Use of anti-infective drugs during pregnancy : prevalence, predictors of use and the risk of preterm birth and small-for-gestational-age newborns

Résumé: Les anti-infectieux sont parmi les médicaments les plus utilisés pendant la grossesse. Les indications pour l’utilisation de ces médicaments, telles que les infections bactériennes, figurent parmi les facteurs de risque les plus importants pour la prématurité et les enfants nés petits pour l'âge gestationnel («Small-for-gestational-age », SGA). Ces complications de la grossesse peuvent avoir des incidences sur la santé du nouveau né et sur son développement futur. Compte tenu des impacts sur la santé de la mère et de l’enfant, la prise en charge et le traitement efficace de ces infections sont impératifs. Cependant, l'utilisation des anti-infectieux, pour éviter des issues de grossesse défavorables, fait l’objet d’une controverse dans la littérature. Cette controverse est en partie liée à la qualité méthodologique discutable des études disponibles sur le sujet. Les quatre études présentées dans cette thèse ont donc pour objectif d’investiguer l’utilisation des anti-infectieux durant la grossesse ainsi que d’évaluer le risque de prématurité et de SGA après utilisation de ces médicaments en période gestationnelle. Une révision systématique de la littérature sur l’utilisation du métronidazole durant la grossesse est également présentée. Nous avons utilisé, comme source de données le Registre des Grossesses du Québec, une cohorte longitudinale conçue à partir du jumelage de trois bases de données administratives de la province du Québec (RAMQ, Med-Echo et ISQ). Le registre fournit des informations sur les prescriptions, les services pharmaceutiques et médicaux, ainsi que des donnés sur les soins d’hospitalisation de courte durée et démographiques. Les deux premières études présentées dans cette thèse ont eu pour objectif d’évaluer la prévalence, les tendances, les indications et les prédicteurs de l’utilisation des anti-infectieux dans une cohorte, extraite du registre, de 97 680 femmes enceintes. A l’aide d’un devis cas-témoins, les 2 dernières études ont mesuré l’association entre l’utilisation d’anti-infectieux durant les 2 derniers trimestres de grossesse et le risque de prématurité et de SGA, respectivement. Un cas de prématurité a été défini comme un accouchement survenu avant 37 semaines de gestation. Un cas de SGA a été défini comme l’accouchement d’un enfant dont le poids à la naissance se situe sous le 10ème percentile du poids normalisé à la naissance (compte tenu de l’âge gestationnel et du sexe du bébé). Les données ont été recueillies pour les agents systémiques oraux, ainsi que pour les classes et les agents individuels. Nos résultats ont montré que la prévalence de l’utilisation des anti-infectieux durant la grossesse était comparable à celle d’autres études déjà publiées (25%). Nous avons observé une augmentation de l’utilisation des agents plus anciens et ayant des profils d’innocuité connus. Les prédicteurs de l’usage en début de grossesse identifiés sont : avoir eu plus de deux différentes prescriptions (OR ajusté = 3,83, IC 95% : 3,3-4,3), avoir eu un diagnostic d’infection urinaire (OR= 1,50, IC 95% : 1,3-1,8) et un diagnostic d’infection respiratoire (OR= 1,40, IC 95% : 1,2-1,6). L’utilisation des macrolides a été associée à une diminution du risque de prématurité (OR =0,65, IC 95% : 0,50-0,85). En revanche, les femmes ayant été exposées au métronidazole ont vu leur risque augmenté de 80% (OR=1,81, IC 95% : 1,30-2,54). L’utilisation d’azithromycine a été associée à une diminution importante du risque chez les femmes ayant un diagnostic de rupture prématurée des membranes (OR=0,31, IC 95% : 0,10-0,93). Cependant, l'utilisation de sulfaméthoxazole-triméthoprime (SXT) a été significativement associée à une augmentation du risque de SGA (OR= 1,61, IC 95% : 1,16-2,23), tandis que celle des anti-infectieux urinaires a été associée à une diminution du risque (OR= 0,80, 95%CI : 0.65-0.97). Les conclusions de nos travaux suggèrent que l’utilisation des macrolides et des pénicillines diminuent le risque de prématurité et de SGA. Nous devons considérer l'utilisation de différents choix thérapeutiques tels que l’azithromycine, lors de la prise en charge des infections pouvant induire la prématurité et le SGA.

Electrophysiological study of hearing in full-term small-for-gestational-age newborns

PURPOSE: To describe the Brainstem Auditory Evoked Potential (BAEP) results of full-term small-for-gestational-age newborns, comparing them to the results of full-term appropriate-for-gestational-age newborns, in order to verify whether the small-for-gestational-age condition is a risk indicator for retrocochlear hearing impairment. METHODS: This multicentric prospective cross-sectional study assessed 86 full-term newborns - 47 small- (Study Group) and 39 appropriate-for-gestational-age (Control Group - of both genders, with ages between 2 and 12 days. Newborns with presence of transient evoked otoacoustic emissions and type A tympanometry were included in the study. Quantitative analysis was based on the mean and standard deviation of the absolute latencies of waves I, III and V and interpeak intervals I-III, III-V and I-V, for each group. For qualitative analysis, the BAEP results were classified as normal or altered by analyzing these data considering the age range of the newborn at the time of testing. RESULTS: In the Study Group, nine of the 18 (38%) subjects with altered BAEP results had the condition of small-for-gestational-age as the only risk factor for hearing impairments. In the Control Group, seven (18%) had altered results. Female subjects from the Study Group tended to present more central alterations. In the Control Group, the male group tended to have more alterations. CONCLUSION: Full-term children born small or appropriate for gestational age might present transitory or permanent central hearing impairments, regardless of the presence of risk indicators.

Comparisons of Mortality and Pre-discharge Respiratory Outcomes in Small-for-gestational-age and Appropriate-for-gestational-age Premature Infants.

BACKGROUND: There are differences in the literature regarding outcomes of premature small-for-gestational-age (SGA) and appropriate-for gestational-age (AGA) infants, possibly due to failure to take into account gestational age at birth. OBJECTIVE: To compare mortality and respiratory morbidity of SGA and AGA premature newborn infants. DESIGN/METHODS: A retrospective study was done of the 2,487 infants born without congenital anomalies at RESULTS: Controlling for GA, premature SGA infants were at a higher risk for mortality (Odds ratio 3.1, P = 0.001) and at lower risk of respiratory distress syndrome (OR = 0.71, p = 0.02) than AGA infants. However multivariate logistic regression modeling found that the odds of having respiratory distress syndrome (RDS) varied between SGA and AGA infants by GA. There was no change in RDS risk in SGA infants at GA 32 wk (OR = 0.41, 95% CI 0.27 - 0.63; p < 0.01). After controlling for GA, SGA infants were observed to be at a significantly higher risk for developing chronic lung disease as compared to AGA infants (OR = 2.2, 95% CI = 1.2 - 3.9, P = 0.01). There was no significant difference between SGA and AGA infants in total days on ventilator. Among infants who survived, mean length of hospital stay was significantly higher in SGA infants born between 26-36 wks GA than AGA infants. CONCLUSIONS: Premature SGA infants have significantly higher mortality, significantly higher risk of developing chronic lung disease and longer hospital stay as compared to premature AGA infants. Even the reduced risk of RDS in infants born at >/=32 wk GA, (conferred possibly by intra-uterine stress leading to accelerated lung maturation) appears to be of transient effect and is counterbalanced by adverse effects of poor intrauterine growth on long term pulmonary outcomes such as chronic lung disease.

A 2-year multicentre, open-label, randomized, controlled study of growth hormone (Genotropin(®) ) treatment in very young children born small for gestational age: Early Growth and Neurodevelopment (EGN) Study

OBJECTIVE In Europe, growth hormone (GH) treatment for children born small for gestational age (SGA) can only be initiated after 4 years of age. However, younger age at treatment initiation is a predictor of favourable response. To assess the effect of GH treatment on early growth and cognitive functioning in very young (<30 months), short-stature children born SGA. DESIGN A 2-year, randomized controlled, multicentre study (NCT00627523; EGN study), in which patients received either GH treatment or no treatment for 24 months. PATIENTS Children aged 19-29 months diagnosed as SGA at birth, and for whom sufficient early growth data were available, were eligible. Patients were randomized (1:1) to GH treatment (Genotropin(®) , Pfizer Inc.) at a dose of 0·035 mg/kg/day by subcutaneous injection, or no treatment. MEASUREMENTS The primary objective was to assess the change from baseline in height standard deviation score (SDS) after 24 months of GH treatment. RESULTS Change from baseline in height SDS was significantly greater in the GH treatment vs control group at both month 12 (1·03 vs 0·14) and month 24 (1·63 vs 0·43; both P < 0·001). Growth velocity SDS was significantly higher in the GH treatment vs control group at 12 months (P < 0·001), but not at 24 months. There was no significant difference in mental or psychomotor development indices between the two groups. CONCLUSIONS GH treatment for 24 months in very young short-stature children born SGA resulted in a significant increase in height SDS compared with no treatment.

Differences in small-for-gestational-age and preterm birth among Asian subgroups in relation to nativity status

This retrospective cohort study examined the association between nativity status and very preterm birth, preterm birth, and small-for-gestational-age (SGA) among Asian subgroups using Texas birth certificate data with no personal identifiers. A total of 877,322 birth certificates of Asian and US-born white women with a singleton birth in Texas from 2001-2004 were analyzed. Birth certificate records of US-born white, Chinese, Japanese, Korean, Vietnamese, Filipino, and Asian Indian women with a singleton birth were included in the analysis. Logistic regressions models were used to explore and understand the differences of the effect of nativity status on birth outcomes in Asian subgroups with US-born whites as the reference group. Most of the Asian subgroups had a lower risk of preterm births compared with US born whites, with reductions in risk ranging from 19% to 49% and the lowest risk of preterm birth observed among foreign-born Chinese mothers. Only Filipino mothers had a higher risk of preterm birth compared to US-born whites. Overall, foreign-born Asians had lower risks for very preterm birth and preterm birth than US-born Asians and US-born whites. US-born Asians were at higher risk for preterm birth than US-born whites. For SGA, all Asian subgroups and Asian subgroups by nativity status were at higher risk of SGA than US-born whites. Asian Indians and Japanese were at highest risk for SGA infants with 2.5 to 3 times the risk of SGA present in US-born whites. Foreign-born Asian women were at higher risk for SGA than their US-born counterparts. This study showed that health disparities among Asian subgroups are hidden by classifying Asians into a single group. By examining Asian subgroups separately and looking at nativity status, the differences in risk of SGA and preterm birth can be revealed so prevention efforts can focus on high risk groups. ^

Associations between ambient levels of combustion pollutants and small for gestational age infants in Texas

There is scant evidence regarding the associations between ambient levels of combustion pollutants and small for gestational age (SGA) infants. No studies of this type have been completed in the Southern United States. The main objective of the project presented was to determine associations between combustion pollutants and SGA infants in Texas using three different exposure assessments. ^ Birth certificate data that contained information on maternal and infant characteristics were obtained from the Texas Department of State Health Services (TX DSHS). Exposure assessment data for the three aims came from: (1) U.S. Environmental Protection Agency (EPA) National Air Toxics Assessment (NATA), (2) U.S. EPA Air Quality System (AQS), and (3) TX Department of Transportation (DOT), respectively. Multiple logistic regression models were used to determine the associations between combustion pollutants and SGA. ^ For the first study looked at annual estimates of four air toxics at the census tract level in the Greater Houston Area. After controlling for maternal race, maternal education, tobacco use, maternal age, number of prenatal visits, marital status, maternal weight gain, and median census tract income level, adjusted ORs and 95% confidence intervals (CI) for exposure to PAHs (per 10 ng/m3), naphthalene (per 10 ng/m3), benzene (per 1 µg/m3), and diesel engine emissions (per 10 µg/m3) were 1.01 (0.97–1.05), 1.00 (0.99–1.01), 1.01 (0.97–1.05), and 1.08 (0.95–1.23) respectively. For the second study looking at Hispanics in El Paso County, AORs and 95% confidence intervals (CI) for increases of 5 ng/m3 for the sum of carcinogenic PAHs (Σ c-PAHs), 1 ng/m3 of benzo[a]pyrene, and 100 ng/m3 in naphthalene during the third trimester of pregnancy were 1.02 (0.97–1.07), 1.03 (0.96–1.11), and 1.01 (0.97–1.06), respectively. For the third study using maternal proximity to major roadways as the exposure metric, there was a negative association with increasing distance from a maternal residence to the nearest major roadway (Odds Ratio (OR) = 0.96; 95% CI = 0.94–0.97) per 1000 m); however, once adjusted for covariates this effect was no longer significant (AOR = 0.98; 95% CI = 0.96–1.00). There was no association with distance weighted traffic density (DWTD). ^ This project is the first to look at SGA and combustion pollutants in the Southern United States with three different exposure metrics. Although there was no evidence of associations found between SGA and the air pollutants mentioned in these studies, the results contribute to the body of literature assessing maternal exposure to ambient air pollution and adverse birth outcomes. ^

Differences in late fetal death rates in association with determinants of small for gestational age fetuses: population based cohort study

Objective: To examine differences in late fetal death rates in association with determinants of small for gestational age fetuses.

Alkaline ribonuclease activity in maternal serum and in serum of newborns from birth up to thirty days of age. A study made with full-term appropriate-, full-term small- and preterm appropriate-for-gestational-age infants

We have studied the alkaline ribonuclease (RNase) activity in maternal serum and serum of full-term small- (T-SGA), full-term appropriate- (T-AGA) and preterm appropriate-for-gestational age (PT-AGA) newborns. A significantly lower level of RNase was observed in T-AGA and T-SGA newborns on the 30th day of age and in PT-AGA newborns on the 15th and 30th days of age, as compared to other T-AGA, T-SGA and PT-AGA groups of infants at birth. RNase activity was significantly higher in cord blood than in the maternal blood in all categories studied. Moreover, in preterm newborns, RNase activity in cord blood was significantly higher in those presenting a lower gestational age. We did not observe any significant difference in RNase levels in the cord blood of newborns from the 3 categories studied. The same results were observed concerning maternal blood. We, therefore, conclude that RNase activity in cord blood or in maternal blood is not a very statisfactory indicator of fetal malnutrition.

Growth patterns in preterm infants born appropriate for gestational age

Aim: This study aimed to document the growth patterns of a contemporary cohort of preterm infants born appropriate for gestational age (AGA). It was hypothesised that preterm AGA (PT-AGA) infants would display poorer growth than full-term AGA (FT-AGA) infants. Methods: Sixty-four PT-AGA infants and 64 FT-AGA infants were assessed at 0, 4, 8 and 12 months of corrected age (CA). Measurements of weight and length were recorded at each of the specified ages. Centers for Disease Control and Prevention growth data were used to calculate Z-scores for weight and length based on CA. Results: The mean length and weight Z-scores of PT-AGA infants were found to be significantly less than those of FT-AGA infants at term, 4, 8 and 12 months of CA (P < 0.001). The mean weight Z-score of PT-AGA infants was found to be less than their mean length Z-score at each time point, though the differences were not significant. Conclusions: The results of this study suggest that PT-AGA infants are likely to display poorer growth than FT-AGA infants until at least 1 year of CA. Long-term growth monitoring in this population is recommended. © 2008 The Authors.

ACE Research Vignette 051: How and Why is Small Business Managers’ Age Related To Business Growth?

This series of research vignettes is aimed at sharing current and interesting research findings from our team of international entrepreneurship researchers. This vignette, written by Professor Hannes Zacher, Professor Michael M. Gielnik and Dr Antje Schmitt, reports findings on relationships between small business managers’ age, their focus on opportunities, and business growth (sales and number of employees) over five years.

How small business managers’ age and focus on opportunities affect business growth: A mediated moderation growth model

Research on business growth has been criticized for methodological weaknesses. We present a mediated moderation growth model as a new methodological approach. We hypothesized that small business managers' age negatively affects business growth through focus on opportunities. We sampled 201 small business managers and obtained firm performance data over 5 years, resulting in 836 observations. Growth modeling showed systematic differences in firm performance trajectories. These differences could be explained by modeling focus on opportunities as a mediator of the relationship between small business managers' age and business growth. The study illustrates how mediation models can be tested using growth modeling.