BACKGROUND: The concept of fetal pain results from procedures conducted without anesthesia in preterm newborns and fetuses, which indicate that it is possible to examine fetal pain based on stress hormone, metabolic, and behavioral changes. Anatomical and physiological data suggest that fetuses become capable of processing nociceptive stimuli around midgestation, although the associated changes in fetal brain development remain unclear. What constitutes fetal pain remains controversial in the light of the definition of pain adopted by the International Association for the Study of Pain (IASP), which posits pain as an \"unpleasant sensory and emotional experience.\"
CONCLUSIONS: Here, we examine the notion that human fetuses cannot \"experience\" pain and potential implications of this claim. We highlight the key scientific evidence related to fetal pain, including clinical studies on pain in fetuses and preterm newborns. We argue that consistent patterns of stress hormones, metabolic changes, body movements, hemodynamic changes, and pain-related facial expressions in fetuses exposed to invasive procedures overcome the need for subjective proof of pain as articulated in the IASP definition. No study to date has conclusively proven the absence of fetal pain beyond the age of viability.
CONCLUSIONS: Based on the current evidence, we propose that all fetuses receive anesthesia regardless of the invasive procedures being performed to guarantee the least possible pain and physiological, behavioral, or hormonal responses without exposing the mother or her baby to unnecessary complications.

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Spontaneous preterm birth is the endpoint of multiple different pathophysiological pathways. Fetal growth restriction, assessed by serial ultrasonic fetal biometry, has been shown to predict both preterm and early-term spontaneous labor. The soluble fms-like tyrosine kinase-1 to placental growth factor ratio is predictive of early-term spontaneous labor, but its association with spontaneous preterm birth is unclear.
This study aimed to determine whether maternal serum levels of soluble fms-like tyrosine kinase-1, placental growth factor, and the soluble fms-like tyrosine kinase-1: placental growth factor ratio at 20 and 28 weeks\' gestation, and the rate of change in these biomarkers between 20 and 28 weeks were predictive of risk of spontaneous preterm birth.
The biomarkers were measured in maternal serum at 20- and 28-weeks\' gestation in women recruited to a prospective cohort of unselected nulliparous women as part of the Pregnancy Outcome Prediction study in Cambridge, United Kingdom. The risk of spontaneous preterm birth was assessed using Cox regression and competing-risks regression. Associations from Cox regression were quantified by the adjusted hazard ratio for a 1 standard deviation higher level of a given biomarker or a 1 standard deviation increase in the marker between 20 and 28 weeks\' gestation. A previously identified risk factor, slow femur length growth, was used as an additional predictor of spontaneous preterm birth for the purpose of risk stratification.
Of the 3763 participants in the analysis, 95 (2.5%) had spontaneous preterm birth and 54 (1.4%) had medically indicated preterm birth. At 20 weeks\' gestation, higher levels of soluble fms-like tyrosine kinase-1 and the soluble fms-like tyrosine kinase-1:placental growth factor ratio were associated with reduced risk of spontaneous preterm birth (adjusted hazard ratio [95% confidence interval], 0.75 [0.61-0.92]; P=.006 and 0.71 [0.59-0.87]; P=.0009, respectively). At 28 weeks\' gestation, there was no association between either soluble fms-like tyrosine kinase-1 or placental growth factor and the risk of spontaneous preterm birth, but there was a U-shaped relation with the soluble fms-like tyrosine kinase-1:placental growth factor ratio. However, when the biomarkers were quantified as the rate of increase between 20 and 28 weeks\' gestation, there were strong positive associations between spontaneous preterm birth and rate of increase in soluble fms-like tyrosine kinase-1 (1.36 [1.13-1.63]; P=.001) and the soluble fms-like tyrosine kinase-1:placental growth factor ratio (1.50 [1.30-1.73]; P<.0001), and a strong negative association with the rate of increase in placental growth factor (0.71 [0.61-0.82]; P<.0001). Women who were in the highest decile of increase in the soluble fms-like tyrosine kinase-1:placental growth factor ratio and the lowest decile of femur length growth between 20 and 28 weeks\' gestation had approximately 9-fold risk of spontaneous preterm birth (9.27 [4.21-20.37]; P<.0001). Competing-risks regression yielded similar results.
Changing levels of soluble fms-like tyrosine kinase-1 and placental growth factor are indicative of placental dysfunction and are strongly associated with the risk of spontaneous preterm birth, especially when combined with slower fetal femur length growth.

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The physiological control of human parturition at term is unknown.
This study aimed to test the hypothesis that slowing of fetal growth or elevated maternal serum levels of markers of placental hypoxia in late gestation will be associated with earlier term labor.
We observed 2208 women having first births and performed serial blinded ultrasonography and immunoassay of soluble fms-like tyrosine kinase-1 and placenta growth factor. We estimated the probability of spontaneous delivery from 37 weeks of gestational age concerning (1) fetal growth between 20 and 36 weeks of gestational age and (2) the maternal serum soluble fms-like tyrosine kinase-1-to-placenta growth factor ratio measured at approximately 36 weeks of gestational age. Data were analyzed using logistic regression and Cox regression.
Fetal size at 36 weeks of gestational age was not independently associated with the timing of delivery at term. However, there was an inverse relationship between fetal growth between 20 weeks of gestational age and 36 weeks of gestational age and the probability of spontaneous labor at 37 to 38 weeks\' gestation (hazard ratio [95% confidence interval] for a 50 percentile increase in abdominal circumference growth velocity, 0.60 [0.47-0.78]; P=.0001). This association was weaker at 39 to 40 weeks\' gestation (0.83 [0.74-0.93]; P=.0013), and there was no association at ≥41 weeks\' gestation. Very similar associations were observed for estimated fetal weight growth velocity. There was a positive relationship between soluble fms-like tyrosine kinase-1-to-placenta growth factor ratio and the probability of spontaneous labor at 37 to 38 weeks\' gestation (hazard ratio [95% confidence interval] for a 50 percentile increase in soluble fms-like tyrosine kinase-1-to-placenta growth factor ratio, 3.05 [2.32-4.02]; P<.0001). This association was weaker at 39 to 40 weeks\' gestation (1.46 [1.30-1.63]; P<.0001), and there was no association at ≥41 weeks\' gestation. Adjustment for maternal characteristics was without material effect on any of these associations.
Slowing of fetal growth and biomarkers of placental insufficiency were associated with an increased probability of early onset of spontaneous term labor. We speculated that progressive placental insufficiency may be a physiological phenomenon that occurs with advancing gestational age near and at term and promotes the initiation of labor.

An accurate, practical, and low-cost method for predicting parturition is urgently needed in the dairy industry. The objective of this study was to evaluate changes in plasma progesterone concentration ([prog]) and glucose concentration in whole blood ([gluc]b) and plasma ([gluc]p) as predictors of parturition within 6, 12, and 24 h in primiparous and multiparous Holstein cows. Blood samples were obtained daily at approximately 0900 h from 34 primiparous and 72 multiparous Holstein cows in late gestation and the time of calving recorded to the nearest hour. Plasma [prog] was measured using an ELISA, and [gluc]b and [gluc]p using a low-cost point-of-care glucose meter. The optimal cut-point for predicting parturition was determined using binomial logistic regression with general estimating equations, because the data set consisted of repeated measures for each cow. Diagnostic test performance was evaluated by comparing the area under the receiver operating characteristic curve (AUC) and calculating the sensitivity, specificity, and κ at the optimal cut-point for predicting parturition. Plasma [prog] was the most accurate predictor of parturition within 24 h (AUC = 0.96) and 12 h (AUC = 0.93), whereas [gluc]b was the most accurate predictor of parturition within 6 h (primiparous, AUC = 0.96; multiparous, AUC = 0.86). We conclude that a decrease in plasma [prog] is currently the most accurate test for predicting calving within 24 h. Measurement of [gluc]b is a promising new test for the cow-side prediction of parturition in dairy cows due to its accuracy, practicality, and low cost.

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Objective To assess fetal behavioral changes in response to vibroacoustic stimulation (VAS) in normal singleton pregnancies using four-dimensional (4D) ultrasound. Methods Ten types of fetal movements and facial expressions in 68 healthy pregnant women between 24 and 40 weeks were studied using 4D ultrasound for 3 min before and after 3-s VAS. The frequencies of mouthing, yawning, tongue expulsion, back arch, jerky arm movement, startle movement, smiling, scowling, hand-to-face movement, and blinking were evaluated. The fetuses were subdivided into four gestational age groups (24-27, 28-31, 32-35, and ≥36 weeks). Comparison of the frequencies of the fetal behaviors before and after the stimulation in each gestational age group was conducted to detect the response to stimulation with advancing gestation. Results There were no significant differences in the frequency of each fetal behavior before and after VAS at 24-27, 28-31, and 32-35 weeks of gestation. However, the frequencies of blinking and startle movements were significantly higher after VAS in the 36-40 gestational age group (P < 0.05). Conclusion The age of 36 weeks of gestation might represent an advanced stage of brain and central nervous system development and maturation as the response to stimuli is prominent at this age compared with earlier gestation.

Fetal stress induces developmental adaptations that result in intrauterine growth restriction (IUGR) and low birthweight. These adaptations reappropriate nutrients to the most essential tissues, which benefits fetal survival. The same adaptations are detrimental to growth efficiency and carcass value in livestock, however, because muscle is disproportionally targeted. IUGR adipocytes, liver tissues, and pancreatic β-cells also exhibit functional adaptations. Identifying mechanisms underlying adaptive changes is fundamental to improving outcomes and value in low birthweight livestock. The article outlines studies that have begun to identify stress-induced fetal adaptations affecting growth, metabolism, and differential nutrient utilization in IUGR-born animals.

Complications in pregnancy elevate fetal norepinephrine (NE) concentrations. Previous studies in NE-infused sheep fetuses revealed that sustained exposure to high NE resulted in lower expression of α2-adrenergic receptors in islets and increased insulin secretion responsiveness after acutely terminating the NE infusion. In this study, we determined if the compensatory increase in insulin secretion after chronic elevation of NE is independent of hyperglycemia in sheep fetuses and whether it is persistent in conjunction with islet desensitization to NE. After an initial assessment of glucose-stimulated insulin secretion (GSIS) at 129 ± 1 days of gestation, fetuses were continuously infused for seven days with NE and maintained at euglycemia with a maternal insulin infusion. Fetal GSIS studies were performed again on days 8 and 12. Adrenergic sensitivity was determined in pancreatic islets collected at day 12. NE infusion increased (P < 0.01) fetal plasma NE concentrations and lowered (P < 0.01) basal insulin concentrations compared to vehicle-infused controls. GSIS was 1.8-fold greater (P < 0.05) in NE-infused fetuses compared to controls at both one and five days after discontinuing the infusion. Glucose-potentiated arginine-induced insulin secretion was also enhanced (P < 0.01) in NE-infused fetuses. Maximum GSIS in islets isolated from NE-infused fetuses was 1.6-fold greater (P < 0.05) than controls, but islet insulin content and intracellular calcium signaling were not different between treatments. The half-maximal inhibitory concentration for NE was 2.6-fold greater (P < 0.05) in NE-infused islets compared to controls. These findings show that chronic NE exposure and not hyperglycemia produce persistent adaptations in pancreatic islets that augment β-cell responsiveness in part through decreased adrenergic sensitivity.