Volume 41, Issue 6

Aims: Psychosocial stress during pregnancy (PSP) is a risk factor of growing interest in the etiology of preterm birth (PTB). This literature review assesses the published evidence concerning the association between PSP and PTB, highlighting established and hypothesized physiological pathways mediating this association. Method: The PubMed and Web of Science databases were searched using the keywords “psychosocial stress”, “pregnancy”, “pregnancy stress”, “preterm”, “preterm birth”, “gestational age”, “anxiety”, and “social support”. After applying the exclusion criteria, the search produced 107 articles. Results: The association of PSP with PTB varied according to the dimensions and timing of PSP. Stronger associations were generally found in early pregnancy, and most studies demonstrating positive results found moderate effect sizes, with risk ratios between 1.2 and 2.1. Subjective perception of stress and pregnancy-related anxiety appeared to be the stress measures most closely associated with PTB. Potential physiological pathways identified included behavioral, infectious, neuroinflammatory, and neuroendocrine mechanisms. Conclusions: Future research should examine the biological pathways of these different psychosocial stress dimensions and at multiple time points across pregnancy. Culture-independent characterization of the vaginal microbiome and noninvasive monitoring of cholinergic activity represent two exciting frontiers in this research.

Over a 20-month period we identified several cases of neonatal pneumonia associated with prelabour rupture of membranes (PROM) at term. PROM complicates 8%–10% of all pregnancies, yet 60% of cases occur at term. Ascending infection is a contributing factor and the incidence of chorioamnionitis in these patients is relatively high, especially with prolonged membrane rupture. The signs and symptoms NICE recommends patients look out for are not always present as the majority of infections are subclinical, yet associated maternal and neonatal morbidity of chorioamnionitis is potentially devastating. A survey of maternity units in the West Midlands reveals significant variance in management of these cases. Given the lack of consensus and clear evidence on optimal management of PROM at term, we believe early detection of developing infections could be enhanced by using a combination of investigations (at presentation, 12 and 24 h), as well as current advice to self-monitor temperature and vaginal loss.

Objective: This study aims to treat patients with preterm premature rupture of the membranes (PPROM) and anhydramnion using continuous amnioinfusion through a subcutaneously implanted port system. Methods: An amniotic fluid replacement port system was implanted in seven patients with PPROM and anhydramnion starting at the 20 th week of gestation (range, 14–26 weeks) for long-term amnioinfusion. Saline solutions (2 L/day; Jonosteril ® , Sterofundin ® , isotonic NaCl 0.9% solution, lactated Ringer’s solution) and a hypotonic aqueous composition with reduced chloride content similar to the electrolyte concentration of human amniotic fluid were used for the continuous amnioinfusion. Results: The mean duration of the PPROM delivery interval continued for 49 days (range, 9–69 days), with 3 weeks of amnioinfusion via the port system (range, 4–49). The newborns showed no signs of lung hypoplasia. Conclusion: Long-term lavage of the amniotic cavity via a subcutaneously implanted port system in patients with PPROM and anhydramnion may help prolong the pregnancy and avoid fetal lung hypoplasia. A hypotonic aqueous composition with reduced chloride content similar to human amniotic fluid can be safely used for amnioinfusion. Prospective randomized studies are ongoing.

Objective : The molecular basis of failure to progress in labor is poorly understood. This study was undertaken to characterize the myometrial transcriptome of patients with an arrest of dilatation (AODIL). Study design : Human myometrium was prospectively collected from women in the following groups: (1) spontaneous term labor (TL; n=29) and (2) arrest of dilatation (AODIL; n=14). Gene expression was characterized using Illumina® HumanHT-12 microarrays. A moderated Student’s t -test and false discovery rate adjustment were used for analysis. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) of selected genes was performed in an independent sample set. Pathway analysis was performed on the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database using Pathway Analysis with Down-weighting of Overlapping Genes (PADOG). The MetaCore knowledge base was also searched for pathway analysis. Results : (1) Forty-two differentially expressed genes were identified in women with an AODIL; (2) gene ontology analysis indicated enrichment of biological processes, which included regulation of angiogenesis, response to hypoxia, inflammatory response, and chemokine-mediated signaling pathway. Enriched molecular functions included transcription repressor activity, heat shock protein (Hsp) 90 binding, and nitric oxide synthase (NOS) activity; (3) MetaCore analysis identified immune response chemokine (C-C motif) ligand 2 (CCL2) signaling, muscle contraction regulation of endothelial nitric oxide synthase (eNOS) activity in endothelial cells, and triiodothyronine and thyroxine signaling as significantly overrepresented (false discovery rate <0.05); (4) qRT-PCR confirmed the overexpression of Nitric oxide synthase 3 ( NOS3 ); hypoxic ischemic factor 1A ( HIF1A ); Chemokine (C-C motif) ligand 2 ( CCL2 ); angiopoietin-like 4 ( ANGPTL4 ); ADAM metallopeptidase with thrombospondin type 1, motif 9 ( ADAMTS9 ); G protein-coupled receptor 4 ( GPR4 ); metallothionein 1A ( MT1A ); MT2A ; and selectin E ( SELE ) in an AODIL. Conclusion : The myometrium of women with AODIL has a stereotypic transcriptome profile. This disorder has been associated with a pattern of gene expression involved in muscle contraction, an inflammatory response, and hypoxia. This is the first comprehensive and unbiased examination of the molecular basis of an AODIL.

Aim: Infection-induced inflammation is a common cause of preterm birth. Pharmacologic inhibition of proinflammatory cytokines improves pregnancy outcome in animal models but there are no universally effective therapies for preterm birth in women. Carbon monoxide (CO) has anti-inflammatory properties at low concentrations but its effects on reproductive tissues is unclear. Therefore, we studied the effect of supplemental CO on the production of cytokines associated with preterm birth by fetal membranes. Methods: Cross-sections of whole fetal membranes, isolated choriodecidua, and isolated amnion were prepared using tissues collected from women who had normal vaginal deliveries at term. Tissues were placed in an organ explant culture system and stimulated with up to 10 8 CFU/mL Escherichia coli . Cultures were incubated under room air or room air+250 ppm CO for 18 h and cytokine concentrations in conditioned medium were quantified by ELISA. Results: CO inhibited IL-1β and TNF-α (P≤0.001) production by cultures stimulated with 10 7 CFU/mL bacteria but had no detectable effect on IL-10 by full-thickness membranes. Although CO also tended to reduce TNF-α production (P=0.053), no effect of CO was detected for IL-10 or IL-1β for membranes stimulated with 10 8 CFU/mL E. coli . TNF-α, but not IL-1β or IL-10 production, was inhibited by CO for choriodecidual cultures stimulated with 10 7 or 10 8 CFU/mL E. coli (P<0.001). IL-1β production was significantly inhibited by CO for amnion cultures stimulated with 10 7 (P=0.002) and 10 8 (P=0.017) CFU/mL E. coli . Exposure to bacteria had no effect on TNF-α or IL-10 production but CO tended to increase IL-10 production by amnion cultures stimulated with 10 8 CFU/mL E. coli (P=0.037). Conclusions: These results suggest that CO may help promote an anti-inflammatory environment during intrauterine infections by inhibiting TNF-α and IL-1β production.

Aim: The aim of this study was to assess the risk of subsequent delivery complications after extremely preterm deliveries by initial (index) pregnancy mode of delivery (MOD): cesarean (CD) versus vaginal (VD). Methods: This is a retrospective, longitudinal cohort study using Washington State birth certificate data and International Classification of Diseases, Ninth Revision codes, 1989–2008, identifying women with deliveries 20–26 weeks’ gestation and linked subsequent deliveries. Index MOD was considered as a predictor of adverse subsequent maternal and neonatal outcomes, using t-test, χ 2 -test or Fisher’s exact test, and regression analysis. Results: Of 2472 women with periviable delivery and subsequent birth, index CD (n=386) and index VD (n=2086) showed similar risks of composite morbidity (16.1% vs. 15.4%, P=0.76) and subsequent hemorrhage (9.6% vs. 11.1%, P=0.39). Women with index CD were more likely than index VD to experience uterine rupture (1.8% vs. 0.1%, P<0.001), to deliver earlier (35.9 vs. 36.9 weeks, P<0.001), and to have lower birth weight (2736 vs. 3014 g, P<0.001) subsequently. Neonatal hospital charges and lengths of stay were also higher after index CD. Conclusions: MOD at extreme prematurity did not impact subsequent maternal hemorrhage or overall morbidity. However, CD was associated with substantial uterine rupture risk despite evidence of practice to avoid labor (lower birth weight and earlier delivery) in the subsequent pregnancy.

Background: Pathology laboratories often receive requests for confirmation of abruption; however, pathologically, abruption can only be confirmed by the presence of adherent blood clot on the maternal surface that is indenting the underlying placental parenchyma. Design: We evaluated whether abruptions due to more chronic underlying medical conditions are more likely to have a retained indenting retroplacental clot that is detectable by the pathologist than abruptions due to acute etiologies. This was a retrospective review from January 1995 to June 2012 of cases with a clinical and/or pathologic diagnosis of abruption. Data were analyzed utilizing Fisher’s exact test. Results: Ninety-six cases had sufficient available information for analysis. There was a significant association between pathologic identification of abruption and chronic risk factors (P=0.03). Twenty-five percent of cases with acute risk factors and 60% of cases with chronic risk factors had abruption confirmed at pathologic evaluation (P=0.12). Conclusion: Pathologically confirmable abruption is associated with chronic risk factors. There was a trend towards chronic risk factors leading to greater likelihood of pathologic confirmation of abruption than acute risk factors, but it did not reach statistical significance.

Aim: To compare the efficiency of endouterine hemostatic square suture and the Bakri balloon tamponade in the treatment of bleeding due to complete placenta previa (CPP). Methods: Thirteen patients with the diagnosis of CPP and intractable bleeding were randomly divided into two groups in a single blind study. Group 1 (n=6) included patients in whom endouterine hemostatic square suture was applied, while group 2 (n=7) included patients in whom Bakri balloon tamponade was applied. The two groups were compared according to the maternal outcomes, the duration of caesarean section, the preoperative and the postoperative hemoglobin and hematocrit (Htc) values, the intraoperative and postoperative blood loss, as well as the newborn characteristics. Results: The duration of operation and the amount of intraoperative bleeding were significantly higher in group 1 (time: 78.3±8.1 vs. 62.8±3.9 min; P<0.05; intraoperative bleeding: 1946±242 vs. 1520±92 mL; P<0.05). The postoperative 24 th h Htc values were found to be significantly lower in group 1 than in group 2 (25.6±3.7 vs. 29.5±1.3 g/dL; P<0.05). The postoperative blood loss was higher in group 1 than in group 2. (351±70 vs. 120±56 mL; P<0.05). Conclusion: There are two methods that are effective in preventing bleeding in CPP. However, the Bakri balloon tamponade may be a better alternative due to a shorter operation time and less blood loss.

Aim: We investigated the combined effects of intra-amniotic lipopolysaccharide (LPS) and maternal betamethasone (BMZ) on alveolarization using a newborn rat model. Methods: LPS (1.0 μg/sac) or vehicle was injected into the amniotic sacs of pregnant rats and BMZ (170 μg/kg) or vehicle was injected intramuscularly into the pregnant rats twice at 8-h intervals on gestation day 20. The rat pups were delivered spontaneously after 2–2.5 days and raised until the measurements were taken. Bronchoalveolar lavage was performed on days 2 and 5, and morphometric analyses of the lungs were performed on days 5 and 14. Results: Intra-amniotic LPS significantly increased the neutrophils in the bronchoalveolar lavage fluid (BALF) on day 2, but double exposure to LPS and BMZ significantly alleviated the neutrophil increase in the BALF. On day 5, while the neutrophils in the BALF decreased in the animals exposed to LPS alone, the neutrophil numbers in the BALF were steady in the animals exposed to both LPS and BMZ. Morphometric analyses on days 5 and 14 revealed a significant disruption of alveolarization only in the animals exposed to both LPS and BMZ. Conclusions: Our results suggested that double exposure to maternal BMZ and intra-amniotic LPS induces sustained increase of neutrophils in the lungs and disrupts alveolarization.

Objective: The objective of this study was to analyze the effect of using inhaled nitrous oxide (N 2 O) for analgesia in external cephalic version (ECV) at term on the success rate of the procedure, on pain, and on obstetric and perinatal outcomes. Methods: A prospective comparative cohort study among 300 women with singleton pregnancy in breech presentation at term undergoing an ECV with inhaled N 2 O in a 50:50 mix with oxygen for analgesia and 150 ECVs with no analgesia. Results: The success rate was 52.3% in the N 2 O cohort and 52.7% in the controls (P=0.94), whereas the median level of pain was statistically lower in women given N 2 O (median, 6; range, 4–7, vs. median, 7; range, 5–8; P<0.01). This improvement is mainly from a 49% decrease in severe pain. There were no significant differences in the rate of complications associated with the ECV, in the rate of cesarean sections, or in perinatal outcomes. Furthermore, there were no severe complications secondary to N 2 O inhalation. Conclusions: N 2 O inhalation at a concentration of 50% for analgesia during ECV decreases the level of severe pain experienced by women, appears to be safe both for mother and child, and has no influence on the success rate of ECV or the perinatal outcomes.

Introduction: Current standard methods of monitoring fetal heart function are mainly based on echocardiography, which provides indirect information (through mechanical assessment) of the fetal heart rhythm. Fetal magnetocardiography (fMCG) allows a reliable quantification of the temporal structure of fetal heart signals. However, its application in clinical studies is difficult because extracting the fetal heart signal for most current applications requires user intervention. To overcome this limitation, we developed a completely automated extraction algorithm. Patients and methods: The fMCG recordings were acquired using a 156-channel biomagnetic system. To perform an automated analysis, a combination of orthogonal projection and independent component analysis was used. fMCG recordings from 69 healthy uncomplicated singleton pregnancies with normally developing fetuses were included in the study. Results: The normal values achieved by the automated algorithm were comparable to previously published data. The majority of the cardiac time intervals were positively correlated with gestational age (GA). The ST segment, T wave and QT interval did not show any correlation. Conclusions: The automated detection of fetal heart signals was possible beginning at a GA of 19 weeks. This automated analysis of fMCG recordings might be an objective and easily applicable approach for clinicians to analyze fetal heart signals.

Aim: To assess the impact of a high enteral protein nutrition strategy in human milk-fed very low birth weight (VLBW) infants (<1500 g) on growth during the first 5 weeks of life. Design: Weight, length and head circumference of VLBW infants were recorded after introduction of a high protein strategy. Results: Forty-three infants (median/interquartile range) of gestational age 27+6 weeks (26+0/29+6), birth weight 984 g (675/1130) were included. Parenteral nutrition was administered for 16 (14/18) days and the nutritional intakes achieved target values 4.3 g/kg/day protein (4.0/4.4); 128 kcal/kg/day energy (119/131). Human milk was fortified with 0.5–2.3 g/kg/day protein powder in addition to a fortifier. Near-intrauterine growth was observed: Weight gain from days 8–35: 17.6 g/kg/day (14.9/20.5); head growth from day 1–35: 0.70 cm/week (0.50/0.80); length growth from day 1–35: 1.0 cm/week (0.8/1.2). The total protein intake was shown to have a significant impact on infant’s weight gain up to the 35 th day of life. Conclusion: High protein nutrition enables similar to fetal growth weight gain and head growth of VLBW infants during the first 5 weeks of life. These data support recently published ESPGHAN recommendations.