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Optimal timing of antenatal corticosteroid administration and preterm neonatal and early childhood outcomes
Original Research 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55
Optimal timing of antenatal corticosteroid administration and preterm neonatal and early childhood outcomes Q4
Ashley N. Battarbee, MD, MSCR; Stephanie T. Ros, MD; M. Sean Esplin, MD; Joseph Biggio, MD; Radek Bukowski, MD, PhD; Samuel Parry, MD; Heping Zhang, PhD; Hao Huang, MD, MPH; William Andrews, MD; George Saade, MD; Yoel Sadovsky, MD; Uma M. Reddy, MD, MPH; Michael W. Varner, MD; Tracy A. Manuck, MD; for the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Genomics and Proteomics Network for Preterm Birth Research (GPN-PBR)
BACKGROUND: Antenatal corticosteroids reduce morbidity and mortality among preterm neonates. However, the optimal timing of steroid administration with regard to severe neonatal and early childhood morbidity is uncertain. OBJECTIVE: To evaluate the association between the timing of antenatal corticosteroid administration and preterm outcomes. We hypothesized that neonates exposed to antenatal corticosteroids 2 to <7 days before delivery would have the lowest risks of neonatal and childhood morbidity. STUDY DESIGN: Secondary analysis of 2 prospective multicenter studies enriched for spontaneous preterm birth, Genomics and Proteomics Network for Preterm Birth Research (11/2007e1/2011) and Beneficial Effect of Antenatal Magnesium (12/1997e5/2004). We included women with singleton gestations who received antenatal corticosteroids and delivered at 23 0/7 to 33 6/7 weeks’ gestation. Women who received 1 course of corticosteroids were excluded. Neonatal outcomes were compared by the timing of the first dose of antenatal corticosteroids in relation to delivery: <2 days, 2 to <7 days, 7 to <14 days, and 14 days. The primary outcome was respiratory distress syndrome. Secondary outcomes included composite neonatal morbidity (death, intraventricular hemorrhage grade III or IV, periventricular leukomalacia, bronchopulmonary dysplasia, or necrotizing enterocolitis) and early childhood morbidity (death or moderate to severe cerebral palsy at age 2). Multivariable logistic regression estimated the association between timing of antenatal corticosteroid administration and study outcomes. RESULTS: A total of 2259 subjects met inclusion criteria: 622 (27.5%) received antenatal corticosteroids <2 days before delivery, 821 (36.3%) 2 to <7 days, 401 (17.8%) 7 to <14 days, and 415 (18.4%) 14 days. The majority (78.1%) delivered following idiopathic spontaneous preterm labor or preterm premature rupture of membranes at a mean gestational age of
P
reterm birth is the leading cause of morbidity and mortality among nonanomalous neonates in the United States.1 Compared with term neonates, neonates born prior to 37 weeks’
Cite this article as: Battarbee AN, Ros ST, Esplin MS, et al. Optimal timing of antenatal corticosteroid administration and preterm neonatal and early childhood outcomes. Am J Obstet Gynecol MFM 2019;XX:XX. 2589-9333/$36.00 ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.ajogmf.2019.100077
29.5 2.8 weeks. Neonates exposed to antenatal corticosteroids 2 to <7 days before delivery were the least likely to develop respiratory distress syndrome (51.3%), compared to those receiving antenatal corticosteroids <2 days, 7 to <14 days, and 14 days before delivery (62.7%, 55.9%, and 57.6%, respectively, P < .001). Compared to receipt 2 to <7 days before delivery, there was an increased odds of respiratory distress syndrome with receipt of antenatal corticosteroids <2 days (adjusted odds ratio, 2.07; 95% confidence interval, 1.61e2.66), 7 to <14 days (adjusted odds ratio, 1.40; 95% confidence interval, 1.07e1.83), and 14 days (adjusted odds ratio, 2.34; 95% confidence interval, 1.78e3.07). Neonates exposed to antenatal corticosteroids 14 days before delivery were at increased odds for severe neonatal morbidity (adjusted odds ratio, 1.57; 95% confidence interval, 1.12e2.19) and early childhood morbidity (adjusted odds ratio, 1.74; 95% confidence interval, 1.02e2.95), compared to those exposed 2 to <7 days before delivery. There was no significant association between antenatal corticosteroid receipt <2 days or 7 to <14 days and severe neonatal morbidity or severe childhood morbidity. CONCLUSIONS: Preterm neonates exposed to antenatal corticosteroids 2 to <7 days before delivery had the lowest odds of respiratory distress syndrome, compared to shorter and longer time intervals between steroid administration and delivery. Antenatal corticosteroid administration 14 days before delivery is associated with an increased odds of severe neonatal and childhood morbidity, compared to 2 to <7 days before delivery. These results emphasize the importance of optimally timed antenatal corticosteroids to improve both short- and longterm outcomes. Key words: antenatal corticosteroids, childhood morbidity, neonatal
morbidity, preterm birth, respiratory distress syndrome
gestation are at increased risk for complications such as respiratory distress syndrome (RDS), bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis, and death.2,3 Administration of antenatal corticosteroids prior to preterm delivery is one of the most effective interventions in improving neonatal outcomes.3 Glucocorticoid exposure promotes maturation of various fetal organ systems, including respiratory, gastrointestinal, and central nervous systems. Antenatal corticosteroid administration reduces rates of
numerous complications of prematurity, including RDS (relative risk [RR], 0.66; 95% confidence interval [CI], 0.59e0.73), intraventricular hemorrhage (RR, 0.54; 95% CI, 0.43e0.69), necrotizing enterocolitis (RR, 0.46; 95% CI, 0.29e0.74), and neonatal death (RR, 0.69; 95% CI, 0.58e0.81).3 For this reason, antenatal corticosteroids are recommended for all women at risk of preterm birth.4 Though previous studies have demonstrated improved respiratory outcomes when antenatal corticosteroids are MONTH 2019 AJOG MFM
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Original Research 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166
AJOG MFM at a Glance Why was this study conducted? Although previous studies have demonstrated improved respiratory outcomes when antenatal corticosteroids are administered within 7 days of delivery, the optimal timing of corticosteroids with regard to other severe neonatal morbidities and early childhood morbidity is unknown. This study was conducted to evaluate the association between timing of antenatal corticosteroids and neonatal and early childhood morbidity. Key findings Administration of antenatal corticosteroids 2 to <7 days before delivery was associated with the lowest odds of respiratory distress syndrome, compared to shorter and longer intervals. Antenatal corticosteroid administration 14 days before delivery was associated with an increased odds of severe neonatal and childhood morbidity. What does this add to what is known? Optimally timed antenatal corticosteroids 2e7 days before preterm birth is important for both neonatal and early childhood outcomes.
administered within 7 days of delivery, the evidence for optimal timing of corticosteroid exposure with regard to other severe neonatal morbidities is conflicting.5e7 Additionally, data regarding the effect of antenatal corticosteroid timing on early childhood outcomes is scarce. We hypothesized that neonatal RDS and severe neonatal morbidity as well as early childhood morbidity vary based on the timing of antenatal corticosteroid exposure in relation to delivery, and that those neonates who are exposed to steroids 2 to <7 days prior to delivery would have the lowest rates of morbidity.
Materials and Methods This was a secondary analysis of 2 prospective, multicenter studies: the NICHD Genomics and Proteomics Network for Preterm Birth Research (GPN-PBR observational cohort, enrolled 11/2007 to 1/2011)8 and the NICHD Maternal Fetal Medicine Units Network Beneficial Effects of Antenatal Magnesium Sulfate (BEAM randomized controlled trial, enrolled 12/1997 to 5/2004) in order to optimize sample size for the primary outcome.9 Results from both studies have been previously reported. Briefly, for the GPN-PBR study, women with a history of a prior documented singleton spontaneous preterm birth between 20.0 and
36.6 weeks’ gestation were recruited across 8 clinical sites from November 2007 through January 2011 and followed prospectively (longitudinal arm). Women delivering preterm <34.0 weeks’ gestation owing to spontaneous preterm labor or preterm premature rupture of membranes were also included in the GPN-PBR study (casecontrol arm).8 For the BEAM study, women at imminent risk for preterm delivery <32 weeks’ gestation were randomized to receive intravenous magnesium sulfate or placebo. Briefly, the main trial found that fetal exposure to MgSO4 did not reduce the prespecified primary outcome of the combined risk of moderate or severe cerebral palsy or death, but did reduce the rate of moderate-to-severe cerebral palsy among surviving children (1.9% vs 3.5%; RR, 0.55; 95% CI, 0.32e0.95).9 For both studies, the gestational age was determined by a combination of last menstrual period (if available) and ultrasound, using American College of Obstetricians and Gynecologists dating criteria.10 Further, in both studies, research nurses conducted in-person interviews with participants and abstracted additional clinical and demographic data from medical records. Data collected included demographics; medical, social, family, and obstetric
histories; and obstetric course and complications during the current pregnancy (including intrapartum course, mode of delivery, and neonatal outcomes). With the exception of the study drug provided by the BEAM study, all obstetric management, including decisions regarding whether to administer antenatal corticosteroids and the timing of such administration, was at the discretion of each woman’s primary obstetric provider. Women carrying nonanomalous, singleton gestations who delivered between 23 0/7 and 33 6/7 weeks’ gestation were included. Women were excluded if they received more than 1 course of antenatal corticosteroids, carried a fetus with major congenital anomalies or aneuploidy, or had unknown timing of antenatal corticosteroid exposure. We chose to evaluate a primary neonatal outcome and a primary childhood outcome. The primary neonatal outcome was RDS, defined as a clinical diagnosis of respiratory distress (including hyaline membrane disease or respiratory insufficiency of the premature neonate, but not transient tachypnea of the newborn) and oxygen therapy (FiO2 0.40) for greater than or equal to 24 hours, or a clinical diagnosis of respiratory distress with death before 24 hours of age. The secondary neonatal outcome was a composite severe neonatal morbidity including death, intraventricular hemorrhage grade III or IV, periventricular leukomalacia, bronchopulmonary dysplasia, or necrotizing enterocolitis prior to hospital discharge. The primary childhood outcome was a composite of death or moderate-to-severe cerebral palsy at age 2 among those enrolled in the BEAM study. Study outcomes were compared by timing of antenatal corticosteroid exposure prior to delivery, defined as the interval between the first dose of antenatal corticosteroids and delivery: <2 days (Group 1), 2 to <7 days (Group 2), 7 to <14 days (Group 3), and 14 days (Group 4). Demographic and antenatal characteristics were compared using c2, Kruskal-Wallis, and analysis of variance as appropriate. The
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167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222
Original Research 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260½F1 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277½T1 278
Pearson correlation was used to evaluate for correlation among characteristics found to be significant in bivariable analysis. Multivariable logistic regression was performed to estimate the association between timing of antenatal corticosteroid administration and the primary outcomes. Antenatal corticosteroid administration 2 to <7 days before delivery served as the referent group. Initial models included factors that were significant at P < .05 in bivariate analyses but not significantly correlated with one another. Factors with P < .20 were retained in final regression models. Statistical significance was defined as P < .05 unless otherwise specified, and all tests were 2tailed. No imputation for missing data was performed. All statistical analyses were performed using Stata (StataCorp, College Station, TX). Institutional Review Board approval and written informed consent was obtained for both original studies at all participating institutions. This analysis was conducted using de-identified databases and was approved by the Institutional Review Board at the University of North Carolina-Chapel Hill (#152099).
Results Of 2631 women enrolled in GPN-PBR and 2244 women enrolled in the BEAM study, 2259 women met inclusion criteria for this analysis (Figure). Of these, 681 (30.1%) were participants in the GPN-PBR study and 1578 (69.9%) were enrolled in the BEAM study. Six hundred and twenty-two (27.5%) were exposed <2 days, 821 (36.3%) 2 to <7 days, 401 (17.8%) 7 to <14 days, and 415 (18.4%) 14 days prior to delivery. The majority of women (n ¼ 1764, 78.1%) delivered following preterm premature rupture of membranes (defined as membrane ruptured for at least 72 hours prior to delivery, or preterm prelabor rupture of membranes was the primary reason for antepartum admission). The mean gestational age at delivery was 29.5 2.8 weeks (Table 1). Overall, 1274 neonates were diagnosed with RDS (56.4%) and 616
279 280 281 Flow diagram of study cohort 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 Battarbee et al. Optimal timing of antenatal corticosteroid administration. AJOG MFM 2019. 300 301 302 303 (27.3%) with major neonatal delivery were included as possible 304 morbidity (Table 2). Neonates who confounding factors. Marital status, ½T2 305 were exposed to antenatal corticoste- maternal education level, and study 306 roids at 2 to <7 days before delivery enrollment were not included, as they 307 were the least likely to develop RDS were correlated with other variables 308 (51.3%), compared to 62.7% of those considered above (r 0.25 and P < 309 exposed <2 days before delivery, .001 for all). In the final regression 310 55.9% of those exposed 7 to <14 days model evaluating factors associated 311 before delivery, and 57.6% of those with RDS, we found an increased odds 312 exposed 14 days before delivery (P < of RDS in those with steroid receipt 313 .001). There was also a statistically <2 days before delivery (adjusted odds 314 significant difference in severe ratio [aOR], 2.07; 95% CI, 1.61e2.66), 315 neonatal morbidity between groups 7 to <14 days before delivery (aOR, 316 (Table 2). Of the 1578 neonates in this 1.40; 95% CI, 1.07e1.83), and 14 317 cohort whose mothers were originally days before delivery (aOR, 2.34; 95% 318 enrolled in the BEAM study, 1511 CI, 1.78e3.07), compared to receipt 2 319 (95.7%) neonates had outcome data to <7 days before delivery (Table 3). ½T3 320 available at age 2, and overall 153 Furthermore, in the final regression 321 (10.1%) had the adverse childhood models evaluating factors associated 322 outcome (moderate or severe cerebral with severe neonatal morbidity, we 323 palsy or death). The frequency of found increased odds of severe 324 childhood morbidity was similar neonatal morbidity when antenatal 325 among those exposed to antenatal corticosteroids were received 14 days 326 corticosteroids <2 days, 2 to <7 days, before delivery (aOR, 1.57; 95% CI, 327 7 to <14 days, and 14 days before 1.12e2.19), compared to 2 to <7 days 328 delivery (P ¼ .57). before delivery (Table 4). Similarly, ½T4 329 In initial multivariable logistic antenatal corticosteroid receipt 14 330 regression models, nulliparity, magne- days before delivery was associated 331 sium, spontaneous preterm birth, with an increased odds of severe 332 gestational age at delivery, male childhood morbidity (aOR, 1.74; 95% 333 neonate, maternal age, black race, CI, 1.02e2.95), compared to 2 to <7 334 chorioamnionitis, and cesarean days before delivery (Table 5). There ½T5 FIGURE
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Original Research 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390
TABLE 1
Demographic and antenatal characteristics by timing of antenatal corticosteroid administration Timing of administration <2 days (n ¼ 622)
2 to <7 days (n ¼ 821)
Enrolled in Genomics and Proteomics Network for Preterm Birth Research study
352 (56.6)
174 (21.2)
Maternal age (years)
25.9 6.1
Nulliparous
298 (47.9)
7 to <14 days (n ¼ 401)
14 days (n ¼ 415)
P value
73 (18.2)
82 (19.8)
<.001
25.0 6.2
26.4 5.9
26.9 6.2
<.001
317 (38.6)
147 (36.7)
135 (32.5)
<.001
Black race
179 (28.8)
351 (42.8)
171 (42.6)
131 (31.6)
<.001
Less than a high school level education
408 (65.8)
522 (64.0)
281 (70.1)
300 (72.3)
.01
Married
312 (50.2)
372 (45.5)
194 (48.5)
229 (55.2)
.01
18 (2.9)
36 (4.4)
9 (2.2)
22 (5.3)
.06
356 (57.2)
670 (81.6)
363 (90.5)
375 (90.4)
<.001
216 (169, 271)
435 (329, 636)
<.001
Gestational or pregestational diabetes mellitus Preterm prelabor rupture of membranes Duration of ruptured membranes (hours)
3 (0.1, 19)
79 (33, 122)
56 (9.0)
140 (17.1)
88 (22.0)
67 (16.1)
<.001
Tobacco use during pregnancy
135 (21.7)
232 (28.3)
100 (24.9)
110 (26.5)
.04
Gestational age at delivery (weeks)
29.7 2.9
29.0 2.7
29.2 2.7
30.9 2.3
<.001
Cesarean delivery
167 (26.9)
271 (33.0)
142 (35.4)
162 (39.0)
<.001
Chorioamnionitis suspected prior to delivery
Data presented as n (%) or mean standard deviation or median (25%, 75% interquartile range). Battarbee et al. Optimal timing of antenatal corticosteroid administration. AJOG MFM 2019.
was no significant association between antenatal corticosteroid administration < 2 days before delivery or 7 to <14 days before delivery and severe neonatal or childhood morbidity, compared to antenatal corticosteroid administration 2 to <7 days before delivery. In all models, male sex and delivery gestational age were important factors associated with RDS and the composite severe neonatal and childhood morbidities (Tables 3, 4, and 5).
Comment Principal findings In this retrospective cohort study of over 2000 preterm neonates, we found that neonates who were exposed to antenatal corticosteroids 2 to <7 days prior to delivery had the lowest odds of RDS compared to both shorter and longer intervals from steroid receipt to delivery. In addition, we found an increased odds of severe neonatal morbidity and severe childhood morbidity among neonates who were exposed to antenatal corticosteroids 14 days before delivery,
compared to 2 to <7 days before delivery. These results suggest that the ideal timing of antenatal corticosteroids to optimize neonatal short- and long-term outcomes among babies born <34 weeks is 2 to <7 days prior to delivery.
Results of the study in the context of other observations Our findings confirm and extend those demonstrated in previous retrospective cohort studies.11e13 Compared to infants born at 26e34 weeks’ gestation to women who had received antenatal corticosteroids more than 7 days prior to delivery, Peaceman et al11 demonstrated a lower incidence of need for respiratory support among infants born to women who had received antenatal corticosteroids within 7 days of delivery. There was no significant difference, however, in the association between timing of antenatal corticosteroids and necrotizing enterocolitis, intraventricular hemorrhage, or mortality.11 One explanation for their negative finding was insufficient
power, as a previous meta-analysis had demonstrated increased risk of perinatal mortality when corticosteroids were administered more than 7 days before delivery.7 In a retrospective cohort study of 707 infants born at 22e26 weeks’ gestation, the risk of mortality was doubled when the interval from antenatal corticosteroid exposure to delivery was either too short (<24 hours) or too long (>7 days), compared to optimal timing (24 hours to 7 days).14 In contrast to our findings, however, these authors found no association between severe neonatal morbidity and timing of antenatal corticosteroids. It is likely that our study found differences in neonatal morbidity based on duration of antenatal corticosteroid exposure as we evaluated neonates born up to 34 weeks’ gestation, and also included mortality in our composite, as a competing outcome. In vitro and in vivo animal studies provide biologic plausibility as to why the effect of antenatal corticosteroids appears to be transient. In an in vitro
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391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446
Original Research 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484Q2 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502
TABLE 2
Neonatal outcomes by timing of antenatal corticosteroid administration Timing of administration
Male neonate
<2 days (n ¼ 622)
2 to <7 days (n ¼ 821)
7 to <14 days (n ¼ 401)
14 days (n ¼ 415)
P value
331 (53.2)
434 (52.9)
214 (53.4)
248 (59.8)
.11
Birthweight (mean grams, SD)
1486 550
1296 475
1310 458
1585 469
<.001
Respiratory distress syndrome
390 (62.7)
421 (51.3)
224 (55.9)
239 (57.6)
<.001
146 (23.5)
253 (30.8)
124 (30.9)
93 (22.4)
.001
Neonatal death
41 (6.6)
59 (7.2)
31 (7.7)
21 (5.1)
.43
Neonatal severe morbidity
a
Intraventricular hemorrhage grade III/IV
42 (6.8)
20 (2.4)
11 (2.7)
11 (2.7)
<.001
Periventricular leukomalacia
14 (2.2)
17 (2.1)
8 (2.0)
9 (2.2)
.99
Bronchopulmonary dysplasia
67 (10.8)
146 (17.9)
67 (16.8)
41 (10.0)
<.001
Necrotizing enterocolitis
31 (5.0)
80 (9.8)
45 (11.3)
33 (8.0)
.001
33/316 (10.4)
26/323 (8.1)
.570
b
Childhood morbidity
65/610 (10.7)
29/262 (11.1)
Data presented as n (%) or mean standard deviation. a
Composite included death, severe intraventricular hemorrhage grade III or IV, periventricular leukomalacia, bronchopulmonary dysplasia, or necrotizing enterocolitis; b Composite included death or moderate-to-severe cerebral palsy at age 2 among the 1511 women included in this analysis who were originally enrolled in the BEAM study and had longer-term follow-up data available. Battarbee et al. Optimal timing of antenatal corticosteroid administration. AJOG MFM 2019.
study of human lung cells, corticosteroids were found to increase transcription of surfactant genes with maximum stimulation at 48 hours and return to near control levels by day 8.15 Similarly, an in vivo study of lung function in preterm lambs demonstrated that although the
hormonal effects of corticosteroid treatment were transient, some functional responses persisted over the 2to 7-day interval to delivery.16,17 Although many of these studies have been limited by the stability of the cultured fetal lung beyond 7 days, our results and the previously published
clinical studies support the transient nature of biochemical changes after corticosteroid administration.
Strengths and weaknesses Our study has several strengths. These data are from previous prospective studies of preterm birth with rigorous
TABLE 3
Multivariable regression of respiratory distress syndrome by timing of antenatal corticosteroid administration Respiratory distress syndrome adjusted odds ratio (95% confidence interval)
P value
2.07 (1.61-2.66)
<.001
Timing of antenatal corticosteroid administration <2 days before delivery 2 to <7 days before delivery 7 to <14 days before delivery 14 days before delivery
1.0 (referent)
-
1.40 (1.07e1.83)
.015
2.34 (1.78e3.07)
<.001
Gestational age at delivery, per completed week
0.68 (0.65e0.71)
<.001
Black race
0.59 (0.48e0.72)
<.001
Male
1.35 (1.12e1.63)
<.01
Preterm prelabor rupture of membranes
0.71 (0.56e0.91)
<.01
Delivered by cesarean section
1.24 (1.02e1.52)
.04
Received magnesium sulfate
0.85 (0.71e1.03)
.09
Other factors considered in initial models but removed owing to P > .20 include nulliparity and maternal smoking during pregnancy. Battarbee et al. Optimal timing of antenatal corticosteroid administration. AJOG MFM 2019.
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5
503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558
Original Research 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614
TABLE 4
Multivariable regression of severe neonatal morbidity by timing of antenatal corticosteroid administration Severe neonatal morbiditya adjusted odds ratio (95% confidence interval)
P value
Timing of antenatal corticosteroid administration <2 days before delivery
0.80 (0.59e1.07)
2 to <7 days before delivery
.135
1.0 (referent)
-
7 to <14 days before delivery
1.15 (0.83e1.58)
.404
14 days before delivery
1.57 (1.12e2.19)
.009
Gestational age at delivery, per completed week
0.55 (0.53e0.58)
<.001
Male sex
1.31 (1.04e1.65)
.022
Nulliparous mother
1.18 (0.93e1.49)
.185
Delivery by cesarean section
1.23 (0.97e1.56)
.092
Other factors considered in initial models but removed owing to P > .20 include preterm prelabor rupture of membranes, receipt of magnesium sulfate prior to delivery (for any indication), maternal smoking during pregnancy, black race, and suspected clinical chorioamnionitis. a
Composite included death, severe intraventricular hemorrhage grade III or IV, periventricular leukomalacia, bronchopulmonary dysplasia, or necrotizing enterocolitis. Battarbee et al. Optimal timing of antenatal corticosteroid administration. AJOG MFM 2019.
data collection by trained research staff. Our study offers a larger sample size compared to previous retrospective cohort studies, and thus permitted detection of differences in rare adverse neonatal outcomes and also extension to the early childhood period for individuals enrolled in the BEAM study. The findings of our study, however, must be interpreted within the context of the study design. Although we adjusted for many potential confounding factors in multivariable logistic regression, including gestational age, race and ethnicity, neonatal sex, preterm
premature rupture of membranes, and others, we were unable to adjust for parent study enrollment given the high degree of correlation with preterm premature rupture of membranes. The combination of data from 2 different studies, each with distinct aims and protocols and each conducted over different years, may have also unintentionally affected our results. We are not able to estimate the relative benefit or risk compared to women who did not receive corticosteroids in this retrospective cohort study; and given that antenatal corticosteroid administration is
currently considered to be the standard of care for women with anticipated preterm birth, it is unlikely that this question could be answered in a randomized clinical trial. Additionally, as we only included women who delivered at less than 34 weeks and the majority of women had preterm prelabor rupture of membranes, our results may not be generalizable to all populations.
Conclusions and clinical implications Nonetheless, our results demonstrate Q3 that the optimal timing of antenatal
TABLE 5
Multivariable regression of severe childhood morbidity by timing of antenatal corticosteroid administration (note: limited to participants in BEAM study) Severe childhood morbiditya adjusted odds ratio (95% confidence interval)
P value
Timing of antenatal corticosteroid administration <2 days before delivery
1.14 (0.70e1.89)
2 to <7 days before delivery
1.0 (referent)
.595 -
7 to <14 days before delivery
1.10 (0.69e1.77)
.690
14 days before delivery
1.74 (1.02e2.95)
.042
Gestational age at delivery, per completed week
0.62 (0.57e0.67)
<.001
Male sex
1.74 (1.21e2.52)
.003
Other factors considered in initial models but removed owing to P > .20 include preterm prelabor rupture of membranes, receipt of magnesium sulfate prior to delivery (for any indication), maternal smoking during pregnancy, nulliparity, black race, and suspected clinical chorioamnionitis. a
Severe childhood morbidity included death or moderate-to-severe cerebral palsy at age 2. Battarbee et al. Optimal timing of antenatal corticosteroid administration. AJOG MFM 2019.
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615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670
Original Research 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726
corticosteroid administration is 2 to <7 days before preterm delivery between 23 and 34 weeks’ gestation. Unfortunately, however, as clinicians we acknowledge that it remains challenging to accurately predict the timing of preterm delivery even among those at highest risk.18 Future studies are still needed to better understand when preterm delivery is imminent in order to reduce unnecessary exposure to antenatal corticosteroids while optimizing neonatal outcomes. n References 1. Martin JA, Hamilton BE, Osterman MJK, Driscoll AK, Mathews TJ. Births: final data for 2015. Natl Vital Stat Rep 2017;66(1):1. Available at: http://www.ncbi.nlm.nih.gov/pubmed/ 28135188. Accessed November 13, 2018. 2. Crowley PA. Antenatal corticosteroid therapy: a meta-analysis of the randomized trials, 1972 to 1994. Am J Obstet Gynecol 1995;173(1): 322–35. https://doi.org/10.1016/00029378(95)90222-8. 3. Roberts D, Brown J, Medley N, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2017;3: CD004454. https://doi.org/10.1002/ 14651858.CD004454.pub3. 4. Committee Opinion No. 713: antenatal corticosteroid therapy for fetal maturation. Obstet Gynecol 2017;130(2):e102–9. https://doi.org/ 10.1097/AOG.0000000000002237. 5. Sehdev HM, Abbasi S, Robertson P, et al. The effects of the time interval from antenatal corticosteroid exposure to delivery on neonatal outcome of very low birth weight infants. Am J Obstet Gynecol 2004;191(4):1409–13. https:// doi.org/10.1016/j.ajog.2004.06.055. 6. Vermillion S, Soper D, Newman R. Is betamethasone effective longer than 7 days after treatment? Obstet Gynecol 2001;94(4): 491–3. 7. McLaughlin KJ, Crowther CA, Walker N, Harding JE. Effects of a single course of corticosteroids given more than 7 days before birth: a systematic review. Aust N Z J Obstet Gynaecol 2003;43(2):101–6. Available at: http://www.ncbi.nlm.nih.gov/pubmed/ 14712961. Accessed June 12, 2019. 8. Esplin MS, Merrell K, Goldenberg R, et al. Proteomic identification of serum peptides
predicting subsequent spontaneous preterm birth. Am J Obstet Gynecol 2011;204(5):391. e1–8. https://doi.org/10.1016/j.ajog.2010.09. 021. 9. Rouse DJ, Hirtz DG, Thom E, et al. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med 2008;359(9):895–905. https://doi. org/10.1056/NEJMoa0801187. 10. Committee Opinion No 700: methods for estimating the due date. Obstet Gynecol 2017;129(5):e150–4. https://doi.org/10.1097/ AOG.0000000000002046. 11. Peaceman AM, Bajaj K, Kumar P, Grobman WA. The interval between a single course of antenatal steroids and delivery and its association with neonatal outcomes. Am J Obstet Gynecol 2005;193(3):1165–9. https:// doi.org/10.1016/j.ajog.2005.06.050. 12. Ring AM, Garland JS, Stafeil BR, Carr MH, Peckman GS, Pircon RA. The effect of a prolonged time interval between antenatal corticosteroid administration and delivery on outcomes in preterm neonates: a cohort study. Am J Obstet Gynecol 2007;196(5):457.e1–6. https://doi.org/10. 1016/j.ajog.2006.12.018. 13. Wilms FF, Vis JY, Pattinaja DAPM, et al. Relationship between the time interval from antenatal corticosteroid administration until preterm birth and the occurrence of respiratory morbidity. Am J Obstet Gynecol 2011;205(1): 49.e1–7. https://doi.org/10.1016/j.ajog.2011. 03.035. 14. Norberg H, Kowalski J, Marsál K, Norman M. Timing of antenatal corticosteroid administration and survival in extremely preterm infants: a national population-based cohort study. BJOG 2017;124(10):1567–74. https:// doi.org/10.1111/1471-0528.14545. 15. Vidaeff AC, Ramin SM, Gilstrap LC, Alcorn JL. In vitro quantification of dexamethasone-induced surfactant protein B expression in human lung cells. J Matern Fetal Neonatal Med 2004;15(3):155–9. https://doi. org/10.1080/14767050410001668248. 16. Ikegami M, Polk DH, Jobe AH, et al. Effect of interval from fetal corticosteriod treatment to delivery on postnatal lung function of preterm lambs. J Appl Physiol 1996;80(2):591–7. https://doi.org/10.1152/jappl.1996.80.2.591. 17. Ikegami M, Polk D, Jobe A. Minimum interval from fetal betamethasone treatment to postnatal lung responses in preterm lambs. Am J Obstet Gynecol 1996;174(5):1408–13. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9065104. Accessed June 12, 2019.
18. Adams TM, Kinzler WL, Chavez MR, Vintzileos AM. The timing of administration of antenatal corticosteroids in women with indicated preterm birth. Am J Obstet Gynecol 2015;212(5):645.e1–4. https://doi.org/10. 1016/j.ajog.2014.11.021.
Author and article information From the Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina (Drs Battarbee and Manuck); Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of Utah School of Medicine, Salt Lake City, Utah (Drs Ros, Esplin, Varner, and Manuck); Intermountain Healthcare Department of Maternal Fetal Medicine, Salt Lake City, Utah (Drs Ros, Esplin, and Varner); Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of South Florida, Tampa, Florida (Dr Ros); Center for Women’s Reproductive Health, University of Alabama at Birmingham, Birmingham, Alabama (Drs Biggio and Andrews); Department of Women’s Health, Dell Medical School, University of Texas at Austin, Austin, Texas (Drs Bukowski and Saade); Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania (Dr Parry); Collaborative Center for Statistics in Science, Yale University School of Public Health, New Haven, Connecticut (Drs Zhang and Huang); Magee-Womens Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (Dr Sadovsky), and Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Yale University, New Haven, Connecticut (Dr Reddy). Received Sept. 27, 2019; revised Nov. 26, 2019; accepted Dec. 2, 2019. M.S.E. holds stock in Sera Prognostics, a private company that was established to create a commercial test to predict preterm birth and other obstetric complications. R.B. is an advisor and holds stock in Savran Technologies Inc, a company that developed technology to isolate ultra-rare cells from blood for noninvasive diagnostics. The remaining authors report no conflict of interest. Presented in part at the Society for MaternaleFetal Medicine’s 36th Annual Meeting (Atlanta, GA), February 4, 2016, as a poster presentation (final abstract ID #628). This study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Genomic and Proteomic Network for Preterm Birth Research (U01-HD-050062; U01-HD050078; U01-HD-050080; U01-HD-050088; U01-HD050094) (all authors). This study was also funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development 5K23HD067224 (T.A.M.) and R01-MD011609 (T.A.M.). Correspondence: Ashley N. Battarbee, MD. ashley_ [email protected]
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Optimal timing of antenatal corticosteroid administration and preterm neonatal and early childhood outcomes Q4
Ashley N. Battarbee, MD, MSCR; Stephanie T. Ros, MD; M. Sean Esplin, MD; Joseph Biggio, MD; Radek Bukowski, MD, PhD; Samuel Parry, MD; Heping Zhang, PhD; Hao Huang, MD, MPH; William Andrews, MD; George Saade, MD; Yoel Sadovsky, MD; Uma M. Reddy, MD, MPH; Michael W. Varner, MD; Tracy A. Manuck, MD; for the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Genomics and Proteomics Network for Preterm Birth Research (GPN-PBR)
BACKGROUND: Antenatal corticosteroids reduce morbidity and mortality among preterm neonates. However, the optimal timing of steroid administration with regard to severe neonatal and early childhood morbidity is uncertain. OBJECTIVE: To evaluate the association between the timing of antenatal corticosteroid administration and preterm outcomes. We hypothesized that neonates exposed to antenatal corticosteroids 2 to <7 days before delivery would have the lowest risks of neonatal and childhood morbidity. STUDY DESIGN: Secondary analysis of 2 prospective multicenter studies enriched for spontaneous preterm birth, Genomics and Proteomics Network for Preterm Birth Research (11/2007e1/2011) and Beneficial Effect of Antenatal Magnesium (12/1997e5/2004). We included women with singleton gestations who received antenatal corticosteroids and delivered at 23 0/7 to 33 6/7 weeks’ gestation. Women who received 1 course of corticosteroids were excluded. Neonatal outcomes were compared by the timing of the first dose of antenatal corticosteroids in relation to delivery: <2 days, 2 to <7 days, 7 to <14 days, and 14 days. The primary outcome was respiratory distress syndrome. Secondary outcomes included composite neonatal morbidity (death, intraventricular hemorrhage grade III or IV, periventricular leukomalacia, bronchopulmonary dysplasia, or necrotizing enterocolitis) and early childhood morbidity (death or moderate to severe cerebral palsy at age 2). Multivariable logistic regression estimated the association between timing of antenatal corticosteroid administration and study outcomes. RESULTS: A total of 2259 subjects met inclusion criteria: 622 (27.5%) received antenatal corticosteroids <2 days before delivery, 821 (36.3%) 2 to <7 days, 401 (17.8%) 7 to <14 days, and 415 (18.4%) 14 days. The majority (78.1%) delivered following idiopathic spontaneous preterm labor or preterm premature rupture of membranes at a mean gestational age of
P
reterm birth is the leading cause of morbidity and mortality among nonanomalous neonates in the United States.1 Compared with term neonates, neonates born prior to 37 weeks’
Cite this article as: Battarbee AN, Ros ST, Esplin MS, et al. Optimal timing of antenatal corticosteroid administration and preterm neonatal and early childhood outcomes. Am J Obstet Gynecol MFM 2019;XX:XX. 2589-9333/$36.00 ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.ajogmf.2019.100077
29.5 2.8 weeks. Neonates exposed to antenatal corticosteroids 2 to <7 days before delivery were the least likely to develop respiratory distress syndrome (51.3%), compared to those receiving antenatal corticosteroids <2 days, 7 to <14 days, and 14 days before delivery (62.7%, 55.9%, and 57.6%, respectively, P < .001). Compared to receipt 2 to <7 days before delivery, there was an increased odds of respiratory distress syndrome with receipt of antenatal corticosteroids <2 days (adjusted odds ratio, 2.07; 95% confidence interval, 1.61e2.66), 7 to <14 days (adjusted odds ratio, 1.40; 95% confidence interval, 1.07e1.83), and 14 days (adjusted odds ratio, 2.34; 95% confidence interval, 1.78e3.07). Neonates exposed to antenatal corticosteroids 14 days before delivery were at increased odds for severe neonatal morbidity (adjusted odds ratio, 1.57; 95% confidence interval, 1.12e2.19) and early childhood morbidity (adjusted odds ratio, 1.74; 95% confidence interval, 1.02e2.95), compared to those exposed 2 to <7 days before delivery. There was no significant association between antenatal corticosteroid receipt <2 days or 7 to <14 days and severe neonatal morbidity or severe childhood morbidity. CONCLUSIONS: Preterm neonates exposed to antenatal corticosteroids 2 to <7 days before delivery had the lowest odds of respiratory distress syndrome, compared to shorter and longer time intervals between steroid administration and delivery. Antenatal corticosteroid administration 14 days before delivery is associated with an increased odds of severe neonatal and childhood morbidity, compared to 2 to <7 days before delivery. These results emphasize the importance of optimally timed antenatal corticosteroids to improve both short- and longterm outcomes. Key words: antenatal corticosteroids, childhood morbidity, neonatal
morbidity, preterm birth, respiratory distress syndrome
gestation are at increased risk for complications such as respiratory distress syndrome (RDS), bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis, and death.2,3 Administration of antenatal corticosteroids prior to preterm delivery is one of the most effective interventions in improving neonatal outcomes.3 Glucocorticoid exposure promotes maturation of various fetal organ systems, including respiratory, gastrointestinal, and central nervous systems. Antenatal corticosteroid administration reduces rates of
numerous complications of prematurity, including RDS (relative risk [RR], 0.66; 95% confidence interval [CI], 0.59e0.73), intraventricular hemorrhage (RR, 0.54; 95% CI, 0.43e0.69), necrotizing enterocolitis (RR, 0.46; 95% CI, 0.29e0.74), and neonatal death (RR, 0.69; 95% CI, 0.58e0.81).3 For this reason, antenatal corticosteroids are recommended for all women at risk of preterm birth.4 Though previous studies have demonstrated improved respiratory outcomes when antenatal corticosteroids are MONTH 2019 AJOG MFM
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56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110
Original Research 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166
AJOG MFM at a Glance Why was this study conducted? Although previous studies have demonstrated improved respiratory outcomes when antenatal corticosteroids are administered within 7 days of delivery, the optimal timing of corticosteroids with regard to other severe neonatal morbidities and early childhood morbidity is unknown. This study was conducted to evaluate the association between timing of antenatal corticosteroids and neonatal and early childhood morbidity. Key findings Administration of antenatal corticosteroids 2 to <7 days before delivery was associated with the lowest odds of respiratory distress syndrome, compared to shorter and longer intervals. Antenatal corticosteroid administration 14 days before delivery was associated with an increased odds of severe neonatal and childhood morbidity. What does this add to what is known? Optimally timed antenatal corticosteroids 2e7 days before preterm birth is important for both neonatal and early childhood outcomes.
administered within 7 days of delivery, the evidence for optimal timing of corticosteroid exposure with regard to other severe neonatal morbidities is conflicting.5e7 Additionally, data regarding the effect of antenatal corticosteroid timing on early childhood outcomes is scarce. We hypothesized that neonatal RDS and severe neonatal morbidity as well as early childhood morbidity vary based on the timing of antenatal corticosteroid exposure in relation to delivery, and that those neonates who are exposed to steroids 2 to <7 days prior to delivery would have the lowest rates of morbidity.
Materials and Methods This was a secondary analysis of 2 prospective, multicenter studies: the NICHD Genomics and Proteomics Network for Preterm Birth Research (GPN-PBR observational cohort, enrolled 11/2007 to 1/2011)8 and the NICHD Maternal Fetal Medicine Units Network Beneficial Effects of Antenatal Magnesium Sulfate (BEAM randomized controlled trial, enrolled 12/1997 to 5/2004) in order to optimize sample size for the primary outcome.9 Results from both studies have been previously reported. Briefly, for the GPN-PBR study, women with a history of a prior documented singleton spontaneous preterm birth between 20.0 and
36.6 weeks’ gestation were recruited across 8 clinical sites from November 2007 through January 2011 and followed prospectively (longitudinal arm). Women delivering preterm <34.0 weeks’ gestation owing to spontaneous preterm labor or preterm premature rupture of membranes were also included in the GPN-PBR study (casecontrol arm).8 For the BEAM study, women at imminent risk for preterm delivery <32 weeks’ gestation were randomized to receive intravenous magnesium sulfate or placebo. Briefly, the main trial found that fetal exposure to MgSO4 did not reduce the prespecified primary outcome of the combined risk of moderate or severe cerebral palsy or death, but did reduce the rate of moderate-to-severe cerebral palsy among surviving children (1.9% vs 3.5%; RR, 0.55; 95% CI, 0.32e0.95).9 For both studies, the gestational age was determined by a combination of last menstrual period (if available) and ultrasound, using American College of Obstetricians and Gynecologists dating criteria.10 Further, in both studies, research nurses conducted in-person interviews with participants and abstracted additional clinical and demographic data from medical records. Data collected included demographics; medical, social, family, and obstetric
histories; and obstetric course and complications during the current pregnancy (including intrapartum course, mode of delivery, and neonatal outcomes). With the exception of the study drug provided by the BEAM study, all obstetric management, including decisions regarding whether to administer antenatal corticosteroids and the timing of such administration, was at the discretion of each woman’s primary obstetric provider. Women carrying nonanomalous, singleton gestations who delivered between 23 0/7 and 33 6/7 weeks’ gestation were included. Women were excluded if they received more than 1 course of antenatal corticosteroids, carried a fetus with major congenital anomalies or aneuploidy, or had unknown timing of antenatal corticosteroid exposure. We chose to evaluate a primary neonatal outcome and a primary childhood outcome. The primary neonatal outcome was RDS, defined as a clinical diagnosis of respiratory distress (including hyaline membrane disease or respiratory insufficiency of the premature neonate, but not transient tachypnea of the newborn) and oxygen therapy (FiO2 0.40) for greater than or equal to 24 hours, or a clinical diagnosis of respiratory distress with death before 24 hours of age. The secondary neonatal outcome was a composite severe neonatal morbidity including death, intraventricular hemorrhage grade III or IV, periventricular leukomalacia, bronchopulmonary dysplasia, or necrotizing enterocolitis prior to hospital discharge. The primary childhood outcome was a composite of death or moderate-to-severe cerebral palsy at age 2 among those enrolled in the BEAM study. Study outcomes were compared by timing of antenatal corticosteroid exposure prior to delivery, defined as the interval between the first dose of antenatal corticosteroids and delivery: <2 days (Group 1), 2 to <7 days (Group 2), 7 to <14 days (Group 3), and 14 days (Group 4). Demographic and antenatal characteristics were compared using c2, Kruskal-Wallis, and analysis of variance as appropriate. The
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167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222
Original Research 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260½F1 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277½T1 278
Pearson correlation was used to evaluate for correlation among characteristics found to be significant in bivariable analysis. Multivariable logistic regression was performed to estimate the association between timing of antenatal corticosteroid administration and the primary outcomes. Antenatal corticosteroid administration 2 to <7 days before delivery served as the referent group. Initial models included factors that were significant at P < .05 in bivariate analyses but not significantly correlated with one another. Factors with P < .20 were retained in final regression models. Statistical significance was defined as P < .05 unless otherwise specified, and all tests were 2tailed. No imputation for missing data was performed. All statistical analyses were performed using Stata (StataCorp, College Station, TX). Institutional Review Board approval and written informed consent was obtained for both original studies at all participating institutions. This analysis was conducted using de-identified databases and was approved by the Institutional Review Board at the University of North Carolina-Chapel Hill (#152099).
Results Of 2631 women enrolled in GPN-PBR and 2244 women enrolled in the BEAM study, 2259 women met inclusion criteria for this analysis (Figure). Of these, 681 (30.1%) were participants in the GPN-PBR study and 1578 (69.9%) were enrolled in the BEAM study. Six hundred and twenty-two (27.5%) were exposed <2 days, 821 (36.3%) 2 to <7 days, 401 (17.8%) 7 to <14 days, and 415 (18.4%) 14 days prior to delivery. The majority of women (n ¼ 1764, 78.1%) delivered following preterm premature rupture of membranes (defined as membrane ruptured for at least 72 hours prior to delivery, or preterm prelabor rupture of membranes was the primary reason for antepartum admission). The mean gestational age at delivery was 29.5 2.8 weeks (Table 1). Overall, 1274 neonates were diagnosed with RDS (56.4%) and 616
279 280 281 Flow diagram of study cohort 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 Battarbee et al. Optimal timing of antenatal corticosteroid administration. AJOG MFM 2019. 300 301 302 303 (27.3%) with major neonatal delivery were included as possible 304 morbidity (Table 2). Neonates who confounding factors. Marital status, ½T2 305 were exposed to antenatal corticoste- maternal education level, and study 306 roids at 2 to <7 days before delivery enrollment were not included, as they 307 were the least likely to develop RDS were correlated with other variables 308 (51.3%), compared to 62.7% of those considered above (r 0.25 and P < 309 exposed <2 days before delivery, .001 for all). In the final regression 310 55.9% of those exposed 7 to <14 days model evaluating factors associated 311 before delivery, and 57.6% of those with RDS, we found an increased odds 312 exposed 14 days before delivery (P < of RDS in those with steroid receipt 313 .001). There was also a statistically <2 days before delivery (adjusted odds 314 significant difference in severe ratio [aOR], 2.07; 95% CI, 1.61e2.66), 315 neonatal morbidity between groups 7 to <14 days before delivery (aOR, 316 (Table 2). Of the 1578 neonates in this 1.40; 95% CI, 1.07e1.83), and 14 317 cohort whose mothers were originally days before delivery (aOR, 2.34; 95% 318 enrolled in the BEAM study, 1511 CI, 1.78e3.07), compared to receipt 2 319 (95.7%) neonates had outcome data to <7 days before delivery (Table 3). ½T3 320 available at age 2, and overall 153 Furthermore, in the final regression 321 (10.1%) had the adverse childhood models evaluating factors associated 322 outcome (moderate or severe cerebral with severe neonatal morbidity, we 323 palsy or death). The frequency of found increased odds of severe 324 childhood morbidity was similar neonatal morbidity when antenatal 325 among those exposed to antenatal corticosteroids were received 14 days 326 corticosteroids <2 days, 2 to <7 days, before delivery (aOR, 1.57; 95% CI, 327 7 to <14 days, and 14 days before 1.12e2.19), compared to 2 to <7 days 328 delivery (P ¼ .57). before delivery (Table 4). Similarly, ½T4 329 In initial multivariable logistic antenatal corticosteroid receipt 14 330 regression models, nulliparity, magne- days before delivery was associated 331 sium, spontaneous preterm birth, with an increased odds of severe 332 gestational age at delivery, male childhood morbidity (aOR, 1.74; 95% 333 neonate, maternal age, black race, CI, 1.02e2.95), compared to 2 to <7 334 chorioamnionitis, and cesarean days before delivery (Table 5). There ½T5 FIGURE
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Original Research 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390
TABLE 1
Demographic and antenatal characteristics by timing of antenatal corticosteroid administration Timing of administration <2 days (n ¼ 622)
2 to <7 days (n ¼ 821)
Enrolled in Genomics and Proteomics Network for Preterm Birth Research study
352 (56.6)
174 (21.2)
Maternal age (years)
25.9 6.1
Nulliparous
298 (47.9)
7 to <14 days (n ¼ 401)
14 days (n ¼ 415)
P value
73 (18.2)
82 (19.8)
<.001
25.0 6.2
26.4 5.9
26.9 6.2
<.001
317 (38.6)
147 (36.7)
135 (32.5)
<.001
Black race
179 (28.8)
351 (42.8)
171 (42.6)
131 (31.6)
<.001
Less than a high school level education
408 (65.8)
522 (64.0)
281 (70.1)
300 (72.3)
.01
Married
312 (50.2)
372 (45.5)
194 (48.5)
229 (55.2)
.01
18 (2.9)
36 (4.4)
9 (2.2)
22 (5.3)
.06
356 (57.2)
670 (81.6)
363 (90.5)
375 (90.4)
<.001
216 (169, 271)
435 (329, 636)
<.001
Gestational or pregestational diabetes mellitus Preterm prelabor rupture of membranes Duration of ruptured membranes (hours)
3 (0.1, 19)
79 (33, 122)
56 (9.0)
140 (17.1)
88 (22.0)
67 (16.1)
<.001
Tobacco use during pregnancy
135 (21.7)
232 (28.3)
100 (24.9)
110 (26.5)
.04
Gestational age at delivery (weeks)
29.7 2.9
29.0 2.7
29.2 2.7
30.9 2.3
<.001
Cesarean delivery
167 (26.9)
271 (33.0)
142 (35.4)
162 (39.0)
<.001
Chorioamnionitis suspected prior to delivery
Data presented as n (%) or mean standard deviation or median (25%, 75% interquartile range). Battarbee et al. Optimal timing of antenatal corticosteroid administration. AJOG MFM 2019.
was no significant association between antenatal corticosteroid administration < 2 days before delivery or 7 to <14 days before delivery and severe neonatal or childhood morbidity, compared to antenatal corticosteroid administration 2 to <7 days before delivery. In all models, male sex and delivery gestational age were important factors associated with RDS and the composite severe neonatal and childhood morbidities (Tables 3, 4, and 5).
Comment Principal findings In this retrospective cohort study of over 2000 preterm neonates, we found that neonates who were exposed to antenatal corticosteroids 2 to <7 days prior to delivery had the lowest odds of RDS compared to both shorter and longer intervals from steroid receipt to delivery. In addition, we found an increased odds of severe neonatal morbidity and severe childhood morbidity among neonates who were exposed to antenatal corticosteroids 14 days before delivery,
compared to 2 to <7 days before delivery. These results suggest that the ideal timing of antenatal corticosteroids to optimize neonatal short- and long-term outcomes among babies born <34 weeks is 2 to <7 days prior to delivery.
Results of the study in the context of other observations Our findings confirm and extend those demonstrated in previous retrospective cohort studies.11e13 Compared to infants born at 26e34 weeks’ gestation to women who had received antenatal corticosteroids more than 7 days prior to delivery, Peaceman et al11 demonstrated a lower incidence of need for respiratory support among infants born to women who had received antenatal corticosteroids within 7 days of delivery. There was no significant difference, however, in the association between timing of antenatal corticosteroids and necrotizing enterocolitis, intraventricular hemorrhage, or mortality.11 One explanation for their negative finding was insufficient
power, as a previous meta-analysis had demonstrated increased risk of perinatal mortality when corticosteroids were administered more than 7 days before delivery.7 In a retrospective cohort study of 707 infants born at 22e26 weeks’ gestation, the risk of mortality was doubled when the interval from antenatal corticosteroid exposure to delivery was either too short (<24 hours) or too long (>7 days), compared to optimal timing (24 hours to 7 days).14 In contrast to our findings, however, these authors found no association between severe neonatal morbidity and timing of antenatal corticosteroids. It is likely that our study found differences in neonatal morbidity based on duration of antenatal corticosteroid exposure as we evaluated neonates born up to 34 weeks’ gestation, and also included mortality in our composite, as a competing outcome. In vitro and in vivo animal studies provide biologic plausibility as to why the effect of antenatal corticosteroids appears to be transient. In an in vitro
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391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446
Original Research 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484Q2 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502
TABLE 2
Neonatal outcomes by timing of antenatal corticosteroid administration Timing of administration
Male neonate
<2 days (n ¼ 622)
2 to <7 days (n ¼ 821)
7 to <14 days (n ¼ 401)
14 days (n ¼ 415)
P value
331 (53.2)
434 (52.9)
214 (53.4)
248 (59.8)
.11
Birthweight (mean grams, SD)
1486 550
1296 475
1310 458
1585 469
<.001
Respiratory distress syndrome
390 (62.7)
421 (51.3)
224 (55.9)
239 (57.6)
<.001
146 (23.5)
253 (30.8)
124 (30.9)
93 (22.4)
.001
Neonatal death
41 (6.6)
59 (7.2)
31 (7.7)
21 (5.1)
.43
Neonatal severe morbidity
a
Intraventricular hemorrhage grade III/IV
42 (6.8)
20 (2.4)
11 (2.7)
11 (2.7)
<.001
Periventricular leukomalacia
14 (2.2)
17 (2.1)
8 (2.0)
9 (2.2)
.99
Bronchopulmonary dysplasia
67 (10.8)
146 (17.9)
67 (16.8)
41 (10.0)
<.001
Necrotizing enterocolitis
31 (5.0)
80 (9.8)
45 (11.3)
33 (8.0)
.001
33/316 (10.4)
26/323 (8.1)
.570
b
Childhood morbidity
65/610 (10.7)
29/262 (11.1)
Data presented as n (%) or mean standard deviation. a
Composite included death, severe intraventricular hemorrhage grade III or IV, periventricular leukomalacia, bronchopulmonary dysplasia, or necrotizing enterocolitis; b Composite included death or moderate-to-severe cerebral palsy at age 2 among the 1511 women included in this analysis who were originally enrolled in the BEAM study and had longer-term follow-up data available. Battarbee et al. Optimal timing of antenatal corticosteroid administration. AJOG MFM 2019.
study of human lung cells, corticosteroids were found to increase transcription of surfactant genes with maximum stimulation at 48 hours and return to near control levels by day 8.15 Similarly, an in vivo study of lung function in preterm lambs demonstrated that although the
hormonal effects of corticosteroid treatment were transient, some functional responses persisted over the 2to 7-day interval to delivery.16,17 Although many of these studies have been limited by the stability of the cultured fetal lung beyond 7 days, our results and the previously published
clinical studies support the transient nature of biochemical changes after corticosteroid administration.
Strengths and weaknesses Our study has several strengths. These data are from previous prospective studies of preterm birth with rigorous
TABLE 3
Multivariable regression of respiratory distress syndrome by timing of antenatal corticosteroid administration Respiratory distress syndrome adjusted odds ratio (95% confidence interval)
P value
2.07 (1.61-2.66)
<.001
Timing of antenatal corticosteroid administration <2 days before delivery 2 to <7 days before delivery 7 to <14 days before delivery 14 days before delivery
1.0 (referent)
-
1.40 (1.07e1.83)
.015
2.34 (1.78e3.07)
<.001
Gestational age at delivery, per completed week
0.68 (0.65e0.71)
<.001
Black race
0.59 (0.48e0.72)
<.001
Male
1.35 (1.12e1.63)
<.01
Preterm prelabor rupture of membranes
0.71 (0.56e0.91)
<.01
Delivered by cesarean section
1.24 (1.02e1.52)
.04
Received magnesium sulfate
0.85 (0.71e1.03)
.09
Other factors considered in initial models but removed owing to P > .20 include nulliparity and maternal smoking during pregnancy. Battarbee et al. Optimal timing of antenatal corticosteroid administration. AJOG MFM 2019.
MONTH 2019 AJOG MFM FLA 5.6.0 DTD AJOGMF100077_proof 27 December 2019 2:23 pm ce
5
503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558
Original Research 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614
TABLE 4
Multivariable regression of severe neonatal morbidity by timing of antenatal corticosteroid administration Severe neonatal morbiditya adjusted odds ratio (95% confidence interval)
P value
Timing of antenatal corticosteroid administration <2 days before delivery
0.80 (0.59e1.07)
2 to <7 days before delivery
.135
1.0 (referent)
-
7 to <14 days before delivery
1.15 (0.83e1.58)
.404
14 days before delivery
1.57 (1.12e2.19)
.009
Gestational age at delivery, per completed week
0.55 (0.53e0.58)
<.001
Male sex
1.31 (1.04e1.65)
.022
Nulliparous mother
1.18 (0.93e1.49)
.185
Delivery by cesarean section
1.23 (0.97e1.56)
.092
Other factors considered in initial models but removed owing to P > .20 include preterm prelabor rupture of membranes, receipt of magnesium sulfate prior to delivery (for any indication), maternal smoking during pregnancy, black race, and suspected clinical chorioamnionitis. a
Composite included death, severe intraventricular hemorrhage grade III or IV, periventricular leukomalacia, bronchopulmonary dysplasia, or necrotizing enterocolitis. Battarbee et al. Optimal timing of antenatal corticosteroid administration. AJOG MFM 2019.
data collection by trained research staff. Our study offers a larger sample size compared to previous retrospective cohort studies, and thus permitted detection of differences in rare adverse neonatal outcomes and also extension to the early childhood period for individuals enrolled in the BEAM study. The findings of our study, however, must be interpreted within the context of the study design. Although we adjusted for many potential confounding factors in multivariable logistic regression, including gestational age, race and ethnicity, neonatal sex, preterm
premature rupture of membranes, and others, we were unable to adjust for parent study enrollment given the high degree of correlation with preterm premature rupture of membranes. The combination of data from 2 different studies, each with distinct aims and protocols and each conducted over different years, may have also unintentionally affected our results. We are not able to estimate the relative benefit or risk compared to women who did not receive corticosteroids in this retrospective cohort study; and given that antenatal corticosteroid administration is
currently considered to be the standard of care for women with anticipated preterm birth, it is unlikely that this question could be answered in a randomized clinical trial. Additionally, as we only included women who delivered at less than 34 weeks and the majority of women had preterm prelabor rupture of membranes, our results may not be generalizable to all populations.
Conclusions and clinical implications Nonetheless, our results demonstrate Q3 that the optimal timing of antenatal
TABLE 5
Multivariable regression of severe childhood morbidity by timing of antenatal corticosteroid administration (note: limited to participants in BEAM study) Severe childhood morbiditya adjusted odds ratio (95% confidence interval)
P value
Timing of antenatal corticosteroid administration <2 days before delivery
1.14 (0.70e1.89)
2 to <7 days before delivery
1.0 (referent)
.595 -
7 to <14 days before delivery
1.10 (0.69e1.77)
.690
14 days before delivery
1.74 (1.02e2.95)
.042
Gestational age at delivery, per completed week
0.62 (0.57e0.67)
<.001
Male sex
1.74 (1.21e2.52)
.003
Other factors considered in initial models but removed owing to P > .20 include preterm prelabor rupture of membranes, receipt of magnesium sulfate prior to delivery (for any indication), maternal smoking during pregnancy, nulliparity, black race, and suspected clinical chorioamnionitis. a
Severe childhood morbidity included death or moderate-to-severe cerebral palsy at age 2. Battarbee et al. Optimal timing of antenatal corticosteroid administration. AJOG MFM 2019.
6 AJOG MFM MONTH 2019 FLA 5.6.0 DTD AJOGMF100077_proof 27 December 2019 2:23 pm ce
615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670
Original Research 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726
corticosteroid administration is 2 to <7 days before preterm delivery between 23 and 34 weeks’ gestation. Unfortunately, however, as clinicians we acknowledge that it remains challenging to accurately predict the timing of preterm delivery even among those at highest risk.18 Future studies are still needed to better understand when preterm delivery is imminent in order to reduce unnecessary exposure to antenatal corticosteroids while optimizing neonatal outcomes. n References 1. Martin JA, Hamilton BE, Osterman MJK, Driscoll AK, Mathews TJ. Births: final data for 2015. Natl Vital Stat Rep 2017;66(1):1. Available at: http://www.ncbi.nlm.nih.gov/pubmed/ 28135188. Accessed November 13, 2018. 2. Crowley PA. Antenatal corticosteroid therapy: a meta-analysis of the randomized trials, 1972 to 1994. Am J Obstet Gynecol 1995;173(1): 322–35. https://doi.org/10.1016/00029378(95)90222-8. 3. Roberts D, Brown J, Medley N, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2017;3: CD004454. https://doi.org/10.1002/ 14651858.CD004454.pub3. 4. Committee Opinion No. 713: antenatal corticosteroid therapy for fetal maturation. Obstet Gynecol 2017;130(2):e102–9. https://doi.org/ 10.1097/AOG.0000000000002237. 5. Sehdev HM, Abbasi S, Robertson P, et al. The effects of the time interval from antenatal corticosteroid exposure to delivery on neonatal outcome of very low birth weight infants. Am J Obstet Gynecol 2004;191(4):1409–13. https:// doi.org/10.1016/j.ajog.2004.06.055. 6. Vermillion S, Soper D, Newman R. Is betamethasone effective longer than 7 days after treatment? Obstet Gynecol 2001;94(4): 491–3. 7. McLaughlin KJ, Crowther CA, Walker N, Harding JE. Effects of a single course of corticosteroids given more than 7 days before birth: a systematic review. Aust N Z J Obstet Gynaecol 2003;43(2):101–6. Available at: http://www.ncbi.nlm.nih.gov/pubmed/ 14712961. Accessed June 12, 2019. 8. Esplin MS, Merrell K, Goldenberg R, et al. Proteomic identification of serum peptides
predicting subsequent spontaneous preterm birth. Am J Obstet Gynecol 2011;204(5):391. e1–8. https://doi.org/10.1016/j.ajog.2010.09. 021. 9. Rouse DJ, Hirtz DG, Thom E, et al. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med 2008;359(9):895–905. https://doi. org/10.1056/NEJMoa0801187. 10. Committee Opinion No 700: methods for estimating the due date. Obstet Gynecol 2017;129(5):e150–4. https://doi.org/10.1097/ AOG.0000000000002046. 11. Peaceman AM, Bajaj K, Kumar P, Grobman WA. The interval between a single course of antenatal steroids and delivery and its association with neonatal outcomes. Am J Obstet Gynecol 2005;193(3):1165–9. https:// doi.org/10.1016/j.ajog.2005.06.050. 12. Ring AM, Garland JS, Stafeil BR, Carr MH, Peckman GS, Pircon RA. The effect of a prolonged time interval between antenatal corticosteroid administration and delivery on outcomes in preterm neonates: a cohort study. Am J Obstet Gynecol 2007;196(5):457.e1–6. https://doi.org/10. 1016/j.ajog.2006.12.018. 13. Wilms FF, Vis JY, Pattinaja DAPM, et al. Relationship between the time interval from antenatal corticosteroid administration until preterm birth and the occurrence of respiratory morbidity. Am J Obstet Gynecol 2011;205(1): 49.e1–7. https://doi.org/10.1016/j.ajog.2011. 03.035. 14. Norberg H, Kowalski J, Marsál K, Norman M. Timing of antenatal corticosteroid administration and survival in extremely preterm infants: a national population-based cohort study. BJOG 2017;124(10):1567–74. https:// doi.org/10.1111/1471-0528.14545. 15. Vidaeff AC, Ramin SM, Gilstrap LC, Alcorn JL. In vitro quantification of dexamethasone-induced surfactant protein B expression in human lung cells. J Matern Fetal Neonatal Med 2004;15(3):155–9. https://doi. org/10.1080/14767050410001668248. 16. Ikegami M, Polk DH, Jobe AH, et al. Effect of interval from fetal corticosteriod treatment to delivery on postnatal lung function of preterm lambs. J Appl Physiol 1996;80(2):591–7. https://doi.org/10.1152/jappl.1996.80.2.591. 17. Ikegami M, Polk D, Jobe A. Minimum interval from fetal betamethasone treatment to postnatal lung responses in preterm lambs. Am J Obstet Gynecol 1996;174(5):1408–13. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9065104. Accessed June 12, 2019.
18. Adams TM, Kinzler WL, Chavez MR, Vintzileos AM. The timing of administration of antenatal corticosteroids in women with indicated preterm birth. Am J Obstet Gynecol 2015;212(5):645.e1–4. https://doi.org/10. 1016/j.ajog.2014.11.021.
Author and article information From the Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina (Drs Battarbee and Manuck); Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of Utah School of Medicine, Salt Lake City, Utah (Drs Ros, Esplin, Varner, and Manuck); Intermountain Healthcare Department of Maternal Fetal Medicine, Salt Lake City, Utah (Drs Ros, Esplin, and Varner); Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of South Florida, Tampa, Florida (Dr Ros); Center for Women’s Reproductive Health, University of Alabama at Birmingham, Birmingham, Alabama (Drs Biggio and Andrews); Department of Women’s Health, Dell Medical School, University of Texas at Austin, Austin, Texas (Drs Bukowski and Saade); Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania (Dr Parry); Collaborative Center for Statistics in Science, Yale University School of Public Health, New Haven, Connecticut (Drs Zhang and Huang); Magee-Womens Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (Dr Sadovsky), and Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Yale University, New Haven, Connecticut (Dr Reddy). Received Sept. 27, 2019; revised Nov. 26, 2019; accepted Dec. 2, 2019. M.S.E. holds stock in Sera Prognostics, a private company that was established to create a commercial test to predict preterm birth and other obstetric complications. R.B. is an advisor and holds stock in Savran Technologies Inc, a company that developed technology to isolate ultra-rare cells from blood for noninvasive diagnostics. The remaining authors report no conflict of interest. Presented in part at the Society for MaternaleFetal Medicine’s 36th Annual Meeting (Atlanta, GA), February 4, 2016, as a poster presentation (final abstract ID #628). This study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Genomic and Proteomic Network for Preterm Birth Research (U01-HD-050062; U01-HD050078; U01-HD-050080; U01-HD-050088; U01-HD050094) (all authors). This study was also funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development 5K23HD067224 (T.A.M.) and R01-MD011609 (T.A.M.). Correspondence: Ashley N. Battarbee, MD. ashley_ [email protected]
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