“Multiple courses of antenatal corticosteroids for preterm birth Study (MACS)” was a double-blind randomized controlled trial of single vs. multiple courses of antenatal corticosteroids in women at risk of preterm birth. In MACS, children born to women with preterm premature rupture of membranes (PPROM) were at increased risk of long term neurodevelopmental disability, at five years of age, defined as death or neurodevelopmental disability (neuromotor, neurosensory or neurocognitive function) OR=2.31 [95% CI: 1.74,3.07]; p<0.0001. The objective of these secondary analyses was to identify factors, within the PPROM cohort, associated with long term neurodevelopmental disability at 5 years of age. Children (n=246) in MACS, born to women (n=223) with PPROM and followed to 5 years of age were included. Univariate and multiple linear regression analyses were undertaken to assess the factors associated with adverse neurodevelopmental disability at 5 years of age. Within the MACS PPROM cohort, factors associated with an increased risk of long-term neurodevelopmental disability at 5 years of age were gestational age at randomization (OR 1.39 [95% CI: 1.21,1.59]; p<0.0001, OR for one week younger) and chorioamnionitis (OR 2.83 [95% CI: 1.16,6.95]; p<0.037). Antibiotics at randomization were associated with a decreased risk of disability (OR 0.37 [95% CI: 0.16,0.88] p<0.023). In the setting of PPROM, chorioamnionitis appears to increase the long-term risk of neurodevelopmental disability at 5 years of age. Therefore, clinical actions such as early identification, aggressive antibiotic treatment and delivery should be taken in effort to avoid clinical chorioamnionitis.

The Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study (MACS) showed no benefit in the reduction of major neonatal mortality/morbidity or neurodevelopment at 2 and 5 years of age. Using the data from the randomized controlled trial and its follow-up, the aim of this study was to evaluate the association between gestational ages at birth in children exposed to single versus multiple courses of antenatal corticosteroid (ACS) therapy in utero and outcomes at 5 years of age.

The Multiple Courses of Antenatal Corticosteroid Study (MACS) showed no benefit in the reduction of major neonatal mortality/morbidity or neurodevelopment at 2 and 5 years of age. Using the data from MACS and its follow-up, the aim of this study was to evaluate the association between gestational ages at birth in children exposed to single versus multiple courses of antenatal corticosteroid (ACS) therapy in utero and outcomes at 5 years of age. A total of 1719 children contributed to the primary outcome, which was death at 5 years or survival with a disability in at least one of the following domains: neuromotor, neurosensory, and neurobehavioral/emotional. Of the 873 children in the multiple ACS arm, 658 (75%) were preterm, compared to 213 (25%). Of the 855 children in the single ACS arm, 599 (70%) were preterm, compared to 249 (30%). The incidence of the primary outcome by gestational age at birth and treatment is outlined in the table. Gestational age at birth is strongly associated with outcome, p < 0.001. The interaction between treatment group and gestational age at birth was marginally significant, p = 0.06. In the term group, there was a statistically significant treatment effect, 48/213 (22.5%) vs. 38/249 (15.3%), OR= 1.69 [95% CI: 1.04, 2.77]; P = 0.037, with a significant difference in neurosensory disability, OR= 3.70 [95% CI: 1.57, 8.75]; P = 0.004. Preterm birth (<37 weeks) remains the primary factor contributing to an adverse neurodevelopmental outcome regardless of the courses of ACS treatment. Children born ≥ 37 weeks and exposed to multiple ACS therapy may have an increased risk of neurodevelopmental/neurosensory impairment. To optimize outcomes for infants/children, efforts in reducing the incidence of preterm birth should be the primary focus in perinatal research. More is needed to be learned about the long-term effects of multiple ACS.Tabled 1 Open table in a new tab

OBJECTIVE: The aim of this study was to determine the effects of repeated courses of prenatal corticosteroid therapy versus placebo on death or neurologic impairment among the children enrolled in the Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study, at 18 to 24 months of age. METHODS: A total of 2305 infants were eligible for follow-up evaluation; 2104 infants (1069 in the prenatal corticosteroid therapy group and 1035 in the placebo group) were monitored. The primary outcome was death or neurologic impairment, defined as either cerebral palsy or cognitive delay, at 18 to 24 months of age. The secondary outcomes were measurements of growth (height, weight, and head circumference). RESULTS: Children exposed to multiple courses of prenatal corticosteroid therapy had similar rates of death or neurologic impairment, compared with children exposed to placebo (148 children [13.8%] vs 142 children [13.7%]; odds ratio: 1.001[95% confidence interval: 0.75–1.30]; P = .95). They had a mean weight of 11.94 kg, compared with 12.14 kg in the placebo group (P = .04), a mean height of 85.51 cm, compared with 85.46 cm (P = .87), and a mean head circumference of 48.18 cm, compared with 48.25 cm (P = .45). CONCLUSIONS: Multiple courses of prenatal corticosteroid therapy, given every 14 days, did not increase or decrease the risk of death or neurologic impairment at 18 to 24 months of age, compared with a single course of prenatal corticosteroid therapy. Continued follow-up monitoring of these children is necessary to assess neurobehavioral function, school performance, and possible susceptibility to disease.

OBJECTIVE: To estimate the effect of multiple courses of antenatal corticosteroids on neonatal size, controlling for gestational age at birth and other confounders, and to determine whether there was a dose-response relationship between number of courses of antenatal corticosteroids and neonatal size.METHODS: This is a secondary analysis of the Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study, a double-blind randomized controlled trial of single compared with multiple courses of antenatal corticosteroids in women at risk for preterm birth and in which fetuses administered multiple courses of antenatal corticosteroids weighed less, were shorter, and had smaller head circumferences at birth. All women (n=1,858) and children (n=2,304) enrolled in the Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study were included in the current analysis. Multiple linear regression analyses were undertaken.RESULTS: Compared with placebo, neonates in the antenatal corticosteroids group were born earlier (estimated difference and confidence interval [CI]: -0.428 weeks, CI -0.10264 to -0.75336; P=.01). Controlling for gestational age at birth and confounding factors, multiple courses of antenatal corticosteroids were associated with a decrease in birth weight (-33.50 g, CI -66.27120 to -0.72880; P=.045), length (-0.339 cm, CI -0.6212 to -0.05676]; P=.019), and head circumference (-0.296 cm, -0.45672 to -0.13528; P<.001). For each additional course of antenatal corticosteroids, there was a trend toward an incremental decrease in birth weight, length, and head circumference.CONCLUSION: Fetuses exposed to multiple courses of antenatal corticosteroids were smaller at birth. The reduction in size was partially attributed to being born at an earlier gestational age but also was attributed to decreased fetal growth. Finally, a dose-response relationship exists between the number of corticosteroid courses and a decrease in fetal growth. The long-term effect of these findings is unknown.

OBJECTIVE:A single course of antenatal corticosteroids (ACS) is associated with a reduction in respiratory distress syndrome and neonatal death. Multiple Courses of Antenatal Corticosteroids Study (MACS), a study involving 1858 women, was a multicentre randomized placebo-controlled trial of multiple courses of ACS, given every 14 days until 33+6 weeks or birth, whichever came first. The primary outcome of the study, a composite of neonatal mortality and morbidity, was similar for the multiple ACS and placebo groups (12.9% vs. 12.5%), but infants exposed to multiple courses of ACS weighed less, were shorter, and had smaller head circumferences. Thus for women who remain at increased risk of preterm birth, multiple courses of ACS (every 14 days) are not recommended. Chronic use of corticosteroids is associated with numerous side effects including weight gain and depression. The aim of this postpartum assessment was to ascertain if multiple courses of ACS were associated with maternal side effects.METHODS:Three months postpartum, women who participated in MACS were asked to complete a structured questionnaire that asked about maternal side effects of corticosteroid use during MACS and included the Edinburgh Postnatal Depression Scale. Women were also asked to evaluate their study participation.RESULTS:Of the 1858 women randomized, 1712 (92.1%) completed the postpartum questionnaire. There were no significant differences in the risk of maternal side effects between the two groups. Large numbers of women met the criteria for postpartum depression (14.1% in the ACS vs. 16.0% in the placebo group). Most women (94.1%) responded that they would participate in the trial again.CONCLUSION:In pregnancy, corticosteroids are given to women for fetal lung maturation and for the treatment of various maternal diseases. In this international multicentre randomized controlled trial, multiple courses of ACS (every 14 days) were not associated with maternal side effects, and the majority of women responded that they would participate in such a study again.

Multiple courses of Antenatal Corticosteroids for preterm birth Study (MACS) was an international multi-centered double-blind randomized controlled trial of single vs. multiple courses of antenatal corticosteroids (ACS). Infants exposed to ACS experienced similar composite morbidity and mortality as compared to placebo (12.9 % ACS vs. 12.5% placebo) OR 1.04 (CI 0.77-1.39 p=0.83). Infants in the ACS group were smaller. They weighed less (2216 g vs. 2330 g, p=0.0026), were shorter (44.5 cm vs. 45.4 cm, p=0.001) and had a smaller head circumference (31.1 cm vs. 31.7 cm, p=0.001) vs. placebo. The objective of these secondary analyses was to determine the effect of multiple courses of ACS on infant size, controlling for gestational age at birth and other confounders, and to determine if there was a dose response relationship between infant size and number of courses of ACS. All women (n=1858) and infants (n=2304) enrolled in MACS were included. The gestational age at birth was compared between randomized groups. Multiple linear regression analyses were undertaken to estimate differences (SE) in birth weight, length and head circumference, for the ACS vs. placebo groups, controlling for gestational age at birth and other confounders. Compared to placebo, infants exposed to ACS were born earlier (estimated difference [SE]: −0.43 weeks [0.17], p= 0.0098). Controlling for gestational age at birth and other known confounders, multiple courses of ACS were associated with a decrease in birth weight (-33.5 g [SE 16.7] p=0.045), length (-0.3 cm [SE 0.14] p=0.0187) and head circumference (-0.3 cm [SE 0.08] p=0.0003). Lastly, for each additional course of ACS, there was a trend towards an incremental decrease in birth weight, length and head circumference. Infants exposed to multiple courses of ACS were born earlier and were smaller. In addition, a dose response was noted between the increasing number of courses of ACS and a decrease in birth weight, length and head circumference. Therefore, administration of multiple courses of ACS, every 14 days, is not recommended.

Resumen Un tratamiento con una dosis de corticosteroides prenatales reduce el riesgo de sindrome de dificultad respiratoria y muerte neonatal. La administracion de dosis semanales a pacientes que no dieron a luz despues de una tanda de corticosteroides puede presentar beneficios (menor morbilidad respiratoria) o causar danos (reduccion del crecimiento en el utero). Nuestro objetivo fue determinar si la administracion de varias dosis de corticosteroides prenatales reduce los valores de morbilidad y mortalidad neonatales sin afectar el crecimiento fetal. Metodos . 1.858 mujeres entre 25 y 32 semanas de gestacion, que no habian dado a luz entre 14 y 21 dias despues de una dosis inicial de corticosteroides prenatales y seguian *Los miembros se enumeran al final del articulo.a. Departamento de Obstetricia y Ginecologia, Mount Sinai Hospital.b. Departamento de Obstetricia y Ginecologia, Sunnybrook Health Sciences Centre.c. Programa de Ciencias Evaluativas en Salud Pediatrica, Sic Kids Research Institute, Departamento de Ciencias de la Salud Publica.d. Unidad de Investigacion de Salud Materna, Infantil y Re-productiva del Women’s College Research Institute.e. Departamento de Pediatria, Mount Sinai Hospital, Univer-sity of Toronto, Toronto, Ontario, Canada.f. Departamento de Fisiologia, Obstetricia y Ginecologia y Departamento de Medicina. University of Toronto, Toronto, Ontario, Canada.g. Departamento de Pediatria, McMaster University Medical Centre, Hamilton, Ontario, Canada.h. Departamento de Pediatria Neonatal y del Desarrollo, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.i. Departamento de Obstetricia y Ginecologia, University of Calgary, Calgary, Alberta, Canada.j. Departamento de Obstetricia y Ginecologia, BC Women’s Hospital, University of British Columbia, Vancouver, Colum-bia Britanica, Canada.k. Departamento de Ginecologia y Obstetricia, Women’s and Children’s Hospital, State University of New York at Buffalo, Buffalo, Nueva York, EE. UU.l. Centro de Analisis de Politica y Economia Sanitaria, De-partamento de Epidemiologia Clinica y Bioestadistica, McMaster University, Hamilton, Ontario, Canada.m. Departamento de Pediatria e Integrated Centre for Care Advancement through Research (iCARE), University of Alberta, Edmonton, Alberta, Canada.n. Departamento de Obstetricia y Ginecologia, IWK Health Cen-tre, Dalhousie University, Halifax, Nueva Escocia, Canada.

A single course of antenatal corticosteroids (ACS) is associated with a reduction in respiratory distress syndrome and neonatal death. Our placebo controlled trial of multiple courses of ACS, every 14 days, found no benefit. Infants exposed to multiple courses of ACS weighed less and had smaller head circumferences. Chronic use of corticosteroids are associated with numerous side effects including weight gain and depression. The aim of this postpartum assessment was to see if multiple courses of ACS were associated with increased maternal morbidity. 1858 women were randomized to receive multiple courses of ACS vs. placebo, every 14 days, until 33 6/7 weeks or delivery which ever came first. The primary outcome was a neonatal composite outcome (Lancet 2008;372:2143-51). Women were asked to complete a questionnaire three months post delivery. Inquiry was made regarding potential maternal side effects of corticosteroid use. In addition, the Edinburgh Postnatal Depression Scale was administered. Of the 1858 women randomized, 1712 (92.1%) completed the postpartum questionnaire. The side effect profile was similar between the two groups. However, more women in the ACS group reported difficulties sleeping (OR 1.18 CI: 1.02-1.36) and excess hair growth (OR 1.37 CI: 1.06-1.77). Large numbers of women in both groups met criteria for post partum depression (14.1% in the ACS vs. 16.0% in the placebo group). Finally, 94% of the women responded that they would participate in the trial again. Multiple courses of ACS, every 14 days, were associated with minimal maternal side effects. In addition, women found trial participation acceptable. In this international multi-center randomized controlled trial, women who were at risk of preterm birth had a high rate of post partum depression. (ClinicalTrials.gov number, NCT 00187382)

Gerken, Britany J. MD; Al-Hakeem, Houmam MD; Antonacci, Rebecca MS, RD; Verhulst, Steven PhD; Amankwah, Kofi MD; McAsey, Mary E. PhD Author Information

OBJECTIVE:To compare mothers' views at 2 years postpartum after participation in a randomized trial of planned Caesarean and planned vaginal birth for a singleton fetus in breech presentation at term.STUDY DESIGN:In selected centres in the Term Breech Trial, mothers completed a structured questionnaire at approximately 2 years postpartum to assess their likes and dislikes about their childbirth experiences and their views about their intrapartum care and care providers.RESULTS:Of 1159 mothers from 85 centres, 917 (79.1%) completed a follow-up questionnaire at 2 years postpartum. Baseline information was similar for both the planned Caesarean and planned vaginal birth groups. Planned Caesarean was associated with less worry about the baby's health (P < 0.001). While other differences were noted in likes and dislikes about their childbirth experiences, women's evaluations of the quality of intrapartum care, the helpfulness of staff, and their involvement in decision-making did not differ in the planned Caesarean delivery and planned vaginal birth groups.CONCLUSION:Planned mode of delivery influences aspects of women's evaluations of their childbirth experiences but does not affect evaluations of the quality of intrapartum care, support from care providers, or amount of involvement in decision-making.

Background: The Term Breech Trial compared the safety of planned cesarean and planned vaginal birth for breech presentations at term. The combined outcome of perinatal or neonatal death and serious neonatal morbidity was found to be significantly lower among babies delivered by planned cesarean section. In this study we conducted a cost analysis of the 2 approaches to breech presentations at delivery. Methods: We used a third-party–payer (i.e., Ministry of Health) perspective. We included all costs for physician services and all hospital-related costs incurred by both the mother and the infant. We collected health care utilization and outcomes for all study participants during the trial. We used only the utilization data from countries with low national rates of perinatal death (≤ 20/1000). Seven hospitals across Canada (4 teaching and 3 community centres) were selected for unit cost calculations. Results: The estimated mean cost of a planned cesarean was significantly lower than that of a planned vaginal birth ($7165 v. $8042 per mother and infant; mean difference –$877, 95% credible interval –$1286 to –$473). The estimated mean cost of a planned cesarean was lower than that of a planned vaginal birth for both women having a first birth ($7255 v. $8440) and women having had at least one prior birth ($7071 v. $7559). Although the treatment effect was largest in the subgroup of women having their first child, there was no statistically significant interaction between treatment and parity since the 95% credible intervals for difference in treatment effects between parity equalling zero and parity of one or greater all include zero. Interpretation: Planned cesarean section was found to be less costly than planned vaginal birth for the singleton fetus in a breech presentation at term in the Term Breech Trial.

Objective This study was undertaken to compare maternal outcomes at 2 years postpartum after planned cesarean section and planned vaginal birth for the singleton fetus in breech presentation at term. Study design In selected centers in the Term Breech Trial, mothers completed a structured questionnaire at 2 or more years postpartum to determine their health in the previous 3 to 6 months. Results A total of 917 of 1159 (79.1%) mothers from 85 centers completed a follow-up questionnaire at 2 years postpartum. There were no differences between groups in breast feeding, relationship with child or partner, pain, subsequent pregnancy, incontinence, depression, urinary, menstrual or sexual problems, fatigue, or distressing memories of the birth experience. Planned cesarean section was associated with a higher risk of constipation (P=.02). Conclusion Maternal outcomes at 2 years postpartum are similar after planned cesarean section and planned vaginal birth for the singleton breech fetus at term.

OBJECTIVE:In about 3% to 4% of all pregnancies at term, the fetal presentation will be noncephalic. External cephalic version (ECV) at term has been shown to decrease the rate of noncephalic presentation at birth and to decrease the rate of cesarean section associated with breech presentation. However, success rates for ECV are low. We did a randomized trial to compare a policy of beginning ECV early, at between 34 and 36 weeks' gestation, and beginning ECV at 37 to 38 weeks' gestation. STUDY DESIGN:At 25 centers in seven countries, 233 women with a singleton breech fetus were randomly assigned to having an ECV procedure done early (at between 34 weeks 0 days and 36 weeks 0 days), or delayed (at between 37 weeks 0 days and 38 weeks 0 days). An experienced practitioner undertook the ECV procedure, and repeat ECV procedures were allowed. Tocolytics and use of epidural analgesia were included as part of the protocol. The primary outcome was the rate of noncephalic presentation at birth. An intention-to-treat analysis was used. RESULTS:Data were received for 232 women, with 116 women in each of the early and delayed ECV groups. Of these, 86.2% in the early ECV group and 67.2% in the delayed ECV group had at least one ECV performed. The rate of noncephalic presentation at birth in the early ECV group was 66 of 116 (56.9%) and 77 of 116 (66.4%) in the delayed ECV group (relative risk [RR] [95% CI] 0.86 [0.70-1.05], P =.09). The rate of serious fetal complications and the rate of preterm birth at <37 weeks were not significantly increased in the early ECV group compared with the delayed ECV group (6.9% vs 7.8%, RR [95% CI] 0.89 [0.36-2.22], P =.69 and 8.6% vs 6.1%, RR [95% CI] 1.42 [0.56-3.59], P =.31, respectively). The rate of cesarean section in the early ECV group was 75 of 116 (64.7%) and 83 of 116 (71.6%) in the delayed ECV group (RR [95% CI] 0.90 [0.76-1.08], P =.32). Neonatal outcomes were comparable in the two groups. The rate of reversion to noncephalic was low in both groups. The majority of women in both groups indicated that they would consider having an ECV in another pregnancy. CONCLUSION:Early ECV performed at 34 to 36 weeks compared with 37 to 38 weeks may reduce the risk of noncephalic presentation at delivery. A large pragmatic trial of early ECV is now required to assess this approach further in terms of cesarean section rates and neonatal outcomes before changes in clinical practice.

Abnormal invasion of the cytotrophoblast and restriction of normal remodeling of the spiral arteries occur in intrauterine growth–restricted (IUGR) pregnancies. There are conflicting data regarding the circulating levels of these glycoproteins in idiopathic IUGR. The aim of this study was to compare circulating concentrations of inhibin-A and PlGF in IUGR pregnancies to those in normal pregnancies. Women (n = 626) with a single fetus were recruited at their first prenatal visit. Serum samples were collected during prenatal testing and at delivery. Singleton pregnancies delivered at or beyond 27 weeks' gestational age were included. Exclusion criteria consisted of delivery prior to 27 weeks' gestation and/or stillbirth, multiple gestation, and late prenatal care (>28 wk). IUGR was defined as birthweight below the tenth percentile for gestational age. Inhibin-A and PlGF were measured using enzyme-linked immunosorbent assays. Kruskal-Wallis analysis was performed, followed by Dunnett's multiple comparison test. A total of 51 cases of IUGR were identified and matched with controls according to gestational age at the time of sampling. Median concentrations of inhibin-A in IUGR patients as compared to controls were significantly elevated in the second (206 vs 152 pg/mL; P<0.001) and third trimesters (714 vs 363 pg/mL; P<0.003) but not in the first (192 vs 185 pg/mL) trimester. PlGF levels in IUGR patients were similar to controls in the first (28.0 vs, 27.0 pg/mL), second (169 vs 245 pg.mL), and third (199 vs 193 pg/mL) trimesters. Maternal serum levels of inhibin-A are elevated in pregnancies complicated by IUGR, but PlGF levels are similar to those of controls throughout gestation. This may reflect an alteration in paracrine signaling pathways in order to maintain placental viability. Measurement of inhibin-A levels may be a useful strategy for identifying subclinical IUGR.

Caroline Crowther is listed as a member of the Term Breech Trial 3-Month Follow-up Collaborative Group in the article.

Objectives: (1) To determine the feasibility of a multicentre, randomized, double-masked, placebo-controlled trial to investigate the effects of multiple courses of antenatal corticosteroids (ACS) more than 7 days following the initial course of ACS therapy, on perinatal or neonatal mortality or neonatal morbidity. (2) To determine the risk of complications that would require discontinuation of ACS therapy. (3) To determine if multiple courses of ACS have an effect on the concentrations of plasma cortisol and adrenocorticotropin hormone (ACTH) in cord blood and in maternal blood immediately following delivery, compared to a single course of ACS.