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The role of antenatal corticosteroids in twin pregnancies complicated by preterm birth

American Journal of Obstetrics and Gynecology, Volume 215, Issue 4, October 2016, Pages 482.e1 - 482.e9

Background

Data regarding the effects of antenatal corticosteroids in twin pregnancies are limited because of the insufficient number of women with twins enrolled in randomized controlled trials on antenatal corticosteroids. Furthermore, the interpretation of available data is limited by the fact that the interval from the administration of antenatal corticosteroids to delivery is greater than 7 days in a large proportion of twins, a factor that has been shown to affect the efficacy of antenatal corticosteroids and has not been controlled for in previous studies.

Objective

The objective of the study was to compare neonatal mortality and morbidity in preterm twins receiving a complete course of antenatal corticosteroids 1–7 days before birth to those who did not receive antenatal corticosteroids and to compare these outcome effects with those observed in singletons.

Study Design

We performed a retrospective cohort study using data collected on singleton and twin neonates born between 240/7 and 336/7 weeks’ gestational age and were admitted to tertiary neonatal units in Canada between 2010 and 2014. A comparison of neonatal outcomes between twin neonates who received a complete course of antenatal corticosteroids 1–7 days before birth (n = 1758) and those who did not receive antenatal corticosteroids (n = 758) and between singleton neonates who received a complete course of antenatal corticosteroids 1–7 days before birth (n = 4638) and those did not receive antenatal corticosteroids (n = 2312) was conducted after adjusting for gestational age, sex, hypertension, outborn status, small for gestational age, parity, and cesarean birth. Adjusted odds ratios and 95% confidence intervals for various neonatal outcomes were calculated.

Results

Administration of a complete course of antenatal corticosteroids within 1–7 days before birth in both twins and singletons was associated with similar reduced odds of neonatal death (for twins adjusted odds ratio 0.42 [95% confidence interval, 0.24–0.76] and for singletons adjusted odds ratios, 0.38 [95% confidence interval, 0.28–0.50]; P = .7 for comparison of twins vs singletons), mechanical ventilation (for twins adjusted odds ratio, 0.47 [95% confidence interval, 0.35–0.63] and for singletons adjusted odds ratio, 0.47 [95% confidence interval, 0.41–0.55]; P = .9), respiratory distress syndrome (for twins adjusted odds ratio, 0.53 [95% confidence interval, 0.40–0.69], and for singletons adjusted odds ratio, 0.54 [95% confidence interval, 0.47–0.62]; P = .9) and severe neurological injury (for twins adjusted odds ratio, 0.50 [95% confidence interval, 0.30–0.83] and for singletons adjusted odds ratio, 0.45 [95% confidence interval, 0.34–0.59]; P = .7). Administration of a complete course of antenatal corticosteroids was not associated with a reduced odds of bronchopulmonary dysplasia, severe retinopathy of prematurity, or necrotizing enterocolitis in both twins and singletons.

Conclusion

Administration of a complete course of antenatal corticosteroids 1–7 days before birth in twin pregnancies is associated with a clinically significant decrease in neonatal mortality, short-term respiratory morbidity, and severe neurological injury that is similar in magnitude to that observed among singletons.

Key words: antenatal corticosteroids, multifetal gestations, multiple gestations, steroids twins.

There is abundant evidence suggesting that the administration of antenatal corticosteroids to women who experience preterm labour, between 240/7 and 346/7 weeks of gestation, is associated with a decrease in neonatal morbidity and mortality.1, 2, 3, and 4 However, data regarding the effects of antenatal corticosteroids in specific subgroups of pregnancies are limited.1 Specifically, it has been questioned whether the administration of antenatal corticosteroids in twin pregnancies has similar effects to those observed in singletons.5 This concern is based on physiological and metabolic differences between twin and singleton pregnancies, such as a higher volume of distribution and a shorter half-life of betamethasone (a commonly used antenatal corticosteroids) in twin pregnancies.6

This question regarding the effect of antenatal corticosteroids in twins is of major importance, considering that the number of twin pregnancies is on the rise and the fact that multiple gestations represent a disproportionate number of neonatal intensive care unit admissions and are responsible for more than 20% of preterm births (<32 weeks).7 and 8

In previous studies assessing the effects of antenatal corticosteroids, information regarding twin pregnancies has been limited9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 because multiple gestations were either excluded21, 22, 23, 24, 25, 26, 27, 28, 29, and 30 or constituted a small proportion of subjects.31, 32, 33, 34, 35, 36, 37, 38, 39, 40, and 41 Furthermore, current studies report conflicting results because some studies have proposed a beneficial effect in twin pregnancies similar to that observed in singletons,9, 18, 19, 20, and 42 whereas others fail to document such an effect.11, 12, 15, 17, and 39 These apparently conflicting results may be attributed, at least in part, to limitations of available studies including small sample size18, 42, and 43 and the lack of a control group containing singleton pregnancies.

Another important issue to consider for twins is the time interval between antenatal corticosteroid administration and birth. Many infants are born more than 7 days after the administration of antenatal corticosteroids44 when the beneficial effects of antenatal corticosteroids have likely been attenuated.26 For instance, in a recent study, antenatal corticosteroid exposure in twin pregnancies was associated with a decreased risk of respiratory distress syndrome only when administrated within 2–7 days before birth.9 Thus, inclusion of newborns that received antenatal corticosteroids more than 7 days before birth may result in a diminished overall effect of antenatal corticosteroids and may therefore make it more difficult to detect a beneficial effect of antenatal corticosteroids as significant.

Taking this into consideration, the aim of this study was to determine whether there is an association between antenatal corticosteroids administered 1–7 days before birth and neonatal mortality and morbidity in preterm twin neonates and to compare these effects with those observed in singletons using a large national cohort.

Materials and Methods

Study design population

This retrospective cohort study included all singleton and twin live-born neonates born between 240/7 and 336/7 weeks of gestation and admitted to level III neonatal intensive care units participating in the Canadian Neonatal Network between January 2010 and December 2014. Exclusion criteria included birthweight less than the third percentile (because fetal growth restriction has been shown to affect the impact of antenatal corticosteroids42, 45, 46, 47, 48, 49, 50, 51, and 52), clinical chorioamnionitis, major congenital anomalies, incomplete information on the administration of antenatal corticosteroids, administration of more than 1 course of antenatal corticosteroids, administration of a partial course of antenatal corticosteroids, or administration of antenatal corticosteroids <24 hours or >7 days before birth.

The Canadian Neonatal Network maintains a national database of outcomes, risk factors, and practices for infants admitted to level III neonatal intensive care units in Canada. At each site, data are collected from patient charts by trained abstractors according to standard definitions53 and entered electronically into a customized data entry program with built-in error checks.

Approval for data collection is granted at sites by either the local Research Ethics Board or through an institutional quality improvement process for data collection and benchmarking. For this project, we obtained institutional approval from the Mount Sinai Hospital Research Ethics Board and the Canadian Neonatal Network Executive Committee.

Exposure

Neonatal outcomes were compared between twin neonates that received a complete course of antenatal corticosteroids 1–7 days before birth (Twins–ACS1–7d group) and those that did not receive antenatal corticosteroids (Twins–no ACS group). As a comparison, we performed a similar analysis in singleton neonates that received a complete course of antenatal corticosteroids 1–7 days before birth (Singletons–ACS1–7d group) and those that did not receive antenatal corticosteroids (Singletons–no ACS group). The decision to limit the exposure groups to neonates that received antenatal corticosteroids 1–7 days before birth was based on available evidence that the effect of antenatal corticosteroids in appropriate-for-gestational-age fetuses is highest when the antenatal corticosteroids are administrated within 1–7 days before birth.26

Exposure to antenatal corticosteroids consisted of either betamethasone (intramuscularly, 2 doses of 12 mg 24 hours apart) or dexamethasone (intramuscularly, 4 doses of 6 mg 12 hours apart). Although the type of antenatal corticosteroids used is not documented in the Canadian Neonatal Network database, the majority of women would have received betamethasone because it is the most common type of antenatal corticosteroids used in Canada.

Outcomes

The following neonatal outcomes were evaluated: (1) mortality (death prior to discharge from neonatal intensive care units); (2) respiratory morbidity, including need for and duration of mechanical ventilation, respiratory distress syndrome, and bronchopulmonary dysplasia, defined as the requirement for oxygen at postmenstrual age of 36 weeks or at the time of transfer to a level II facility54; (3) severe neurological injury, defined as grade 3 or 4 intraventricular hemorrhage according to the criteria of Papile et al55 and/or periventricular leukomalacia, diagnosed by cranial ultrasound or magnetic resonance imaging or at autopsy; (4) severe retinopathy of prematurity, defined as stage 3 or higher according to the international classification of retinopathy of prematurity 56 or retinopathy of prematurity requiring treatment; and (5) necrotizing enterocolitis, defined according to the criteria of Bell et al.57

Other variables collected include infant sex, gestational age (determined from date of in vitro fertilization, first-trimester ultrasound, last menstrual period, obstetric estimate, and pediatric estimate, in that order), birthweight, outborn admission, Apgar score at 5 minutes, maternal demographics, and maternal hypertension.

Statistical analysis

Maternal characteristics and neonatal outcomes were compared between the ACS1–7d and no ACS groups using the Student t test and the χ2 test for continuous and categorical variables, respectively. A multivariable logistic regression analysis was used to assess the association between the administration of antenatal corticosteroids 1–7 days before birth and adverse neonatal outcomes after adjustment for variables that were found to be different between the 2 study groups and those variable for which there is biological rationale to consider them as potential confounders.

The strategy described in the previous text regarding which variables would be included in the regression model was determined during the design phase of the study. These models were fitted with generalized estimating equation to account for correlation within a pair of twins from the same mother. Neonates that were not exposed to antenatal corticosteroids were used as a reference groups. Separate analyses were performed for twin and singleton neonates.

Adjusted odds ratios and 95% confidence intervals were calculated for twins and singletons and were compared between the 2 groups to identify the differential effects. The odds ratio for the association of antenatal corticosteroids with neonatal outcome in the twins and singletons groups were compared using the following approach: first, the SE of each odds ratio was obtained from the corresponding adjusted regression models. Then the combined SE for the difference between the 2 odds ratios was calculated (defined as the square root of ([SE1]2 + [SE2]2]).

The Z statistic (defined as the estimate of the difference divided by the combined SE) was calculated, and the associated P value was reported. The significance of statistical tests was evaluated using 2-sided P values at the 5% significance level. Data were analyzed using the statistical package SAS (version 9.3; SAS Institute, Cary, NC).

Results

Characteristics of the study groups

A total of 25,536 neonates born at a gestational age of 240/7 to 336/7 weeks were identified during the study period from the Canadian Neonatal Network database, of which 9466 were eligible for the study. Of the 2516 twin neonates, 1758 (69.9%) received antenatal corticosteroids within 1–7 days before birth and 758 (30.1%) did not receive antenatal corticosteroids (Figure). Of the 6950 singletons, 4638 (66.7%) received antenatal corticosteroids within 1–7 days before birth, whereas 2312 (33.3%) were not exposed to antenatal corticosteroids (Figure).

gr1

Figure

Description of the study groups

n refers to the number of neonates in each group.

ACS, antenatal corticosteroids; CNN, Canadian Neonatal Network.

Melamed et al. Antenatal corticosteroids in twin pregnancies. Am J Obstet Gynecol 2016.

 

The characteristics of the study groups are presented in Table 1. In both twin and singleton pregnancies, women who received antenatal corticosteroids were more likely to be nulliparous and experience hypertension, less likely to deliver outside a tertiary center (outborn), and had a lower gestational age at birth compared with women who did not receive antenatal corticosteroids (Table 1). In the twins group, women who received antenatal corticosteroids were older than women who did not. Among singletons, there were small but significant differences in the proportion of male fetuses and the rate of cesarean delivery between women who received and did not receive antenatal corticosteroids (Table 1).

Table 1

Characteristics of the ACS and no-ACS groups among twin and singleton pregnancies

 

Characteristics Twins Singletons
ACS within 1–7 d
(n = 1068)a
No ACS
(n = 497)a
P value ACS within 1–7 d
(n = 4638)
No ACS
(n = 2312)
P value
Maternal age >35 y 193 (25%) 59 (19%) .046 660 (19%) 247 (19%) .72
Nulliparity 625 (62%) 226 (47%) < .001 2365 (53%) 989 (44%) < .001
Gestational diabetes 105 (10%) 41 (9%) .40 539 (12%) 261 (12%) .98
Maternal hypertension 185 (18%) 43 (9%) < .001 1466 (32%) 322 (15%) < .001
Outborn status 59 (6%) 154 (31%) < .001 307 (7%) 935 (40%) < .001
Cesarean birth 720 (67%) 316 (64%) .15 2569 (55%) 1096 (48%) < .001
Gestational age, wks, mean (SD) 29.8 (2.7) 30.6 (2.7) < .001 29.5 (2.7) 30.4 (2.6) < .001
Gestational age <320/7 wks 710 (66%) 227 (46%) < .001 3280 (71%) 1219 (53%) < .001
Antenatal MgSO4 for neuroprotection 418 (40%) 39 (8%) < .01 2081 (46%) 207 (10%) < .001

a n refers to the number of mothers in each group.

Values are presented as n (%) unless stated otherwise. Statistically significant differences (P < .05) are emphasized in bold.

ACS, antenatal corticosteroids.

Melamed et al. Antenatal corticosteroids in twin pregnancies. Am J Obstet Gynecol 2016.

Neonatal outcomes

Unadjusted estimates of neonatal outcomes are presented in Table 2. Twin and singleton neonates born to women who received antenatal corticosteroids had lower rates of mortality, mechanical ventilation, and severe neurological injury as compared with neonates born to women who did not receive antenatal corticosteroids (Table 2). Among twins, no differences were observed between the ACS1-7d and no ACS groups with respect to the rate of respiratory distress syndrome, bronchopulmonary dysplasia, and necrotizing enterocolitis. Among singletons, neonates exposed to antenatal corticosteroids 1–7 days prior to birth had a lower rate of respiratory distress syndrome and a higher rate of bronchopulmonary dysplasia and necrotizing enterocolitis in comparison with those who did not receive antenatal corticosteroids (Table 2).

Table 2

Neonatal growth parameters at birth and outcomes for the ACS and no-ACS groups

 

Variables Twins Singletons
ACS within 1–7 d
(n = 1758)a
No ACS
(n = 758)a
P value ACS within 1–7 d (n = 4638) No ACS
(n = 2312)
P value
Male sex 916 (52%) 407 (54%) .46 2546 (55%) 1333 (58%) .03
Growth parameters at birth
 Birthweight, g, mean (SD) 1458 (456) 1646 (482) < .001 1398 (501) 1665 (569) < .001
 Birthweight (Z score), mean (SD)b –0.07 (0.87) 0.29 (0.92) < .001 –0.18 (0.96) 0.33 (1.09) < .001
 Birthweight <10th percentileb 139 (8%) 38 (5%) .009 511 (11%) 155 (7%) < .001
 Head circumference, cm, mean (SD) 28.1 (2.9) 29.1 (2.9) < .001 27.3 (3.1) 28.7 (3.1) < .001
 Head circumference (Z score), mean (SD)b 0.07 (0.98) 0.40 (0.98) < .001 –0.19 (1.04) 0.26 (1.03) < .001
Neonatal outcomes
 Mortality 57 (3%) 42 (6%) .007 211 (5%) 171 (7%) < .001
 Mechanical ventilation 617 (35%) 314 (41%) .003 1870 (40%) 1088 (47%) < .001
 Mechanical ventilation days, median (IQR) 0 (0-2) 0 (0-2) .09 0 (0-3) 0 (0-3) .004
 Respiratory distress syndrome 807 (46%) 374 (50%) .10 2254 (49%) 1183 (52%) .009
 Bronchopulmonary dysplasia 172 (10%) 60 (8%) .17 597 (14%) 215 (10%) < .001
 Severe neurological injuryc 74 (6%) 42 (9%) .02 230 (7%) 201 (14%) < .001
 Retinopathy of prematurity ≥stage 3 40 (7%) 6 (4%) .14 130 (7%) 38 (7%) .77
 Necrotizing enterocolitis (stage 2 or 3) 71 (4%) 22 (3%) .16 190 (4%) 70 (3%) .03

a n refers to the number of neonates in each group

b Calculated using mean and SD from the whole Canadian neonate population of 24–34 weeks of gestational age

c Defined as grade 3 or 4 intraventricular hemorrhage and/or periventricular leukomalacia.

Values are presented as n (%) unless stated otherwise. Significant differences (P < .05) are emphasized in bold.

ACS, antenatal corticosteroids.

Melamed et al. Antenatal corticosteroids in twin pregnancies. Am J Obstet Gynecol 2016.

Both twin and singleton neonates in the ACS1–7d groups had a lower mean birthweight Z-score, a lower head circumference Z-score, and a higher birthweight below the 10th percentile for gestational age as compared with those not exposed to antenatal corticosteroids (Table 2); however, they were born at a lower gestational age in both populations.

Association between antenatal corticosteroids and neonatal outcomes in twins and singletons: multivariable analysis

A multivariable logistic regression analysis was performed to examine the association between antenatal corticosteroids and various neonatal outcomes, which are reported in Table 3. Analyses were adjusted for gestational age, maternal hypertension, outborn status, parity, sex, small-for-gestational-age status, and cesarean birth. Using newborns who did not receive antenatal corticosteroids as a reference, the administration of antenatal corticosteroids 1–7 days before birth was associated with a lower odds of neonatal mortality, mechanical ventilation, respiratory distress syndrome, and severe neurological morbidity in both twins and singletons, and the corresponding adjusted odds ratios were similar between the 2 groups (0.42 vs 0.38, P = .69; 0.47 vs 0.47, P = .93; 0.53 vs 0.54, P = .89; and 0.50 vs 0.45, P = .75, respectively) (Table 3). There was no association between the administration of antenatal corticosteroids and the odds of bronchopulmonary dysplasia, severe retinopathy, or necrotizing enterocolitis in either twins or singletons.

Table 3

Multivariable analysis of the association between administration of ACS 1–7 days before birth and neonatal outcomes

 

Outcome ACS administrated 1–7 d before birth compared with no ACS
Twin pregnancies
AOR (95% CI)a,b
Singleton pregnancies
AOR (95% CI)a
P valuec
Mortality 0.42 (0.24–0.76) 0.38 (0.28–0.50) .69
Mechanical ventilation 0.47 (0.35–0.63) 0.47 (0.41–0.55) .93
Respiratory distress syndrome 0.53 (0.40–0.69) 0.54 (0.47–0.62) .89
Bronchopulmonary dysplasia 0.69 (0.42–1.11) 0.80 (0.63–1.02) .57
Severe neurological injuryd 0.50 (0.30–0.83) 0.45 (0.34–0.59) .75
Retinopathy of prematurity ≥stage 3 2.37 (0.74–7.59) 0.79 (0.47–1.32) .09
Necrotizing enterocolitis (stage 2 or 3) 1.24 (0.65–2.38) 1.07 (0.78–1.47) .69

a Model adjusted for gestational age, sex, hypertension, outborn status, small for gestational age (<10th percentile), parity, and cesarean birth

b Modeled using logistic regression fitted with generalized estimating equation to account for correlation within a pair of twins from the same mother

c Refers to the comparison of odds ratios in twin vs singleton pregnancies

d Defined as grade 3 or 4 intraventricular hemorrhage and/or periventricular leukomalacia.

Significant associations are emphasized in bold font.

ACS, antenatal corticosteroids; AOR, adjusted odds ratio; CI, confidence interval.

Melamed et al. Antenatal corticosteroids in twin pregnancies. Am J Obstet Gynecol 2016.

Comment

Principal findings of the study

In this large population-based cohort study, we have demonstrated that the administration of antenatal corticosteroids in twin pregnancies within the ideal interval of 1–7 days prior to birth is associated with a clinically significant decrease in the odds of neonatal death, short-term respiratory morbidity (ie, mechanical ventilation and respiratory distress syndrome), and severe neurological injury, which is similar in magnitude to that observed among singletons. There was no impact of antenatal corticosteroids on any of the remaining morbidities in either the twin or singleton groups.

Results of the study in the context of other observations

Research addressing the effects of antenatal corticosteroids in twins is limited and conflicting. Possible reasons for this include the fact that many of the studies conducted to date are of a small sample size11, 15, 18, 39, 42, and 58 and are based on retrospective cohorts of neonates born 2–3 decades ago.10, 11, 15, 16, 19, 20, 39, 42, 58, and 59 Therefore, given the dramatic advances in neonatal care, the existing research may not reflect the impact of antenatal corticosteroids in the current era. In addition, many studies have used respiratory distress syndrome as the main outcome,11, 12, 17, and 19 which is a diagnosis that reflects short-term rather than long-term morbidity, and is complicated by considerable variation in its diagnostic criteria.

Finally, most studies conducted thus far did not consider the interval between the administration of antenatal corticosteroids and birth, even though there is substantial evidence that the beneficial effects of antenatal corticosteroids decrease when this interval exceeds 7 days.26 For example, a recent study of 234 women with twins illustrated that antenatal corticosteroids was associated with a decrease in respiratory distress syndrome only when administered within 2–7 days before birth.9 To overcome this limitation, in the current study, we included only women who received antenatal corticosteroids within 1–7 days before birth.

We have found that the administration of antenatal corticosteroids 1–7 days before birth in twin pregnancies was associated with a 58% reduction in the odds of neonatal death and that the magnitude of this decrease was similar to that observed in singletons. Only a small number of studies have assessed the impact of antenatal corticosteroids on neonatal mortality in twins,9, 10, 18, 39, 42, and 59 and most of these were underpowered to detect such an association. In a retrospective cohort study of 652 preterm twins and 1705 singletons born between 1991 and 1999 with a birthweight of 500–1500 g, Hashimoto et al10 reported no interaction between twin pregnancy and the effect of antenatal corticosteroids for any of the neonatal adverse outcomes studied including neonatal death. This suggests that the effect of antenatal corticosteroids on neonatal mortality in twin pregnancies is not different from that observed in singletons, which is in agreement with our findings.

We have also demonstrated that the administration of antenatal corticosteroids 1–7 days before birth is associated with a similar decrease in the odds of severe neurological injury in both twins and singletons. Data regarding the impact of antenatal corticosteroids on the risk of neurological morbidity in twins are scarce. In a retrospective study of 2032 twins and 5022 singleton neonates with a birthweight of less than 1500 g, Blickstein et al20 reported that twins who received antenatal corticosteroids had an increased odds of severe intraventricular hemorrhage (odds ratio, 1.3, 95% confidence interval, 1.0–1.7) compared with singletons who received antenatal corticosteroids (reference group).

These findings suggest that antenatal corticosteroids is less effective in preventing severe intraventricular hemorrhage in twins than in singletons. However, the odds for severe intraventricular hemorrhage in twins who received antenatal corticosteroids (1.3, 95% confidence interval, 1.0–1.7) were significantly lower than in twins who did not receive antenatal corticosteroids (2.4, 95% confidence interval, 1.8–33), suggesting that antenatal corticosteroids decrease the risk of intraventricular hemorrhage in twins as well, which corresponds with our findings.

The administration of antenatal corticosteroids 1–7 days before birth was associated with a considerable decrease in the odds of short-term respiratory morbidity both in twins and singletons. At the same time, the association of antenatal corticosteroids with the risk of long-term respiratory morbidity (ie, bronchopulmonary dysplasia) was not significant in both the twins and singletons groups. This latter observation may be attributed to the considerable advances in neonatal care over the last 2 decades, which may decrease the risk of long-term morbidity in this new era of neonatal care. As a result, larger study samples may be needed to detect smaller effects, if they still exist.

Strengths and limitations

We do acknowledge that the current study has several limitations. First, given the study is retrospective in nature, it may be limited by associated biases, such as the differences in the characteristics of women who received or did not receive antenatal corticosteroids.60, 61, 62, and 63 For example, women who received antenatal corticosteroids were more likely to have hypertension and less likely to deliver outside a level III center (outborn status). We recognize that such a retrospective design may provide support only for an association between antenatal corticosteroids and perinatal outcome but that the ability to draw causal conclusions based on these findings is limited. We acknowledge that a randomized controlled trial would be the ideal design to address this research question. However, we appreciate that conducting a properly powered randomized controlled trial to answer this question would be challenging and thus the likelihood of it being conducted in the near future is low.

Second, data on various potential confounding factors such as chorionicity in twin pregnancies, maternal body mass index, and etiology for preterm birth were not available. Thus, residual confounding and potential selection bias cannot be excluded.

Finally, it is possible that our study was underpowered to detect small differences in neonatal outcomes. On the other hand, the main strengths of our study include a large population-based contemporary (2010–2014) cohort, meticulous data collection, information on important confounding factors, the ability to assess the effects of antenatal corticosteroid exposure within the ideal interval of 1–7 days prior to birth, and the inclusion of a comparison group of singletons.

Conclusion

In summary, we have identified that despite the theoretical concerns regarding the effect of antenatal corticosteroids in twin pregnancies and even in the current era of neonatal care, a complete course antenatal corticosteroids administrated 1–7 days before birth was associated with a statistically and clinically significant decrease in neonatal mortality, short-term respiratory morbidity, and severe neurological morbidity, similar in magnitude to that observed among singletons.

Clinical implications

These findings provide support to the current recommendations that antenatal corticosteroids should be administered to women with twins at risk of preterm birth between 240/7 and 336/7 weeks.2, 45, 46, and 47 Further research on the biological effects of antenatal corticosteroids is needed to provide insight into the mechanisms by which antenatal corticosteroids contributes to this positive effect.

Acknowledgment

We thank the staff of the Canadian Neonatal Network Coordinating Centre for their hard work and Dr Natasha Musrap from the Maternal-Infant Care Research Centre for editorial help during manuscript preparation. The Maternal-Infant Care Research Center is supported by grant funding from the Canadian Institutes of Health Research and in-kind support from Mount Sinai Hospital, Toronto.

Supplementary Appendix. Canadian Neonatal Network Investigators

Prakesh S Shah, MD, MSc (Director, Canadian Neonatal Network and site investigator), Mount Sinai Hospital, Toronto, Ontario;

Adele Harrison, MD, MBChB, Victoria General Hospital, Victoria, British Columbia;

Anne Synnes, MDCM, MHSC, and Joseph Ting, MD, British Columbia Children’s Hospital, Vancouver, British Columbia;

Zenon Cieslak, MD, Royal Columbian Hospital, New Westminster, British Columbia;

Rebecca Sherlock, MD, Surrey Memorial Hospital, Surrey, British Columbia;

Wendy Yee, MD, Foothills Medical Centre, Calgary, Alberta;

Khalid Aziz, MBBS, MA, MEd, and Jennifer Toye, MD, Royal Alexandra Hospital, Edmonton, Alberta;

Carlos Fajardo, MD, Alberta Children’s Hospital, Calgary, Alberta;

Zarin Kalapesi, MD, Regina General Hospital, Regina, Saskatchewan;

Koravangattu Sankaran, MD, MBBS, and Sibasis Daspal, MD, Royal University Hospital, Saskatoon, Saskatchewan;

Mary Seshia, MBChB, Winnipeg Health Sciences Centre, Winnipeg, Manitoba;

Ruben Alvaro, MD, St. Boniface General Hospital, Winnipeg, Manitoba;

Sandesh Shivananda, MBBS, MD, DM, Hamilton Health Sciences Centre, Hamilton, Ontario;

Orlando Da Silva, MD, MSc, London Health Sciences Centre, London, Ontario;

Chuks Nwaesei, MD, Windsor Regional Hospital, Windsor, Ontario;

Kyong-Soon Lee, MD, MSc, Hospital for Sick Children, Toronto, Ontario;

Michael Dunn, MD, Sunnybrook Health Sciences Centre, Toronto, Ontario;

Brigitte Lemyre, MD, Children’s Hospital of Eastern Ontario and Ottawa General Hospital, Ottawa, Ontario;

Kimberly Dow, MD, Kingston General Hospital, Kingston, Ontario;

Ermelinda Pelausa, MD, Jewish General Hospital, Montréal, Québec;

Keith Barrington, MBChB, Hôpital Sainte-Justine, Montréal, Québec;

Christine Drolet, MD, and Bruno Piedboeuf, MD, Centre Hospitalier Universitaire de Québec, Sainte Foy Québec;

Martine Claveau, and Daniel Faucher, MD, McGill University Health Centre, Montréal, Québec;

Valerie Bertelle, MD, and Edith Masse, MD, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Québec;

Roderick Canning, MD, Moncton Hospital, Moncton, New Brunswick;

Hala Makary, MD, Dr. Everett Chalmers Hospital, Fredericton, New Brunswick;

Cecil Ojah, MBBS, and Luis Monterrosa, MD, Saint John Regional Hospital, Saint John, New Brunswick;

Akhil Deshpandey, MBBS, MRCPI, Janeway Children’s Health and Rehabilitation Centre, St. John’s, Newfoundland;

Jehier Afifi, MB BCh, MSc, IWK Health Centre, Halifax, Nova Scotia;

Andrzej Kajetanowicz, MD, Cape Breton Regional Hospital, Sydney, Nova Scotia;

Shoo K Lee, MBBS, PhD (Chairman, Canadian Neonatal Network), Mount Sinai Hospital, Toronto, Ontario.

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Footnotes

a Department of Obstetrics and Gynaecology, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada

b Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada

c Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada

d Department of Paediatrics, Mount Sinai Hospital, Toronto, Ontario, Canada

e Department of Obstetrics and Gynaecology, Mount Sinai Hospital, Toronto, Ontario, Canada

f Maternal-Infant Care (MiCare) Research Centre, Mount Sinai Hospital, Toronto, Ontario, Canada

g Department of Neonatology, Jewish General Hospital, Montreal, Quebec, Canada

h Department of Pediatrics, McGill University, Montreal, Quebec, Canada

Corresponding author: Nir Melamed, MD, MSc.

The funding agencies had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.

Although no funding was received specifically for this study, the Canadian Neonatal Network Coordinating Centre is based at the Maternal-Infant Care Research Centre at Mount Sinai Hospital, Toronto, Ontario, Canada. The Maternal-Infant Care Research Center is supported by grant funding from the Canadian Institutes of Health Research and in-kind support from Mount Sinai Hospital.

The authors report no conflict of interest.

Cite this article as: Melamed N, Shah J, Yoon EW, et al. The role of antenatal corticosteroids in twin pregnancies complicated by preterm birth. Am J Obstet Gynecol 2016;215:482.e1-9.