Volume 43, Issue 5 - Highlight: Preterm Labor

Background: The long-term outcomes of antenatal glucocorticoids (GCs) vary between reports, and have generated controversy in terms of repeated and single-course events, causing irreversible effects on endocrine set points. Aim: This study aimed to assess the effects of alternative therapeutic agents other than synthetic glucocorticoid GC administration for fetal lung maturation. Methods: A review of literature from PubMed, EMBASE, Cochrane Library, and Google Scholar was conducted to assess the use of alternative therapies to synthetic GCs using recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA). End points included the rates of respiratory distress syndrome (RDS), mRNA expression for pneumocyte type II, concentration of surfactant proteins in alveolar lavage, morphological differences, histological proof of lung maturation, and angiogenesis or quantification of the surfactant pool. Results: In all 41 studies examined, we found that ambroxol showed positive effects on lung maturation, but it has yet to be analyzed with sufficient significance in humans. Interleukins and TNF-alpha produce accelerated lung maturation, but have only been evaluated in basic research/experimental studies. Growth factors promote structural and functional growth in all phases of lung maturation, but little is known about their reciprocal effects and exact mechanisms as therapeutics. Thyroid releasing hormone or vitamin A cause detrimental side effects or were less effective for lung maturation. Conclusions: The efficacy and safety of these alternative agents are differentiated and none up to now can be recommended as an alternative to GCs.

Introduction: Preterm birth (PTB) is a predictor of perinatal morbidity and mortality, and prematurity continues to burden public healthcare with growing expenses. First trimester bleeding (FTB) has a well-known association with PTB; however, the relationship with severity of PTB is less obvious. Aim: The primary aim of the study was to analyze the influence of FTB on the risk and severity of PTB, as well as to assess the connection of FTB and other pregnancy complications. Methods: It was an observational case control study. The material consisted of medical records of patients who delivered between 2010 and 2013. Two groups were formed – 497 women with FTB and 500 women without bleeding. Results: Women with FTB were more likely to deliver preterm in general (OR=2.11; 95% CI 1.43–3.10). The risk of extremely PTB (<28 weeks) was almost four-fold (OR=3.76; 95% CI 0.97–17.06) and very PTB (28–31 weeks) more than three-fold (OR=3.41; 95% CI 0.86–15.69). FTB increased the risk of placenta previa (OR=4.81; 95% CI 1.29–20.53; P=0.007). Conclusion: FTB is a risk factor of PTB and is associated with greater risk of PTB-related pregnancy complications. Management of FTB pregnancies should include thorough screening for both preterm delivery and placental pathologies.

Aim: Accurate prediction of the risk of spontaneous preterm birth is crucial for the clinical management of patients with preterm labor. The aim of the study was to investigate whether cervical sonoelastography improves prediction of spontaneous preterm birth compared with cervical length measurement and a fetal fibronectin (fFN) test. Methods: A prospective cohort study was conducted including 64 patients with preterm labor at 23–34 weeks of gestation. Patients had an fFN test and transvaginal cervical length measurement, followed by real-time cervical sonoelastography. The ratio of nondeformable tissue to the total area of a designed region of interest was analyzed and related to the gestational week of delivery. Results: Cervical sonoelastography and fFN test show a significant correlation with spontaneous preterm delivery (P=0.007, P=0.001), resulting in 72.7%/36% sensitivity and 73%/95% specificity. The positive predictive value (PPV) was 61.5%/81.8% and the negative predictive value was 81.8%/70%. The cervical length was not different in cases with and without term delivery (P=0.165). Conclusions: Cervical sonoelastography is a promising technique that can complement routine diagnostic procedures to improve prediction of preterm birth. The PPV is improved by an fFN test.

Objective: To investigate the use of magnesium sulfate (MgSO 4 ) as a neuroprotective agent in a mouse model of inflammation-associated and noninflammation-associated preterm birth. Methods: On embryonic day 15 of gestation, lipopolysaccharide (LPS) and mifepristone (RU486) were used, respectively, to create mouse models of inflammation and noninflammation-associated preterm birth. After intraperitoneal injection of LPS, RU486, or normal saline solution (NS), dams were randomized to intraperitoneal MgSO 4 or NS injection. From the 6 treatment groups (NS+NS, LPS+NS, NS+MgSO 4 , LPS+MgSO 4 , RU486+NS and RU486+MgSO 4 ), fetal brains were collected for Western blot analysis and neuronal cultures. Protein expression of S100B was assessed, and immunohistochemistry was performed to detect NeuN. The numbers of NeuN-labeled cells were counted using confocal laser scanning microscopy. Results: The expression of S100B significantly differed among the groups and was decreased in the LPS+MgSO 4 group compared to the LPS+NS group. The expression of S100B did not differ between the RU486+NS and RU486+MgSO 4 groups. NeuN-labeled cells were increased in the LPS+MgSO 4 group compared with the LPS+NS group. NeuN-labeled cells were decreased in the RU486+MgSO 4 group compared with the RU486+NS group. Conclusions: We observed that prenatal treatment with MgSO 4 was associated with decreased expression of S100B and increased numbers of NeuN-labeled cells in an inflammation-associated preterm mouse model but not in a noninflammation-associated preterm mouse model. Our results suggest that prenatal treatment of MgSO 4 reduces inflammation-associated brain injury in fetal mice.

Objective: The aim of this study was to determine the relationship between sonographic cervical length, fetal fibronectin (fFN), phIGFBP-1 (actim partus test), cytokines (IL-6, IL-2R, and TNF-α), and spontaneous preterm birth (SPTB) up to 14 days from sampling. Methods: Fifty-eight patients were recruited in a period of 6 months from September 2013 until March 2014 with symptoms or complaints suggestive of preterm labor. Consenting women were treated according to usual hospital protocol, with addition of vaginal swabs taken for fetal fibronectin, phIGFBP-1 (actim partus test) and cervical IL6, IL2R, and TNF-α. The outcome variable was occurrence of preterm delivery within 14 days from the day of hospital admission. Results: Thirty-six patients (62.07%) were delivered within 14 days from admission. Our results indicated that the cervical length significantly inversely correlates with the concentration of IL-6 in the CVF (Spearman’s coefficient R=–0.382, P<0.05). Cervical length also correlated with a positive phIGFBP-1 test, i.e., patients with a positive test had an average cervical length of 18.5±4.63 mm, which is significantly lower than patients with a negative test –23.43±7.39 mm (P=0.003). Conclusions: The studied biochemical markers were only moderately successful in the prediction of preterm delivery.

Objective: To evaluate a possible dose-response relationship between active maternal smoking during pregnancy and adverse perinatal outcome. Design: Retrospective cohort study. Setting: Population-based in Montreal, Quebec, Canada. Population: Women who gave birth to a liveborn or stillborn infant during the period of January 2001 to December 2007. Methods: Active smokers of different daily cigarette consumption (n=1646) were identified through maternal self-reporting. The reference group comprised 19,292 non-smoking women who delivered during the same period. Main outcome measures: Birth weight, preterm delivery rate, fetal and neonatal mortality and morbidity, and congenital malformations. Results: Preterm delivery rate was significantly higher in the smoking group compared with controls (22.2% vs. 12.4%, P<0.05), as was intrauterine fetal demise (1.4% vs. 0.3%, P<0.05). Newborns of active smokers were more likely to weigh less (3150±759 g vs. 3377±604 g, P<0.05), suffer from respiratory distress syndrome (2.5% vs. 1.3%, P<0.05), suffer from a cardiac malformation (1.5% vs. 0.8%, P<0.05), and die (neonatal death 1.2% vs. 0.6%, P<0.05). A dose-response relationship was demonstrated between levels of daily cigarette smoking and several adverse outcomes. Using multiple regression models, smoking was found to be an independent predictor of preterm delivery (odds ratios (OR) 1.9, 95% confidence intervals (95%CI) 1.6–2), and intrauterine fetal demise (OR 2.4, 95%CI 1.4–4.2). Conclusion: Any amount of daily smoking appears to harm the fetus and newborn. As pregnancy may be a “window of opportunity” for behavioural changes, efforts to promote smoking cessation should be encouraged.

Objective: The objective of this study was to reproduce and validate the association of group B streptococcus (GBS) colonization resulting in early-term birth (37 0/7 –38 6/7 weeks’ gestation) and lower birth weight, reported in African-American and Caucasian populations, in a Hispanic cohort. Methods: GBS status of women 18–40 years of age with uncomplicated pregnancies who experienced spontaneous labor and vaginal delivery between 37 0/7 and 42 0/7 weeks’ gestation over 5 years were identified. Bivariate analysis was conducted on stratified data (GBS+ vs. GBS–) to assess relationship to early versus late-term delivery. Chi-square, Fisher’s exact, and Student’s t -tests were used for analysis. Results: Our cohort was 86% Hispanic, with a GBS+ rate of 10%. No difference for mean gestational age at delivery for GBS+ (275.9 days±6.8) vs. GBS– (275.6 days±6.9) was seen (P-value=0.61). Birth weight for GBS+ and GBS– groups were similar (3388.5 g±388.6 vs. 3395.1 g±401.7, P-value=0.86). Conclusions: In specific evaluation of Hispanic women experiencing spontaneous, term, vaginal delivery, GBS colonization does not result in early-term delivery. This is not consistent with prior data in the African-American and Caucasian population suggesting racial disparity in outcomes related to GBS colonization.

Objective: To investigate selected fatty acid (FA) profiles in maternal whole blood during normal pregnancy and to evaluate their associations with term birth dimensions. Methods: We characterized nine major maternal blood FAs representing four FA families during the second and third trimester of pregnancy, and explored their associations with birth weight, length, and chest or head circumferences by multivariate regression models, using data from 318 mother-newborn pairs of the Hokkaido Study. Results: The absolute and/or relative contents of maternal blood docosahexaenoic acid and arachidonic acid were lowest at 35–41 gestational weeks during pregnancy, as was the essential FA status index. Different from palmitic and stearic acids, palmitoleic and oleic acid contents were higher at 35–41 gestational weeks than those at 23–31 gestational weeks. Three FA components were identified through principal component analysis, and were used in association analysis. Component 3, which was positively and significantly loaded by eicosapentaenoic acid (EPA), was associated with chest circumference [β=0.281, 95% confidence interval (CI): 0.006, 0.556] at 35–41 gestational weeks (P=0.046). No significant associations were observed for Component 1 and 2 loaded by FAs except EPA. Conclusion: Maternal blood EPA content may have an important influence on infant chest circumference.

Background and aim: On vaginal ultrasonography, cervical gland area (CGA) gradually disappears with advancing gestation. This is attributed in part to the echogenicity of the CGA becoming equal to that of the cervical stroma. The present study aimed to assess the usefulness of echogenicity in the CGA at term for predicting the time of spontaneous onset of labor. Methods: The ratio of mean grayscale level (MGL) in the CGA to that in the cervical stroma (CGA/stroma MGL ratio) was estimated as an index of echogenicity in the CGA in women after 36 weeks of gestation (n=190). Using this ratio, time until onset of labor was predicted among women between 37 and 38 weeks (n=104). Results: CGA/stroma MGL ratio increased with advancing gestation, decreasing cervical length (CL), and increasing Bishop score. Univariate logistic analysis indicated that a combination of CL<20 mm and CGA/stroma MGL ratio ≥100% predicted onset of labor within a week [odds ratio (OR), 22.2; 95% confidence interval (CI), 2.4–202.0] was even better than short CL alone (OR, 6.8; 95%CI, 1.7–26.7; P=0.006). Stepwise logistic analysis identified that this combination was an only independent predictor (OR, 20.8; 95%CI, 2.3–188.5; P=0.007). Conclusion: The combination of CGA/stroma MGL ratio ≥100% and short CL may offer a useful predictor of onset of labor.

Objective: Magnesium sulfate (MgSO 4 ) administered to women at risk for preterm delivery decreases the risk of cerebral palsy in their children. However, the neuroprotective effect of MgSO 4 has not been shown in twin gestations. Thus, the aim of this study was to determine the maternal serum levels of magnesium in twin vs. singleton pregnancies following intravenous treatment of MgSO 4 . Methods: Case control study including two groups of pregnant women who received intravenous MgSO 4 : (1) twin gestations (n=83) and (2) singleton pregnancies (n=83). Maternal serum magnesium levels 6 and 24 h after initiation of treatment were determined in both groups. Results: Maternal serum levels of magnesium were significantly lower among patients with twin gestations compared to those with singleton ones 6 h after initiation of treatment (4.6 vs. 4.8 mg/dL, P=0.003). In addition, the rate of pregnant women who obtained therapeutic levels 6 h after initiation of treatment was significantly lower in twin gestations than in singleton ones (36% vs. 58%, P=0.008). Multiple regression analysis revealed that twin gestations were independently and significantly associated with low maternal serum magnesium levels. Conclusions: Maternal serum concentrations of magnesium are lower in twin pregnancies than in singleton ones following MgSO 4 treatment, which might explain the decreased neuroprotective effect of MgSO 4 reported in twin pregnancies.

Background: Cervicofacial tumors are rarely detected by prenatal ultrasound, and prenatal counseling is very difficult as not much information is available about this problem in the literature, other than cases reports. Objectives: The aim of this study was to know if fetal echocardiography examination is helpful in those cases. Material and methods: Forty-four fetuses with cervicofacial tumors detected in utero by ultrasonography and referred to our unit were assessed and the cardiovascular profile score (CVPS) based on echocardiography examinations was calculated. The data were analyzed by the standard statistical tests and Pearson’s χ 2 -test (significance level P=0.05). Results: CVPS<8 was diagnosed in 10 fetuses (23%). Structural or functional cardiovascular anomalies were present in 17 fetuses (39%). The statistically significant correlation between the CVPS<8 and the poor outcome was confirmed (P<0.05). Conclusion: We recommend fetal echocardiography and CVPS evaluation before counseling in fetuses with cervicofacial tumors as cardiovascular dysfunction diagnosed prenatally may seriously affect survival of the fetus as well as prenatal counseling and need for cardiac treatment.

Background: Tricuspid regurgitation (TR) is a common sonographic finding during the fetal life. It has been reported in 7% of normal fetuses. It may be associated with aneuploidy and with both cardiac and extracardiac defects. Objectives: In this study, we have looked at the characteristics of fetuses with and without TR at 11 +0 to 13 +6 weeks’ gestation. Groups were compared with respect to the following variables: prevalence of chromosomal defects; other markers of aneuploidy; fetal cardiac; and extracardiac anomalies. Methods: The study group included women, who underwent an ultrasound examination at 11–13 +6 weeks’ gestation between 2009 and 2012. The inclusion criteria were singleton pregnancies with crown-rump length measurements of 45–84 mm where the pregnancy outcome was known. Results: Some 1075 patients met our inclusion criteria including 979 fetuses without TR and 96 with TR. There were 72 cases of aneuploidy diagnosed (6.7%). Isolated TR was found in 53 euploid fetuses (5.2%). All of the TR(+) aneuploid fetuses (n=40) had additional ultrasound markers present. Extracardiac anatomy showed a higher prevalence of abnormalities in the group of TR positives (12.5%) vs. TR negatives (1.6%). Abnormal cardiac findings were more frequent in the TR-positive group independently of chromosomal status and were found in 18.8% of fetuses with TR and in 1.9% with a normal tricuspid flow. Conclusions: TR in combination with other markers is the strongest predictor for aneuploidy. TR, as an isolated parameter, is a poor screening tool both for all and for each individual chromosomal abnormality and congenital cardiac defects.

Aims: Fetuses with gastroschisis are at increased risk of intrauterine growth restriction (IUGR). However, there is a tendency for underestimation of fetal abdominal circumference and hence fetal weight, leading to overdiagnosis of IUGR. Our objective was to evaluate the accuracy of ultrasound for the prediction of being small for gestational age (SGA) at birth in these cases. Methods: A retrospective study of prenatally diagnosed cases of gastroschisis was conducted at a tertiary center. Fetal weight was estimated using the formula of Hadlock. IUGR was defined as an estimated fetal weight ≤10th percentile for gestational age. SGA at the time of birth was defined as a birth weight ≤10th percentile for gestational age. The incidence of IUGR on last ultrasound and that of SGA at birth were calculated, and the precision of ultrasound in predicting SGA was determined. Results: IUGR was reported on the last ultrasound prior to delivery in 9/25 cases (36%). Postnatally, 13/25 newborns (52%) were SGA. All sonographically suspected cases of IUGR based on the last ultrasound were SGA at birth. The positive predictive value of the last ultrasound in identifying SGA was 100%. Conclusions: At least half of the infants affected by gastroschisis were SGA at birth. Sonographic estimation of fetal weight within 1 month of birth reliably predicted SGA in infants with gastroschisis.

Aims: The risk of neonates for severe infection/sepsis is reciprocally proportional to gestational age and birth weight. As monocytes and dendritic cells (DC) are recognised key antigen-presenting immune cells, we aimed to elucidate whether neonatal age is associated with reduced expression of human-leukocyte antigen-DR (HLA-DR) antigens on subsets of monocytes and DCs. Methods: Forty-three consecutive neonates (20 male, mean gestational age 236.0±26.8 days; mean 1-min Apgar score 7.5±2.0) were included in a monocentric prospective observational analysis. Patients were grouped according to gestational age (n=15 full-term, n=28 pre-term defined as <33 weeks). Ten healthy adult volunteers were assessed also. Flow-cytometric assessment of HLA-DR expression was performed in subsets of peripheral blood myeloid and plasmacytoid DCs (MDC and PDC) and monocytes (CD14 bright CD16 negative /CD14 positive CD16 positive /CD14 dim CD16 positive ). Clinical and routine laboratory data were followed up. Results: At birth, leukocyte counts were increased in full-term neonates. Monocyte counts were significantly increased in neonates when compared with adults (all P<0.05). A significant numerical increase of CD14 bright CD16 negative and CD14 positive CD16 positive monocytes was noted in pre-term and full-term neonates (all P<0.05), while HLA-DR expression in these subsets was significantly diminished (most pronounced in pre-term infants, P<0.0001). MDC and PDC HLA-DR expression was reduced also (all P<0.05). Clinical indices (e.g., pH, days on antibiotics/mechanical ventilation, fever/sepsis) were not found to correlate with immunological indices. Conclusions: We observed a markedly diminished HLA-DR expression on monocyte and DC subsets in pre-term and full-term neonates, which may contribute to impaired antimicrobial defence mechanisms in the early days of life.

Aims: To determine the infant mortality of newborns with 1- and 5-min Apgar scores of 0–3. Results: Population cohort study with neonates with birth weight ≥400 g, gestational age ≥22 weeks and 1- and 5-min Apgar scores of 0–3, without malformations, born in São Paulo State (Brazil) from January 2006 to December 2007. Apgar scores were confirmed in the original certificates of live births and/or medical records. During this period, among 1,027,132 live births, 1640 met the study criteria, with an incidence of 1.6 per 1000 live births. When the 5-min Apgar score was 0, 1, 2 and 3, the infant mortality rate was 97%, 94%, 64% and 47%, respectively. Risk factors associated with infant deaths were 5-min Apgar score of 0 or 1 [odds ratio (OR) 16.6, 95% confidence interval (CI) 11.1–24.8], birth weight <2500 g (OR 7.5, 95% CI 5.7–9.8), birth at hospitals outside the state capital (OR 1.7, 95% CI 1.3–2.3), in private or charitable hospitals (OR 1.6, 95% CI 1.2–2.0), and during the night shift (OR 1.3, 95% CI 1.0–1.7). Conclusions: For infants with 1- and 5-min Apgar scores of 0–3, the infant mortality is high. Besides the biological variables associated with the chance of dying, the organization of the perinatal care influences the outcome.

This paper describes historic steps in feeding techniques and knowledge on the nutritional needs of premature infants. Devices to overcome weak sucking and swallowing were developed from 1851 to 1920, including tube feeding by gavage, medicine droppers and pipettes, feeding bottles with an air inlet, and beaked spoons for nasal feeding. Indwelling nastrogastric tubes were in use from 1951. For alleged safety concerns in the 1950s, postnatal feeding was postponed until a week of starvation was reached, and studies showed an association with neurological handicaps. The premature infant’s elevated need for energy, protein, and minerals has been established since 1919. However, these remained controversial, and nutritional practices continued to lag behind theoretical knowledge. Concentrated formula was developed in the 1940s, parenteral supplementation in the 1960s, and human milk fortifiers in the 1970s. In the 1990s, necrotizing enterocolitis was found to be more frequent in infants who were fed formula than in those who were fed human milk. Recently, probiotics were shown to reduce the risk of necrotizing enterocolitis. Nevertheless, compared with other aspects of neonatal medicine, there is still remarkably little evidence on how to feed preterm infants.