Volume 44, Issue 6 - Highlight: Prematurity

Objectives: The aim of this study was to determine if the actions of progesterone on preterm labor are accomplished through modulation of the percentage of regulatory T-cells (Treg). Methods: The study was a cohort pilot study made in a single center tertiary obstetrical unit with women in preterm labor arrested with tocolytic treatment. Variation of the number and percentage of Treg cells obtained from peripheral blood samples of women with preterm labor were calculated by flow cytometry, before and after progesterone administration. Results: In the paired samples for each patient, there was a significant difference in the Treg cell pool after progesterone treatment, with an increase in both their percentage (48.9 vs. 53; P=0.07) and absolute number (14.8 vs. 56.5 cells/μL; P=0.046). Conclusions: This research demonstrated a considerable increase in the Treg cell pool after progesterone treatment. This indicates a possible mechanism for progesterone treatment benefits in preterm labor, potentially increasing its more rational use.

Objective: We aimed to evaluate the correlation between clinical parameters and the post-left atrium (LA) space index, which is a candidate screening marker for total anomalous pulmonary venous connection (TAPVC). We also calculated the inter- and intra-observer variabilities of measurements for this parameter. Methods: The LA-descending aorta distance/descending aorta diameter ratios (post-LA space index) were obtained from 165 fetuses between 20 and 24 weeks of gestation. Regression analyses were utilized to evaluate the correlations across clinical parameters and the post-LA space index. Intraclass correlations coefficients were calculated for the intra- and inter-observer agreements of three examiners with different sonographic experience. Results: The mean (±SD) maternal and gestational age (GA) was 28.6±4.9 years and 21.7±0.9 weeks of gestation, respectively. In multivariate analyses, there was no correlation between post-LA space index and maternal age, fetal gender, or GA at cardiac scan. There were moderate to strong correlations across the measurements by different examiners, indicating good inter- and intra-observer agreements. Conclusion: The post-LA space index during 20–24 weeks of gestation is a simple and reliable marker that is not affected by GA. However, its potential as a screening tool for TAPVC warrants further clinical investigation.

Objective: In the management of twin reversed arterial perfusion (TRAP) sequence, we wished to (i) determine if intervention is better than a conservative approach and (ii) assess if any of the apparent adverse prognostic indicators could guide intervention. Methods: A systematic review was conducted between 1994 and 2014. Data extracted were inspected for heterogeneity. Overall rates and confidence intervals (CIs) for each prognostic factor were calculated. Where there were comparative data, the odds ratio (OR) was calculated. Results: Twenty-six studies were included in the review. When all cases were considered, intervention either by cord occlusion or by ablation conferred a better survival rate compared with conservative management (OR=2.22, 95% CI 1.23–4.01, heterogeneity I 2 =37%, P=0.008). This difference was greater in the presence of one or more poor prognostic features (OR=8.58, 95% CI 1.47–49.96, heterogeneity I 2 =0%, P=0.02). Survival was better using ablative techniques compared to cord occlusion (OR=9.84, 95% CI 1.56–62.00, heterogeneity I 2 =0%, P=0.01). Conclusion: Intervention either by cord occlusion or by ablation confers a better survival rate compared to conservative management. This appears more compelling if there are one or more poor prognostic features. Ablative techniques are superior to cord occlusion. There were insufficient data to determine which poor prognostic features should guide management.

Aim: Women do have longer QTc intervals compared to men. The aim of this study was to investigate as-yet undocumented effects of music on QTc intervals from electrocardiogram (ECG) recordings compared to various cardiovascular parameters of women in the prenatal phase. Methods: Forty-four healthy women in pregnancy were exposed to quiet surroundings (Q), self-selected slow music (S), and investigator-provided fast music (F) with different rhythm and frequency characteristics for 3 min each during their routine cardiotocography investigation. QTc intervals from ECG recordings were calculated according to the formulas of Bazett, Fridericia, and Sagie. Results: QTc durations (Bazett) increased from 0.396±0.02 (Q) to 0.401±0.02 s (S) and to 0.407±0.03 s (F). The increase in QTc (delta QTc) value for slow (S) and fast (F) music was found to be 5.3 (S) and 10.1 ms (F, milliseconds) when compared to quiescent (Q) conditions showing a highly significant tripled P-value of 0.002 (Q vs. F). Similar results were found using alternate frequency corrections (Fridericia, Sagie) – QTc (delta QTc): 8.1 (Fridericia) and 7.2 ms (Sagie), quiescent vs. F, with P<0.001. None of the tests for other cardiovascular parameters showed significant differences. Conclusions: As shown from our data, music with different rhythm and frequency characteristics may prolong QTc intervals in healthy preterm pregnant women and may add to other risk factors (e.g., preexisting QTc prolongation or application of QTc prolonging drugs). These data could prove to be relevant in the primary prevention recommendations for women at risk for arrhythmic patterns during pregnancy.

Background: The implementation of music during pregnancy is a topic of interest for parents-to-be accompanied by a growing commercial interest. We evaluated acoustic properties of commercially available music devices. Materials and methods: Sound characteristics of three different music devices designed for fetal acoustical stimulation were analyzed. A white noise sample was presented at a high volume to produce a standardized acoustic stimulus. Sound emissions were registered for each loudspeaker with a sound level meter in order to document the sound pressure levels (SPLs) and to analyze the long-term averaged spectra (LTAS) with the help of PRAAT-sound-analyzing software. Measurements were conducted in open air and under attenuated conditions with interposition of a pork uterus of 5 mm thickness covered by porcine tissue from the abdominal wall of either 3 or 5 cm thickness. Results: Under attenuated conditions, SPLs of all three devices were hardly detectable and interfered with the basal noise of around 50–55 dB (SPL), particularly low and high frequencies ranges were attenuated. Conclusion: Pregnancy music belts seem to be a useless tool to support fetal development. The poor sound characteristics of the loudspeakers and the concept of an isolated stimulation appear not promising to effectively support the complex multimodal maturation of the sensory system. Traditional implementation of music appears maternal singing appears more reasonable.

Objective: To examine the style and content of consultations for maternal-fetal surgery and draw conclusions about best practices for informed consent and shared decision-making. Study design: Qualitative study of 15 h-long consultations with women diagnosed with fetal myelomeningocele (MMC, n=11) or congenital diaphragmatic hernia (CDH, n=4) who were potential candidates for maternal-fetal surgery at a large children’s hospital in the Southwestern US. Results: Major findings were that physicians tended to discuss the risks of fetal prognosis qualitatively more often than quantitatively (70% compared to 30%) and when mortality was a risk the “positive” (percentage survival) frame was always given rather than the morality frame. On average, families only talked 15% of the time and 45% of all their questions were about diagnostic or surgical procedure clarification. Conclusion: Efforts should be made to minimize qualitative presentation of risk, which can be vague and confusing to patients. Both survival and mortality frames should be used to avoid biased decision-making. Communication and decision support tools that facilitate more shared decision-making between families and physicians are needed.

Objectives: Nasal continuous positive airway pressure (NCPAP) is an accepted form of non-invasive ventilation in preterm infants. Few, if any, studies have shown an advantage of one type of NCPAP over another. It has been theorized that bubble-generated NCPAP may be advantageous for the preterm neonate versus traditionally used ventilator-generated NCPAP. The aim of this study was to examine for any short-term differences in physiologic parameters in preterm subjects receiving these two different methods of NCPAP. Methods: We conducted a randomized, prospective, cross-over pilot study of preterm infants being treated with NCPAP in the neonatal intensive care unit. Subjects were continuously monitored for several physiologic parameters including heart rate, respiratory rate, oxygen saturation, cerebral tissue oxygen saturation and cerebral fractional oxygen extraction using routine neonatal monitors and near-infrared spectroscopy (NIRS) while on 2 h of bubble NCPAP and 2 h of ventilator NCPAP. Subjects were randomized to be monitored while either starting on bubble NCPAP and then switching to ventilator NCPAP or starting on ventilator NCPAP and switching to bubble NCPAP. Results: Eighteen subjects were included. We found no statistically significant difference in any of the physiologic parameters while subjects were receiving bubble NCPAP versus ventilator NCPAP during the monitoring time periods. While on bubble NCPAP, subjects showed a trend toward decreasing respiratory rate and decreasing cerebral fractional oxygen extraction over time, but this did not reach statistical significance. Conclusion: There appears to be no difference in immediate physiologic effects between bubble NCPAP and ventilator NCPAP. This does not preclude the possibility of potential long-term differences, but any differences seen would likely be based on mechanisms that take more time to develop. A larger prospective trial is warranted to confirm our findings.

Aim: Inhaled nitric oxide (iNO) is used to treat neonates with hypoxic respiratory failure (HRF). The aim of this study was to determine clinical characteristics and factors associated with non-response to iNO therapy that may assist in clinical management and weaning strategies. Methods: Retrospective chart review. The study cohort included gestational age ≥34 weeks’ infants with acute HRF who received iNO within 7 days of birth. Subjects were stratified as responders or non-responders to iNO. Non-responders were defined as infants with failure to improve their PaO2 >20 mm Hg within 6 h of iNO initiation, need for extracorporeal membrane oxygenation (ECMO), or mortality. Clinical and laboratory characteristics were then compared between groups. Results: Forty four subjects were included. There were 31 responders and 13 non-responders to iNO therapy. Regression analysis showed significant correlation between a non-response to iNO therapy and changes in PaO2 and pH levels. We found for every 10 mm Hg decrease in PaO2 immediate post-iNO therapy there is a 17.5% decrease in the likelihood of responding to iNO (odds ratio [OR] 0.98, P=0.012). Similarly, for every 0.15 point decrease in pH, there is a 16.3% increased chance of not responding to iNO therapy (OR 1.16, P=0.002). The need for pressor support prior to iNO initiation was also found to be associated with a non-response (OR 2. 94, P=0.034). Conclusions: Hypotension requiring treatment with pressors at the time of iNO therapy, as well as changes in pH and PaO2 after iNO initiation can be used as early clinical predictors to identify patients quickly who may be iNO non-responders.

Intrauterine growth retardation/restriction (IUGR) is associated with fetal malnutrition. It has consequences for later life including increased incidence of obesity, diabetes mellitus, cardiovascular disease (CVD), and metabolic syndrome. Adipokines (adiponectin and leptin), adropin, and endothelin-1 are associated with obesity and metabolic syndrome regulation. Intrauterine changes in these mediators could affect programming of later adult obesity and metabolic syndrome. Our objectives were to compare the levels of these mediators in both cord and maternal blood between IUGR pregnancies and control, healthy pregnancies, and to study the correlation of adipokines with adropin and endothelin-1 in maternal and cord blood in IUGR pregnancies as well as in healthy control pregnancies. Maternal and cord blood samples were taken from 16 women with IUGR pregnancies and 16 women with healthy pregnancies. Serum levels of leptin, adiponectin, adropin, and endothelin-1 were measured by ELISA. Maternal blood adropin levels were significantly lower in the IUGR group than in the control group; the other mediators did not differ significantly. There was a positive correlation between maternal blood adropin and endothelin levels. (r=0.731, P=0.001) in the control but not the IUGR group. Cord blood adropin and adiponectin levels were significantly lower in the IUGR group compared with the control group, while leptin or endothelin-1 did not differ significantly. There was a negative correlation between adropin and leptin (r=–0.704, P=0.001) in the IUGR but not the control group cord blood. There were also positive correlations between endothelin and adropin for both groups (r=0.594, P=0.006; r=0.560, P=0.010, respectively); to the best of our knowledge, this is the first report of such a correlation. Differences in fetal expression of adropin and adiponectin in IUGR could influence programming of obesity, metabolic syndrome, diabetes, and CVD in later life.

Aims: To develop a predictive model for assessing the risk of developing neonatal respiratory morbidity using lamellar body counts (LBCs) and gestational age (GA) to provide a more patient-specific assessment. Methods: Retrospective cohort study of patients’ ≥32 weeks’ gestation who received amniocentesis with LBC analysis over a 9-year period. Respiratory morbidity was defined as respiratory distress syndrome, transient tachypnea of the newborn or oxygen requirement for >24 h. Logistic regression analyses were used to predict the absolute risk and odds of respiratory morbidity as a function of GA and lamellar body count. Results: Two hundred and sixty-seven mother-infant pairs included in the analysis with 32 cases (12.0%) of respiratory morbidity. When compared to those without respiratory morbidity, neonates with respiratory morbidity had amniocentesis performed at an earlier median GA, had lower mean birthweight and had lower median LBC (P<0.01). The GA specific absolute risks and odds ratios for the presence of respiratory morbidity were calculated. The predicted absolute risks of neonatal respiratory morbidity ranged from 38% at 32 weeks to 6% at 40 weeks when LBC were 35,000/μL. Conclusion: GA specific predicted risk of neonatal respiratory morbidity using LBC provides a statistical model, which can aid clinicians in individually counseling patients regarding the absolute risk of their neonate developing respiratory morbidity.

Objectives: To assess the effect of surfactant administration, preceded or not by bronchoalveolar lavage (BAL) with dilute surfactant, on pulmonary function in experimental severe meconium aspiration syndrome. Methods: Twenty-one newborn pigs received 20% meconium in saline intratracheally and were randomly allocated to one of three groups: I, control; II, surfactant only (poractant alfa, 200 mg/kg); or III, dilute surfactant BAL followed by 125 mg/kg surfactant. Arterial blood gases (ABGs), lung compliance, and resistance were assessed. Results: Thirty minutes after treatment, mean PaO 2 (mm Hg) increased to 72 in group I, to 106 in group II and to 172 in group III (P=0.01). After 3 h, mean PaO 2 (mm Hg) was 70 in group I, 95 in group II and 198 in group III (P<0.01). After 6 h, it was 79 in group I, 110 in group II, and 217 in group III (P=0.01). From the 30-min point onward, there were significant differences among treatment groups in all other parameters and at every point of assessment, except for compliance and resistance 3 h after treatment. Conclusions: BAL with dilute surfactant, followed by an additional dose of surfactant, produced significant improvements in ABGs and pulmonary mechanics as compared with a single dose of surfactant.

Background: Norepinephrine (NE) and epinephrine (EPI) levels are higher in cord arterial blood relative to venous blood, consistent with active mechanisms of placental-maternal clearance. There are no contemporary studies of cord arteriovenous blood levels of sulfated and non-sulfated catechols. Aim: To assess the arteriovenous differences in cord blood levels of dopamine (DA), the sulfated catecholamines and their sulfated and non-sulfated metabolites. To correlate levels of oxygen, H + /CO 2 , and glucose with cord catecholamine levels. Methods: Fifty-seven term infants, delivered by elective cesarean section, were recruited. Cord arterial and venous blood was sampled; levels of glucose, lactate, blood gases, six catechols and their sulfated conjugates were measured. Results: With one exception (DOPA sulfate), mean cord arterial levels of sulfated and non-sulfated catechols were significantly higher than venous levels. Arterial lactate and glucose levels were independently associated with NE levels, but only lactate was associated with levels of EPI and DA. Conclusion: This study establishes that in vivo metabolic parameters of hypoxia, respiratory and metabolic acidosis are associated with catecholamine levels, a key relationship for perinatal adaptation and homeostasis, and findings that are consistent with in vitro studies of the regulators of catecholamine secretion.

Aim: This study investigates key components of the renin-angiotensin system (RAS) which play a central role in nephrogenesis and possibly in fetal programming of arterial hypertension in adult life. Methods: We compared a genetic rat model with inborn nephron deficit, the Munich Wistar Fromter rat (MWF), to normotensive Wistar rats during nephrogenesis at day 19 of fetal development (E19) and at postnatal day 7 (D7). Results: At E19 renal mRNA of angiotensin II type 1a ( AT1a ) (–50%, P<0.05) and type 1b ( AT1b ) (–55%, P<0.05) receptors were significantly decreased and renal mRNA expression of angiotensin II type 2 (AT2) receptor was fivefold increased in MWF (n=8) as compared to Wistar rats (n=8). At D7 renal mRNA expression of AT1a (–42%, P<0.05) remained lower in MWF (n=8) as compared to Wistar (n=7). Renal mRNA expression of AT2 (–30%, P>0.05) decreased in MWF (n=8) to about the level of the Wistar control (n=6). Conclusions: Altered fetal expression of key molecules of the renin-angiotensin system in MWF indicates a possible role in genetic low nephron number hypertension.

Neonatal immune response is characterized by an uncompensated pro-inflammatory response that can lead to inflammation-related morbidity and increased susceptibility to infection. We investigated the effects of long-chain n -3 polyunsaturated fatty acids ( n -3 PUFAs) docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) pre-treatment on cytokine secretion to low-concentration endotoxin (lipopolysaccharide, LPS) in THP-1 monocytes and neonatal cord blood (CB) from healthy full-term infants. Pre-treatment of THP-1 cells, with either n- 3 PUFA at 25 or 100 μM significantly reduced IL-6, IL-10, and IL-12 secretion while DHA, but not EPA, reduced TNF-α response to LPS. DHA inhibition was stronger compared to EPA and effective at the low concentration. The same concentrations of n -3 PUFAs inhibited IL-12 but not IL-10 cytokine response in whole CB from 9 infants pre-treated for 24 h. To assess clinical relevance for acute response to LPS, the effects of low-concentration DHA at 25 μM or 12.5 μM were assessed before and after LPS exposure of isolated CB mononuclear cells from 20 infants for 1 h. When added before or after LPS, physiologic DHA treatment produced significant concentration-dependent inhibition of TNF-α, IL-6, IL-1β, and IL-8 secretion. The results demonstrate prophylactic and therapeutic modulation of neonatal cytokine response to LPS and provide proof-of-concept that low-concentration administration of n -3 PUFA could attenuate or resolve neonatal inflammatory response.

Aim: To establish reference values for the single deepest vertical pocket to assess the amniotic fluid volume in the second and third trimesters of pregnancy. Methods: We performed a retrospective cross-sectional study with 3554 consecutive singleton low-risk pregnant women between 14 and 41 weeks of gestation. To perform the largest deepest vertical pocket measurement, the transabdominal convex probe was positioned vertical to the uterine contour of abdomen and parallel to the maternal sagittal plane. In order to obtain reference values for the largest deepest vertical pocket measurement and gestational age (GA), we have used a polynomial regression model. Results: The mean±standard deviation for the largest deepest vertical pocket measurement (cm) ranged from 3.1±1.1 (1.5–4.9) at 14–14+6 to 3.7±1.6 (0–6.7) at 41–41+6 weeks, respectively. A best-fit was a second-degree polynomial regression: largest deepest pocket=–1.478+0.197*GA–0.0030*GA 2 (R 2 =0.014). Conclusion: Reference values for the single deepest vertical pocket to assess the amniotic fluid volume in the second and third trimesters of pregnancy in a large heterogeneous population were established.