liver. The expression of HNF4α, LRH1, LXR, ESR1, PXR, CAR, and PPARα/γ were significantly elevated in the liver of the APT Group compared to the Control Group. Moreover, target transporters NTCP, OATP1B3, BSEP, and MRP4 were upregulated, whereas MRP2 and MRP3 were unchanged. Although there was no evidence of liver necrosis or apoptotic changes histologically, there was an impact in the fetal liver of the ATP group at the tissue level with a significant increase in TNFα mRNA, a cytokine involved in liver inflammation, and blood elevation of transaminases. Conclusion A number of NRs in the fetal liver were significantly upregulated after loss of placental-maternal support. However, the expression of target transporter genes appeared to be insufficient to compensate role of the placenta and maternal liver and avoid fetal liver damage, potentially due to insufficient excretion of organic anions.

SFM Fetal Therapy Practice Guidelines: Bipolar Cord Coagulation

AbstractBipolar cord coagulation is modality available for the treatment of monochorionic diamniotic twins with any one of the following indications: discordant anomalous fetus, severe selective Intrauterine growth restriction (IUGR) (type 2 and type 3) in very preterm and premature fetuses, and selected cases of twin-twin transfusion syndrome when LASER photocoagulation is not feasible. Twin reversed arterial perfusion sequence with polyhydramnios and cardiac overload in pump twin, Multifetal reduction involving MCDA pair.

The Role of Reactive Oxygen Species in the Regulation of Blood Vessel Tone in Perinatal and Early Postnatal Ontogenesis

Reactive oxygen species (ROS) have been considered for many years as negative regulators in the cardiovascular system. Indeed, excessive production of ROS characterizes many cardiovascular diseases. The damaging effect of ROS can be especially pronounced in a newborn organism, since during this period their contractile effect in pulmonary arteries remains as high as in the pre-term fetus arteries and the antioxidant systems have not yet formed. Therefore, in the first hours and days of independent life, pulmonary arteries tend to contract, primarily due to the low bioavailability of endothelial NO, which increases the risk of developing pulmonary hypertension in newborns. At the same time, during the perinatal period, ROS play an important role in the adaptive reactions of the circulatory system. ROS provide occlusion of the ductus arteriosus and separation of the pulmonary and systemic circulations soon after birth, and also contribute to the contraction of peripheral vessels during hypoxia, which often accompanies the delivery, and therefore provide priority blood supply to the brain in these conditions. The vasomotor effect of ROS is also pronounced in early postnatal ontogenesis, but it has a different character. In the first weeks of life, the action of ROS serves as one of the mechanisms for increasing endothelium-dependent relaxation of pulmonary vessels. In addition, during early postnatal ontogeny, ROS may play an important role in the regulation of systemic vascular tone. This review outlines the current understanding of the vasomotor role of ROS in the vessels of the pulmonary and systemic circulation and considers the mechanisms of ROS effects on the functioning of vascular endothelial and smooth muscle cells in the perinatal and early postnatal periods.

Long-lasting developmental effects in rat offspring after maternal exposure to acetamiprid in the drinking water during gestation.

Neonicotinoids (NNTs) are a class of insecticides proposed to be safe for pest control in urban, suburban, and agricultural applications. However, little is known about their developmental effects after repeated low-dose exposures during gestation. Here, we tested a dose considered subthreshold for maternal toxicity in rats (6 mg/kg/day) by assessing several morphological, biochemical, and neurobehavioral features in preterm fetuses and developing pups after maternal administration of the NTT acetamiprid (ACP) dissolved in the drinking water during gestational days (GD) 2-19. The exploratory evaluation included monitoring maternal body weight gain, fetal viability, body weight and sex ratio, cephalic length, neonatal body weight and sex ratio, metabolic enzymes in the placenta, maternal blood and fetal liver, and anogenital distance and surface righting response during infancy. We also used the circling training test to study the integrity of the associative-spatial-motor response in adolescence. Results showed no consistent findings indicating maternal, reproductive or developmental toxicity. However, we found ACP effects on maternal body weight gain, placental butyrylcholinesterase activity, and neurobehavioral responses, suggestive of a mild toxic action. Thus, our study showed a trend for developmental susceptibility at a dose so far considered subtoxic. Although the ACP concentration in environmental samples of surface water and groundwater has been mostly reported to be much lower than that used in our study, our results suggest that the ACP point of departure used in current guidelines aimed to prevent developmental effects may need to be verified by complementary sensitive multiple-endpoint testing in the offspring.

Accuracy of Estimated Fetal Weight by Ultrasound Versus Leopold Maneuver.

Estimated fetal weight (EFW) is frequently used for clinical decision-making in obstetrics. The goals of this study were to determine the accuracy of EFW assessments by Leopold and ultrasound and to investigate any associations with maternal characteristics. Postgraduate years 1 and 2 obstetrics and gynecology resident physicians from Harbor-UCLA Medical Center from 2014 to 2020 performed EFW assessments on 10 preterm (<37 weeks' gestational age) fetuses by ultrasound biometry and 10 full-term (≥37 weeks' gestational age) fetuses by ultrasound biometry and Leopold maneuver. Assessments were included if the patients delivered within 2 weeks of the assessments. One thousand six hundred ninety-seven EFW assessments on 1183 patients performed by 33 residents were analyzed; 72.6% of sonographic full-term EFWs, 69% of Leopold full-term EFWs, and 61.5% of sonographic preterm EFWs were within 10% of the neonatal birth weight (BW). The lowest estimation error in our study occurred when actual BW was 3600 to 3700 g. After adjusting for BW, residents were found to have lower accuracy when the mother had a higher body mass index (BMI) for full-term estimation methods (Leopold and ultrasound, β = 0.13 and 0.12, P = 0.001 and 0.002, respectively). Maternal BMI was not related to estimation error for preterm fetuses ( β = 0.01, P = 0.75). Clinical and sonographic EFW assessments performed by obstetrics and gynecology junior residents are within 10% of neonatal BW much of the time. In our cohort, they tended to overestimate EFWs of lower-BW infants and underestimate EFWs of higher-BW infants. Accuracy of full-term EFW assessments seems to decrease with increasing maternal BMI.

Labor Induction in Case of Fetal Growth Restriction (FGR)

Clinicians consider a range of variables when formulating decisions regarding the diagnosis, monitoring plan, and ultimately the decision to recommend the delivery of a growth-restricted fetus. The differential diagnosis of a pathological fetal growth pattern is initially considered via the history, a physical and laboratory examination of the pregnant person, as well as a comprehensive fetal ultrasound examination. These factors allow a broad distinction between pre-existing disease in the pregnant person, constitutionally small normal growth, placenta-mediated Fetal Growth Restriction (FGR), and intrinsic fetal disease. Most commonly, pathological growth restriction is mediated by underlying placental diseases, of which maternal vascular malperfusion is the most common, and often results in co-existent hypertension. A program of combined monitoring of the pregnant person and fetus, comprising hypertension assessment, and serial fetal ultrasound, including Doppler studies is then instituted, and may be combined with biochemical markers, such as Placental Growth Factor, for greater clinical precision. Recommendations on timing to deliver the growth-restricted fetus worldwide are converging, with similar guidance from clinical practice guidelines informed by high-quality Randomized Controlled Trials (RCTs) and large cohort studies. In most instances, it is reasonable to recommend delivery of all growth-restricted fetuses by approximately 38 weeks. Timing of delivery should take into consideration both short-term neonatal outcomes and long-term outcomes at school age. Mode of delivery is based on many factors, and induction of labor is a safe approach, especially after 34 weeks. Mechanical methods of induction may be preferred to pharmacologic methods, although both have a role and the choice of method is based on individualized assessment. Elective Cesarean birth thereby bypassing fetal stress during labor, is recommended in preterm growth-restricted fetuses with signs of adaptive fetal compromise, especially when ductus venosus flow is abnormal, or a contraction stress test is positive.

Treatment, not delivery, of the late preterm and term fetus with supraventricular arrhythmia.

While in-utero treatment of sustained fetal supraventricular arrhythmia (SVA) is standard practice in the previable and preterm fetus, data are limited on best practice for late preterm (34 + 0 to 36 + 6 weeks), early term (37 + 0 to 38 + 6 weeks) and term (> 39 weeks) fetuses with SVA. We reviewed the delivery and postnatal outcomes of fetuses at ≥ 35 weeks of gestation undergoing treatment rather than immediate delivery. This was a retrospective case series of fetuses presenting at ≥ 35 weeks of gestation with sustained SVA and treated transplacentally at six institutions between 2012 and 2022. Data were collected on gestational age at presentation and delivery, SVA diagnosis (short ventriculoatrial (VA) tachycardia, long VA tachycardia or atrial flutter), type of antiarrhythmic medication used, interval between treatment and conversion to sinus rhythm and postnatal SVA recurrence. Overall, 37 fetuses presented at a median gestational age of 35.7 (range, 35.0-39.7)weeks with short VA tachycardia (n = 20), long VA tachycardia (n = 7) or atrial flutter (n = 10). Four (11%) fetuses were hydropic. In-utero treatment led to restoration of sinus rhythm in 35 (95%) fetuses at a median of 2 (range, 1-17)days; this included three of the four fetuses with hydrops. Antiarrhythmic medications included flecainide (n = 11), digoxin (n = 7), sotalol (n = 11) and dual therapy (n = 8). Neonates were liveborn at 36-41 weeks via spontaneous vaginal delivery (23/37 (62%)) or Cesarean delivery (14/37 (38%)). Cesarean delivery was indicated for fetal SVA in two fetuses, atrial ectopy or sinus bradycardia in three fetuses and obstetric reasons in nine fetuses that were in sinus rhythm at the time of delivery. Twenty-one (57%) cases were treated for recurrent SVA after birth. In-utero treatment of the near term and term (≥ 35-week) SVA fetus is highly successful even in the presence of hydrops, with the majority of cases delivered vaginally closer to term, thereby avoiding unnecessary Cesarean section. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Artificial placenta support of extremely preterm ovine fetuses at the border of viability for up to 336 hours with maintenance of systemic circulation but reduced somatic and organ growth.

Introduction: Artificial placenta therapy (APT) is an experimental life support system to improve outcomes for extremely preterm infants (EPI) less than 1,000g by obviating the need for pulmonary gas exchange. There are presently no long-term survival data for EPI supported with APT. To address this, we aimed to maintain 95d-GA (GA; term-150d) sheep fetuses for up to 2weeks using our APT system. Methods: Pregnant ewes (n = 6) carrying singleton fetuses underwent surgical delivery at 95d GA. Fetuses were adapted to APT and maintained for up to 2weeks with constant monitoring of key physiological parameters and extensive time-course blood and urine sampling, and ultrasound assessments. Six age-matched in-utero fetuses served as controls. Data were tested for group differences with ANOVA. Results: Six APT Group fetuses (100%) were adapted to APT successfully. The mean BW at the initiation of APT was 656 ± 42g. Mean survival was 250 ± 72h (Max 336h) with systemic circulation and key physiological parameters maintained mostly within normal ranges. APT fetuses had active movements and urine output constantly exceeded infusion volume over the experiment. At delivery, there were no differences in BW (with edema in three APT group animals), brain weight, or femur length between APT and in-utero Control animals. Organ weights and humerus lengths were significantly reduced in the APT group (p < 0.05). Albumin, IGF-1, and phosphorus were significantly decreased in the APT group (p < 0.05). No cases of positive blood culture were detected. Conclusion: We report the longest use of APT to maintain extremely preterm fetuses to date. Fetal systemic circulation was maintained without infection, but growth was abnormal. This achievement suggests a need to focus not only on cardiovascular stability and health but also on the optimization of fetal growth and organ development. This new challenge will need to be overcome prior to the clinical translation of this technology.

High Expression of Adrenal Cortisol Synthases Is Acquired After Intrauterine Inflammation in Periviable Sheep Fetuses.

Intrauterine inflammation, a representative stressor for the fetus, has been shown to alter the hypothalamus-pituitary-adrenal (HPA) axis reactivity in preterm fetuses and increase postnatal cortisol production. However, the mechanism of this alteration has not yet been elucidated. We aimed to clarify the effects of endotoxin-induced intrauterine inflammation on the HPA axis of periviable sheep fetuses. Fetal sheep (0.63 term) were divided into 2 groups: (1) the endotoxin group, in which the endotoxin was injected into the amniotic fluid; and (2) the control group, in which the saline solution was injected instead. A corticotropin-releasing hormone (CRH) challenge test was performed on the third day after injection to evaluate the cortisol-producing capacity of each group. Gene expression levels in the fetal adrenal glands of each group were analyzed by RNA-seq. The cortisol levels were significantly higher in the endotoxin group than in the control group after CRH challenge (P = .02). There were no significant differences in the responsiveness of adrenocorticotropin and cortisone between the 2 groups. Gene expression levels of the following enzymes involved in cortisol synthesis were significantly elevated in the endotoxin group: cytochrome P450 family (CYP) 11 subfamily A member 1 (log2FC 1.75), CYP 17 subfamily A member 1 (log2FC 3.41), 3β-hydroxysteroid dehydrogenase type I (log2FC 1.13), steroidogenic acute regulatory protein (log2FC 1.09), and CYP 21 (log2FC 0.89). Periviable fetuses exposed to inflammation in utero have altered the responsiveness of the HPA axis with increased expression of enzymes involved in cortisol synthesis in the adrenal gland.

Effect of Steroids on the Biophysical Profile and Doppler Indices of Umbilical and Middle Cerebral Arteries in Preterm Fetuses.

Introduction Preterm birth is a major cause of perinatal death and disability and emerges as an important global public health problem. The antenatal administration of corticosteroids for preventing neonatal death due to respiratory distress syndrome and the serious morbidities associated with preterm birth has become an accepted standard in worldwide obstetric practice since 1994.After administering corticosteroids, the biophysical score deteriorates transiently, leading to a high cesarean section rate. Thus, Doppler indices of the umbilical and middle cerebral arteries are taken into account before the termination of pregnancy in preterm labor. Materials and methods This is an interventional study conducted over a period of one year and six months among 59 eligible singleton pregnancies at risk for preterm delivery, i.e., at risk of preterm birth <34 weeks of gestation, having no contraindication to antenatal steroids, who were admitted to the labor room of the Srirama Chandra Bhanja (SCB) Medical College, Cuttack, India, from January 2014 to August 2015. The participants were prospectively recruited, after giving informed consent to participate in the study. The main indication for hospital admission and steroid use was preterm lower abdominal pain. Results Out of 59 eligible cases, 27 (45.8%) were <25 years of age, 26 (44.1%) were between 25 and 30 years of age, and six (10.2%) were >30 years of age. The range is 14 years (between 19 and 33 years). The mean age is 25.31 years, with a standard deviation of 3.74. The mean of the biophysical profile (BPP) score before steroid administration decreased from 9.19 ± 1.23 to 5.56 ± 1.05 after 48 hours of first dose of steroid. The p-value of this is <0.001, which is statistically significant. The results show that the administration of betamethasone decreased fetal movements by 78.6% and breathing by 71.8%. As a result, the BPP scores decreased significantly. However, the Doppler indices did not change significantly even after administering corticosteroids. Conclusion Doppler indices play an important role in differentiating between steroid-induced compromise in the fetus and real fetal distress. Thus, umbilical and middle cerebral artery (MCA) Doppler should always be done before the termination of pregnancy on the ground of fetal compromise after administering corticosteroids.

In Vivo Real-Time Study of Drug Effects on Carotid Blood Flow in the Ovine Fetus.

The ability of an organism to maintain a constant blood flow to the brain in response to sudden surges in systemic blood pressure (BP) is known as cerebral autoregulation (CAR), which occurs in the carotid artery. In contrast to full-term neonates, preterm neonates are unable to reduce the cerebral blood flow (CBF) in response to increased systemic BP. In preterm neonates, this exposes the fragile cerebral vessels to high perfusion pressures, leading to their rupture and brain damage. Ex vivo studies using wire myography have demonstrated that carotid arteries from near-term fetuses constrict in response to the activation of adrenergic alpha1 receptors. This response is blunted in the preterm fetus. Thus, to examine the role of alpha1-AR in vivo, presented here is an innovative approach to determine the effects of drugs on a carotid arterial segment in vivo in an ovine fetus during the developmental progression of gestation. The presented data demonstrate the simultaneous measurement of fetal blood flow and blood pressure. The perivascular delivery system can be used to conduct a long-term study over several days. Additional applications for this method could include viral delivery systems to alter the expression of genes in a segment of the carotid artery. These methods could be applied to other blood vessels in the growing organism in utero as well as in adult organisms.

Development and Validation of a Small for Gestational Age Screening Model at 21-24 Weeks Based on the Real-World Clinical Data.

Small for gestational age (SGA) is a condition in which fetal birthweight is below the 10th percentile for the gestational age, which increases the risk of perinatal morbidity and mortality. Therefore, early screening for each pregnant woman is of great interest. We aimed to develop an accurate and widely applicable screening model for SGA at 21-24 gestational weeks of singleton pregnancies. This retrospective observational study included medical records of 23,783 pregnant women who gave birth to singleton infants at a tertiary hospital in Shanghai between 1 January 2018 and 31 December 2019. The obtained data were nonrandomly classified into training (1 January 2018 to 31 December 2018) and validation (1 January 2019 to 31 December 2019) datasets based on the year of data collection. The study variables, including maternal characteristics, laboratory test results, and sonographic parameters at 21-24 weeks of gestation were compared between the two groups. Further, univariate and multivariate logistic regression analyses were performed to identify independent risk factors for SGA. The reduced model was presented as a nomogram. The performance of the nomogram was assessed in terms of its discrimination, calibration, and clinical usefulness. Moreover, its performance was assessed in the preterm subgroup of SGA. Overall, 11,746 and 12,037 cases were included in the training and validation datasets, respectively. The developed SGA nomogram, comprising 12 selected variables, including age, gravidity, parity, body mass index, gestational age, single umbilical artery, abdominal circumference, humerus length, abdominal anteroposterior trunk diameter, umbilical artery systolic/diastolic ratio, transverse trunk diameter, and fasting plasma glucose, was significantly associated with SGA. The area under the curve value of our SGA nomogram model was 0.7, indicating a good identification ability and favorable calibration. Regarding preterm SGA fetuses, the nomogram achieved a satisfactory performance, with an average prediction rate of 86.3%. Our model is a reliable screening tool for SGA at 21-24 gestational weeks, especially for high-risk preterm fetuses. We believe that it will help clinical healthcare staff to arrange more comprehensive prenatal care examinations and, consequently, provide a timely diagnosis, intervention, and delivery.

Stable adrenomedullin analog mitigates placental ischemia-induced hypertension and fetal growth restriction in rats.

Preeclampsia is a heterogeneous hypertensive disorder of pregnancy. It affects multiorgans and may lead to fetal growth restriction, organ failure, seizure, and maternal death. Unfortunately, current treatments are ineffective at delaying the progression of preeclampsia even for a few days. Clinicians are often forced to deliver preterm fetus if severe preeclampsia occurred early during pregnancy, leading to premature birth-associated complications. Preeclampsia has been associated with defects at the maternal-fetal interface and maternal vascular dysfunction. Of interest, the adrenomedullin peptide and its cognate receptors, calcitonin receptor-like receptor (CLR)/ receptor activity-modifying protein (RAMP) receptor complexes, have been shown to be important regulators of cardiovascular adaptation and feto-placental development during pregnancy. Although the exact role of adrenomedullin-CLR/RAMP signaling in different feto-maternal compartments during pregnancy and how adrenomedullin expression affects preeclampsia development remains to be clarified, we hypothesized that the sustained activation of CLR/RAMP receptors could be a promising strategy to mitigate placental ischemia-associated vascular dysfunction and fetal growth restriction under preeclampsia-like conditions. To explore this possibility, we have developed a stable adrenomedullin analog, ADE101, and investigated its effects on human lymphatic microvascular endothelial (HLME) cell proliferation, hemodynamics, and pregnancy outcomes in pregnant rats with reduced uteroplacental perfusion pressure (RUPP) induced by clipping of uterine arteries on gestation day 14. The ADE101 analog has a potent effect on CLR/RAMP2 receptor activation, and an enhanced stimulatory effect on HLME cell proliferation compared to wild-type peptides. ADE101 also exhibits a lasting effect on hemodynamics in normal and hypertensive rats. In addition, studies using the RUPP model showed that ADE101 significantly reduces placental ischemia-induced hypertension and fetal growth restriction in a dose-dependent manner. Infusion of ADE101 increased the weight of fetuses and placentas in RUPP animals to 252% and 202% of that of RUPP controls, respectively. These data suggested that long-acting adrenomedullin analog could be useful for quenching hypertension as well as the vascular ischemia-associated organ damages in preeclamptic patients.