http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–6 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2014.978280

ORIGINAL ARTICLE

Antenatal corticosteroids and perinatal outcomes in infants born at 23–25 weeks of gestation

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M. Goya1, M. C. Cespedes2, F. Camba2, S. Capote1, A. Felipe2, A. Reixachs1, D. Medina2, V. Gorraiz1, S. Pin2, C. Halachian1, A. Gracia1, J. Perapoch2, L. Cabero1, and E. Carreras1 1

Department of Obstetrics and Gynecology, Maternal-Fetal Medicine Unit, Hospital Vall d’Hebron, Barcelona, Spain and 2Department of Pediatrics, Neonatal Intensive Care Unit, Hospital Vall d’Hebron, Barcelona, Spain Abstract

Keywords

Objectives: To evaluate the perinatal results of infants born between 23 and 25.6 weeks of gestation. Methods: Medical charts of all women giving birth prematurely (23–25.6 w) from January 2005 to December 2011 were retrospectively reviewed. Cases of malformed infants or deliveries elsewhere were excluded. Results: 198 infants were included. Chorioamnionitis occurred in 86 (43.4%) of the whole group: 26 (86.7%) in the 23-week; 35 (53.8%) in the 24-week and 25 (24.3%) in the 25-week groups. Foetal maturation with antenatal corticosteroids was complete in 119 cases (60.1%): 4 (13.3%) in the 23-week; 35 (53.8%) in the 24-week and 80 (77.7%) in the 25-week groups. Foetal death at birth occurred in 22 cases (11%) and 61 newborns (30.8%) died in the neonatal period. Of the 106 survivors with 2 years complete follow-up, 45 infants (42.4%) did not present sequelae; 16 infants (15.1%) had severe sequelae. A 66.6% (4) of infants born at 23 weeks of gestation did not present sequelae compared with a 32.3% (11) at 24 weeks and 45.4% (30) at 25 weeks. Conclusions: The chorioamnionitis rate was higher when gestational age was lower. The foetal maturation rate was higher when gestational age was higher. A low severe sequelae rate was observed in the whole series, particularly in the 23-week group where the rate was lower than expected; however, these results could have been influenced by the small size of the 23-week group.

Antenatal corticosteroids, corioamnionitis, cervical length, preterm birth

Introduction Preterm birth is a prevalent problem in society owing to the postnatal mortality and morbidity it causes [1–3]. Prematurity itself is responsible for 75% of infant mortality and 50% of impairment in childhood [4]. In 1972, Liggins and Howie demonstrated the benefit of antenatal corticoid therapy in women at risk of preterm delivery which was subsequently confirmed by other randomised trials [5]. Not only has this therapy proved effective in reducing respiratory distress syndrome (RDS), but also in reducing intraventricular haemorrhage (IVH), necrotising enterocolitis (NEC) and mortality in premature infants. The maximum benefit was observed in the subgroup of infants of mothers who received a single dose of corticosteroids between 48 h before and a week after delivery [5]. For this reason, the major health organisations in the world such as the National Institutes of Health, American College of Obstetricians and Gynecologists, Royal College of Address for correspondence: Marı´a Goya, MD, PhD, Maternal Fetal Medicine Unit, Hospital Materno-Infantil, Sixth Floor, Passeig de la Vall d’Hebron, 119-129, 08035 Barcelona, Spain. Tel: +34 934893085. E-mail: [email protected]

History Received 30 September 2014 Accepted 15 October 2014 Published online 25 November 2014

Medicine and others recommend corticosteroid administration in women at risk of preterm delivery between 24 and 34 weeks of pregnancy. However, recent guidelines do not provide sufficient data to support corticosteroid administration before 24 weeks of gestation [6–9]. In fact, two recent meta-analyses that included randomised trials on antenatal corticosteroids administered to women at risk of preterm delivery concluded that there is strong evidence that RDS, IVH and neonatal deaths between 26 and 34 weeks are reduced; however, this effect is not seen prior to 26 weeks of pregnancy [10,11]. The benefit of administering this therapy earlier in gestation was demonstrated in two recent studies: the first, a US cohort including almost 5000 infants concluded that, compared with foetuses not exposed to corticoids, those born between 23 and 25 weeks had reduced death, IVH, leucomalacia and NEC rates [12], and the second, a recent meta-analysis carried out with data from Neonatal Research Work and including a retrospective analysis of 11 607 infants born between 22 and 23 weeks concluded that foetal exposure to antenatal corticosteroids improved survival [13]. These newly-available data render it necessary to determine whether the current recommendations remain valid and whether this

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therapy should be administered to infants between 23 and 24 weeks of gestation, the limits of viability.

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Methods Medical charts of all women with preterm births at the Hospital Vall d’Hebron (HVH) between January 2005 and December 2011 were retrospectively reviewed. All patients with preterm delivery between 23 and 26 weeks of gestation were initially included in the analysis. Cases of deliveries elsewhere were excluded. The main outcomes were neonatal mortality, maternal mortality or severe maternal morbidity, defined as maternal complications due to preterm birth, such as chorioamnionitis, endometritis or maternal sepsis during pregnancy or after delivery. Secondary outcomes were neonatal complications such as respiratory distress syndrome, intraventricular haemorrhage and necrotising enterocolitis. The study was approved by the hospital Ethics Committee. Preterm birth diagnosis Weeks of gestation were calculated by DLM (date of last menstruation) confirmed by first trimester sonography. Diagnosis of preterm labour was made by uterine activity monitoring (non-stressing test – NST) and cervical shortening and/or dilation. Cervical changes were ascertained by digital examination or transvaginal sonography (TVS). Preterm birth management On admission, women presenting preterm labour were questioned and examined for any signs of infection (fever, abdominal hypersensitivity, urinary syndrome, etc.). Blood

test, urine test and vaginal, endocervical and urine cultures were performed seeking infection. Tocolysis with indometacine or ritodrine was applied when no signs of infection were noted. Pulmonary maturation was considered complete if two doses of 12 mg i.m. betamethasone were administered in 24 h. Data collection A specific form was used to extract data from charts; data were then entered in the database. Statistical methods Data were analysed descriptively. Pregnancies resulting in surviving infants were compared with those that did not using the SPSS for Windows, (version 16.0, SPSS Inc., Chicago, IL). Student’s two-tailed t-test, chi-square test and Fisher’s exact test were used, as appropriate. Bonferroni correction for multiple comparisons was used when the results where stratified by gestational age. A p value50.05 was considered statistically significant.

Results One hundred and ninety-eight infants were born alive between 23 and 25.6 weeks of gestation at the Vall d’Hebron Hospital (HVH) from January 2005 to December 2011. Thirty babies were born at 23 weeks, 65 at 24 weeks and 103 at 25 weeks. All cases followed-up were at least two years of corrected gestational age. The baseline and obstetrical characteristics of the group are shown in Table 1. Mean maternal age was 31.4 years (SD 6.0); 9.1% (18) of this group were smokers and 12.6% (25) had a history of one or more preterm births. The type of

Table 1. Obstetrical characteristics of the preterm birth group*. Preterm birth group n ¼ 198 Maternal age (years) Body Mass Indexy Smoking status (%) Previous preterm delivery Gestational age at admission (weeks) Type of pregnancy Singleton Twins BC/BA Twins MC/BA Twins MC/MA Triplets TC/TA Cervical length at admission (mm) Gestational age at delivery (weeks) Positive vaginal cultures (%) Chorioamnionitis rate (%) Maternal pregnancy admission (days) Tocolysis (%) Corticosteroids No Incomplete Complete Unknown Vaginal delivery (%) *

23–23.6 weeks n ¼ 30

31.4 30.7 17 26 24.1

(6.0) (2.2) (8.6) (13.1) (2.5)

30.6 38.8 3 4 22.6

149 34 10 2 3 12.7 25.0 69 86 8 108

(75.3) (17.2) (5.0) (1.0) (1.5) (5.0) (2.0) (34.8) (43.4) (8.5) (54.5)

28 46 119 5 142

(14.1) (23.2) (60.1) (2.5) (71.7)

(5.6) (3.2) (10.0) (13.3) (1.0)

24–24.6 weeks n ¼ 65

25–25.6 weeks n ¼ 103

31.8 (4.5) 37.3 (3.7) 5 (7.7) 14 (21.5) 23.4 (1.0)

32.0 24.8 10 7 24.4

23 (76.7) 4 (13.3) 0 0 3 (10) 4.1 (7.5) 23.2 (0.4) 12 (40.0) 26 (86.7) 4.4 (2.5) 11 (36.7)

51 (78.5) 10 (15.3) 4 (6.2) 0 0 12.5 (14.3) 24.5 (0.2) 24 (36.9) 35 (53.8) 9.9 (7.1) 42 (64.6)

75 (72.8) 20 (19.4) 6 (5.8) 2 (2.0) 0 13.6 (16.3) 25.1 (0.3) 32 (31.1) 25 (24.3) 9.4 (8.0) 57 (55.3)

19 (66.7) 7 (23.3) 4 (13.3) 0 26 (88.6)

7 (10.8) 21 (32.3) 35 (53.8) 2 (3.1) 48 (73.8)

Plus-minus values are means (Standard Deviation, SD). yBody mass index: weight in kilograms divided by the square of height in metres.

2 18 80 3 61

(6.5) (7.0) (9.7) (6.8) (1.1)

(1.9) (17.5) (77.7) (2.9) (59.2)

p value p40.05 p ¼ 0.03 p40.05 p50.01 p40.05 p40.05 p40.05 p ¼ 0.03 p40.05 p ¼ 0.04 p ¼ 0.03 p40.05 p40.05 p ¼ 0.02 p40.05 p ¼ 0.03 p ¼ 0.01 p ¼ 0.02 p50.01 p40.05 p40.05

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DOI: 10.3109/14767058.2014.978280

pregnancy was: singleton in 75.3% (149), twins in 23.2% (46) and triplets 1.5% (3) of cases (Flow-chart 1). The chorioamnionitis rate was 43.4% (86). Tocolysis was required in 55.6% (110). Foetal maturation with corticosteroids was complete in 119 cases (60.1%), started but incomplete in 46 cases (23.2%) and no corticosteroids in 28 cases (14.1%). Delivery was vaginal in 135 cases (68.2%). When baseline and obstetrical characteristics stratified by weeks of gestation were analysed, no significant differences were found in mean maternal age, smoking status or type of pregnancy (except in the MC/BA twin rate, but no significant differences for BC/BA, MC/MA or triplets); however, a significant difference was observed in the history of one or more preterm deliveries: 13.3% (4) in the 23-week, 21.5% (14) in the 24-week, 6.8% (7) in the 25week groups. Significant differences in chorioamnionitis and tocolysis requirement rates were also observed: chorioamnionitis rate was 86.7% (26) for the 23-week, 53.8% (35) for the 24-week and 24.3% (25) for the 25-week groups (Figure 1A); tocolysis administration was required in 36.7% (11) in the 23-week, 64.4% (42) in the 24-week and 55.3% (57) in the 25-week groups. An increase in corticosteroid use was observed associated with greater gestational age, with significant differences: no

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corticosteroids were administered in 63.3% (19) of 23-week cases compared to 10.8% (7) in the 24-week and 1.9% (2) in the 25-week groups; on the other hand, complete treatment with corticosteroids was administered to 13.3% (4) in the 23-week compared to 53.8% (35) in the 24-week and 77.7% (80) in the 25-week groups. No significant differences were found in the vaginal delivery rate (Table 1). Perinatal outcomes Of the 198 infants who born alive between 23 and 25.6 weeks of gestation, 107 newborns survive. We could evaluate 106 newborns with 2-year follow-up. No sequelae were observed in 42.3% of newborns, mild sequelae in 32.7%, moderate sequelae in 10.5% and severe sequelae in 14.4% (Table 2). No significant differences were observed in no or mild sequelae rates, but were found in the moderate sequelae rate: 16.7% (1) in the 23-week, 11.8% (4) in the 24-week, 7.6% (5) in the 25-week groups, and severe sequelae in 16.7% (1) in the 23-week, 23.5% (8) in the 24-week and 10.6% (7) in the 25weeks groups (Table 2). Differences between the chorioamnionitis rate (lower as gestational age increases) and delivery room death rate (also

Figure 1. Perinatal outcomes stratified by gestational age at preterm delivery; (A) Chorioamnionitis rate; (B) Foetal and neonatal death; (C) Several sequelae; mild sequelae; No sequelae.

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Table 2. Perinatal outcomes of the preterm birth group. Preterm birth group n ¼ 198 Birth weight (g.) NICU admission (%) Delivery room death (%) Neonatal death (%)

720.5 168 30 61

(215.2) (84.8) (15.2) (30.8)

23–23.6 weeks n ¼ 30 573.9 18 12 12

24–24.6 weeks n ¼ 65

25–25.6 weeks n ¼ 103

661.9 55 6 25

728.5 95 12 24

(91.7) (60.0) (40.0) (40.0)

(106.8) (84.6) (9.2) (38.5)

(184.8) (92.2) (11.6) (23.3)

p value p40.05 p ¼ 0.01 p50.001 p50.01

Table 3. The infants and survivors considering type of pregnancy (singletons, twins and triplets) and gestational age at delivery.

*

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Newborns with 2 years follow-up Sequelae (%) No Mild Moderate Severe

Preterm birth group n ¼ 106

23–23.6 weeks n¼6

45 (42.4) 35 (33) 10 (9.4) 16 (15.1)

4 (66.6) 0 (0) 1 (16.7) 1 (16.7)

lower as gestational age increases) are shown in Figure 1(A), (B) and (C): significant differences were observed in 40% (12) in the 23-week, 9.2% (6) in the 24-week and 3.9% (4) in the 25 week groups and sequelae per subgroups of gestational age (as described previously) (Tables 2 and 3).

Discussion Neonatal outcomes in extremely premature infants have improved significantly in recent decades. This has been attributed to the administration of antenatal corticosteroids in women at high risk for preterm delivery, regardless of corticosteroid type, dose and need for booster doses. Although the efficacy of antenatal corticosteroid treatment in reducing the incidence and morbidity of respiratory distress syndrome, intraventricular haemorrhage and necrotising enterocolitis is well known [14–16], from which gestational age these benefits will be reaped remains to be established. All recent practice guidelines recommend corticosteroid administration in patients with preterm labour from 24 weeks of gestation, with insufficient evidence to support this intervention. Data from randomised controlled trials of exposure to antenatal corticosteroids in infants born at less than 26 weeks’ gestation are limited, and meta-analyses do not support or refute the benefits of this therapy at these early gestational ages [10]. In multiple studies, antenatal glucocorticosteroid therapy (AGT) was associated with reduced mortality and severe disability in preterm infants; however, only a few focused on the analysis of those born before 24 weeks’ gestation. In Japan, antenatal corticosteroid treatment proved to reduce mortality to hospital discharge in 753 infants from 87 hospitals born at 22–23 weeks’ gestation [17]. However, the major neonatal morbidities were not affected and data were only analysed for the combined weeks. A population-based series of 705 infants born at less than 26 weeks’ gestation showed exposure to antenatal corticosteroids to be associated with reductions in hospital mortality [18], severe motor

24–24.6 weeks n ¼ 34 11 11 4 8

(32.3) (32.3) (11.8) (23.5)

25–25.6 weeks n ¼ 66 (1 survivor lost follow-up)

p value

30 (45.4) 24 (36.4) 5 (7.6) 7 (10.6)

p40.05 p40.05 p ¼ 0.03 p ¼ 0.01

disability, and low scores on the Mental Developmental Index. A study of 181 infants born at 23 weeks’ gestation and followed up for 10 years revealed reductions in mortality only for those exposed to a full course of antenatal corticosteroids [19]. A study of 117 singleton infants exposed to a complete course of antenatal corticosteroids at less than 24 weeks’ gestation and born at 23–25 weeks’ gestation in a single hospital over a 10-year period reported that corticosteroid administration was associated with reduced mortality and severe intraventricular hemorrhage [20]. However, not all studies obtained conclusive results regarding AGT in newborns infants with gestational age close to the limits of viability. In our study, as expected, the majority of preterm infants studied suffered a major complication during their initial hospitalisation, with the risk of morbidity being inversely related to gestational age at birth. Therefore, the search is on for therapeutic tools that can be applied in utero to reduce morbidity and mortality of newborns with gestational age at birth close to the limits of viability. IVH is a major complication of preterm birth. Severe IVH is often associated with a significant increase in neonatal mortality and severe morbidity (poor long-term neurodevelopmental outcomes) in survivors. Our betamethasoneexposed infants had a significantly reduced risk of IVH, particularly in grades III and IV, data consistent with those of large observational and controlled trials [5]. One course of antenatal corticosteroids proved to be sufficient to produce this beneficial effect, which was shown to be, at least in part, independent of the enhanced pulmonary maturation effect [5]. Controversy persists regarding the real benefit of AGT in RDS in preterm infants with 23–25 6/7 weeks of gestation. Concurring with the literature, we found that AGT reduced the incidence of RDS. In the present study, after a complete AGT in premature infants 23–25 6/7 weeks of gestation, a reduction was observed in mortality and chronic lung disease (CLD) in survivors. However, a partial course of AGT was not

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DOI: 10.3109/14767058.2014.978280

associated with a significant and independent reduction in mortality or with decreasing CLD rates; this concurs with the available conflicting data on the effect of corticosteroids on chronic lung disease [15,16]. Thus, RDS appears to be an independent risk factor for CLD. We also found a significant decrease in neonatal morbidities associated with prematurity. Lower incidences of patent of ductus arteriosus (PDA), NEC, periventricular leukomalacia, retinopathy of prematurity and culture-proven sepsis in premature infants exposed to AGT were also observed, which supports the suggested multiorgan system maturational effect of antenatal corticosteroids. These data reflected the most important neonatal outcomes based on a large retrospective database with a high follow-up rate and adjusted for multiple maternal and neonatal variables at our centre. A strong point of this study was that all cases were managed at a single institution using the same protocol. Another strength was the dating of gestation by crown-rump length during the first trimester of gestation, which allows for correct dating of pregnancy and proper grouping of each patient in the gestational age stratum with a very small margin of error. However, the study has limitations of that should be noted, principally the design. An observational design was chosen, since at present, it would not be ethical to perform a prospective randomised trial administering or withholding antenatal corticosteroids as their clinical usefulness has been clearly demonstrated. Potential biases include the fact that mothers who received antenatal corticosteroids and their infants differed in a number of characteristics from those who did not. Adjustments were made using logistic regression models for many maternal, infant and some, but not all, variables. In addition, we lacked data on some potential confounders such as whether women presenting in labour late were more commonly in the group that did not receive corticosteroids because they were no longer to antenatal administration of corticosteroids rate to be an imminent delivery. It is unlikely that the results obtained in this study are due to baseline differences between study groups; however, a possible residual or unmeasured bias between them should be taken into account. The possibility of a postnatal treatment bias based on antenatal corticosteroid administration (e.g. withholding postnatal therapies in infants whose mothers did not receive antenatal corticosteroids) cannot be ruled out. Finally, our study was also limited to the short-term outcomes of extremely preterm and low-birth-weight infants who are also at high risk for poor long-term neurodevelopmental outcome. In summary, AGT in those patients with preterm labour between 23 and 25 6/7 weeks of gestation was associated with lower rates of perinatal mortality and morbidity. These benefits were observed in all the gestational age subgroups studied. Thus, according to our results, antenatal corticosteroids should be started at 23 weeks of gestation. Although the reduction in the incidence of IVH in our corticosteroid-exposed babies was reassuring, the full effects of antenatal corticosteroids at this early gestation on fetal

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growth, RDS prevention and long-term developmental outcomes should be determined by a large randomised trial.

Acknowledgements We thank Christine O’Hara for her help with the English version of this paper.

Declaration of interest We have no conflicts of interest to declare.

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Antenatal corticosteroids and perinatal outcomes in infants born at 23-25 weeks of gestation.

To evaluate the perinatal results of infants born between 23 and 25.6 weeks of gestation...
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