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Implementation of an antenatal late-preterm corticosteroid protocol at a high-volume tertiary care center
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
Q1 Q7 Q2
Implementation of an antenatal late-preterm corticosteroid protocol at a high-volume tertiary care center Nevert Badreldin, MD; Grace G. Willert, BS; Andrea A. Henricks, BS, MD; Alan Peaceman, MD; Leslie A. Caldarelli; Lynn M. Yee, MD, MPH
BACKGROUND: Since publication of the sentinel antenatal late-
preterm steroids clinical trial, the use of antenatal steroids has become a routine aspect of the management of pregnancies at risk for late-preterm delivery. However, in practice, the administration of antenatal corticosteroids in the late-preterm period is widely varied across provider and institution, and the process of implementation of this new practice as well as outcomes associated with implementation are not well understood. OBJECTIVE: The objective was to evaluate institutional adherence to an antenatal late-preterm corticosteroid protocol and to assess neonatal outcomes associated with its introduction. STUDY DESIGN: This is a retrospective cohort study of all women with singleton pregnancies admitted between 34 and 36 5/7 weeks’ who presented in the year before (“preprotocol”: November 2012 to October 2013) and after implementation (“postprotocol”: April 2016 to March 2017). The protocol recommends corticosteroid administration to women 34 to 36 5/7 weeks’ gestation at risk for preterm birth who have not received prior corticosteroids. Women with fetal anomalies or pregestational or gestational diabetes were excluded from analysis. The frequency with which eligible women received corticosteroids and ineligible women were appropriately excluded (adherence) was calculated on a monthly basis. Neonatal outcomes of interest were hypoglycemia, receipt of dextrose, birthweight, 5-minute Apgar less than 7, receipt of surfactant, respiratory distress syndrome, transient tachypnea of the newborn, neonatal intensive care unit length of stay, intraventricular hemorrhage, necrotizing enterocolitis, culture-positive sepsis, bronchopulmonary dysplasia, and death. Bivariable and multivariable analyses were used to
T
he majority of preterm neonates are born in the late-preterm period (>34 weeks), with infants born between 34 and 37 weeks comprising 8% of all deliveries nationwide.1 These neonates are at increased risk for respiratory morbidity compared to neonates born at term.2 Although administration of antenatal corticosteroids has long been a mainstay of obstetrical practice for pregnancies at risk for preterm birth
Q4
Cite this article as: Badreldin N, Willert GG, Henricks AA, et al. Implementation of an antenatal late-preterm corticosteroid protocol at a high-volume tertiary care center. 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.2019.100076
compare neonatal outcomes between (1) all women in the postprotocol cohort to those in the preprotocol cohort and (2) only women who received adherent care in the postprotocol cohort to all women in the preprotocol cohort. RESULTS: A total of 452 women were included in the preprotocol cohort and 451 in the postprotocol cohort. The majority of the postprotocol women (n ¼ 366, 81.2%) received adherent care. Women in both cohorts were similar, with the exception that women in the postprotocol cohort were more likely to be nulliparous (P ¼ .013). Compared to the preprotocol period, neonates of women in the postprotocol period had significantly higher odds of hypoglycemia <50 mg/dL in the first 24 hours of life (adjusted odds ratio, 1.37; 95% confidence interval, 1.05e1.80), without improvements in respiratory outcomes. Results were similar when restricting the analysis to only women in the postprotocol cohort who received adherent care (glucose <50 mg/dL: adjusted odds ratio, 1.52; 95% confidence interval, 1.14e2.03). No differences in composite respiratory morbidity or other neonatal outcomes were observed. CONCLUSION: Uptake of a new institutional protocol for antenatal late-preterm corticosteroids was rapid. Compared with historic controls, neonates exposed to antenatal late-preterm corticosteroid experienced increased odds of hypoglycemia, without significant improvements in respiratory morbidities. Key words: antenatal late-preterm steroids, corticosteroids, late-preterm
delivery, neonatal hypoglycemia, neonatal respiratory outcomes, protocol implementation
before 34 weeks, in 2016 a sentinel multisite, placebo-controlled randomized trial demonstrated the benefits of use of betamethasone for women with singleton gestations at risk for latepreterm birth.3 The Antenatal Late Preterm Steroids (ALPS) trial showed a significant reduction in neonatal respiratory complications with administration of betamethasone for women at high risk of preterm delivery between 34 and 36 6/7 weeks of gestation. Since publication of this clinical trial, the use of antenatal steroids in this population has become a routine aspect of the management of pregnancies at risk for late-preterm delivery.4 In practice, the administration of antenatal corticosteroids in the latepreterm period varies widely across
provider and institution, drawing into question if findings from a randomized trial are demonstrable in clinical practice.5,6 Furthermore, in centers where protocols have been implemented, uptake of the protocol and associated outcomes remain poorly understood. Therefore, the objectives of this study were (1) to evaluate implementation of an institutional antenatal late-preterm corticosteroids protocol and (2) to investigate neonatal outcomes associated with implementation.
Materials and Methods This is a retrospective cohort study of all women with singleton gestations admitted to Northwestern Memorial Hospital between 34 weeks 0 days and 36 weeks 5 days of gestation. MONTH 2019 AJOG MFM
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Original Research AJOG MFM at a Glance Why was this study conducted? This study was conducted to evaluate institutional adherence to an antenatal latepreterm corticosteroid protocol and to assess neonatal outcomes associated with its introduction. Key findings Neonates exposed to antenatal late-preterm corticosteroid experienced increased odds of hypoglycemia, without significant improvements in respiratory morbidities. What does this add to what is known? Unlike the randomized clinical trial, we did not identify improvement in neonatal respiratory outcomes. We did, however, identify an increase in the odds of neonatal hypoglycemia in neonates born in the postprotocol period.
Northwestern Memorial Hospital is a large tertiary hospital with approximately 11,500 births per year. The hospital is a member of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network and participated in recruitment for the ALPS trial during the trial period (October 2010 to November 2012, November 2013 to February 2015). For this analysis, women were eligible for inclusion if they presented to care during the
1-year gap in recruitment for the ALPS trial (preprotocol: November 1, 2012, to October 1, 2013) or the 1 year after (postprotocol: April 1, 2016, to March 30, 2017) implementation of the institutional antenatal late-preterm corticosteroids protocol (described below). The preprotocol period represents a period of time during which women did not receive antenatal latepreterm corticosteroids. Women were excluded if they received antenatal corticosteroids as an outpatient or received a prior course of antenatal
FIGURE
Adherence to antenatal late-preterm corticosteroid protocol web 4C=FPO
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
Badreldin et al. Antenatal late-preterm corticosteroid protocol. AJOG MFM 2019.
corticosteroids. Although our institutional protocol allows for administration of corticosteroids to women with a multiple gestation, pregestational or gestational diabetes, or major fetal anomalies, these women were excluded from this analysis in order to better mirror the ALPS trial criteria. All data were abstracted from the electronic medical record used for clinical care and thus the data are fully inclusive of all eligible patients; data were reviewed by the research team for accuracy. The institution’s protocol was implemented in March 2016 following publication of the ALPS study. Mirroring the trial protocol, our institutional protocol recommends that women who present between 34 weeks 0 days and 36 weeks 5 days receive betamethasone if delivery is planned or if there is substantial risk for delivery prior to 37 weeks 0 days in women who have not previously received a course of corticosteroids. Indications for corticosteroids included signs or symptoms demonstrating risk for late-preterm birth (eg, preterm labor, premature rupture of membranes, new-onset hypertensive disorder) or delivery scheduled prior to 37 weeks (eg, growth restriction, nonreassuring fetal status, abnormal placentation). Health care provider types at Northwestern Memorial Hospital include maternalefetal medicine physicians, general obstetrics and gynecology physicians, and certified nurse-midwives. Women who require evaluation present to a hospital-based obstetrical triage unit and are evaluated by institutionally hired nurses, certified nurse-midwives, and attending physicians. Following evaluation, an antenatal management plan is formed in conjunction with the patient’s primary obstetrical provider. Women may be admitted to the inpatient antepartum service, admitted to labor and delivery, observed in triage, or discharged to home, depending on the clinical circumstances. The institutional protocol was disseminated to clinicians using education sessions, including grand rounds, resident and fellow lectures, labor and delivery unit lectures,
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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 225Q5 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278
TABLE 1
Characteristics of women in the preprotocol cohort compared to all women the postprotocol period Maternal age, years
Preprotocol (n ¼ 452)
Postprotocol (n ¼ 451)
P value
31.9 5.3
32.2 5.1
.347
Race/ethnicity
.193
White/non-Hispanic
228 (50.4)
251 (55.7)
Black/non-Hispanic
43 (9.5)
50 (11.1)
Hispanic
86 (19.0)
62 (13.8)
Asian
33 (7.3)
34 (7.5)
62 (13.7)
54 (12.0)
Other BMI, kg/m
30.2 5.7
30.4 8.5
.638
Nulliparous
257 (54.7)
283 (62.8)
.013
15 (3.3)
20 (4.4)
.385
9 (2.0)
13 (2.9)
.385
130 (28.8)
142 (31.5)
.372
2
Chronic hypertension Preeclampsia Cesarean delivery Gestational age at admission, weeks
35.7 0.8
35.7 0.8
.710
Gestational age at delivery, weeks
36.1 1.2
36.1 1.2
.237
Female neonate
199 (44.0)
191 (42.35)
.611
Received betamethasone
304 (67.4)
Gestational age at betamethasone, weeks
35.6 0.8
Data presented as mean standard deviation and prevalence (%). BMI, body mass index. Badreldin et al. Antenatal late-preterm corticosteroid protocol. AJOG MFM 2019.
and e-mail reminders. Additionally, a member of the maternalefetal medicine division oversees the obstetrical units each day and these faculty provided inperson re-education and reminders throughout the first year of implementation. Maternal characteristics of interest included age, race and ethnicity, parity, and body mass index. Pregnancy characteristics such as gestational age at admission and delivery, mode of delivery, fetal sex, and existence of hypertensive disorders of pregnancy were abstracted from inpatient records. Neonatal outcomes of interest included hypoglycemia, receipt of dextrose, birthweight, 5-minute Apgar less than 7, receipt of surfactant, respiratory distress syndrome, transient tachypnea of the newborn, neonatal intensive care unit length of stay, intraventricular hemorrhage, necrotizing enterocolitis, culturepositive sepsis, bronchopulmonary dysplasia, and death. Neonatal
hypoglycemia was defined as a glucose of less than 40 mg/dL in the first 24 hours; additionally, we also investigated a threshold of less than 50 mg/dL. Two values of glucose were used as a proxy for hypoglycemia, as controversy exists as to the precise numerical threshold at which to intervene.7 At this institution, asymptomatic late-preterm neonates with glucose values of <40e50 mg/dL (depending on age in hours) are treated with an oral feeding and glucose values are repeated in 1 hour. Neonates whose glucose values do not improve with oral feeding are given dextrose. Respiratory distress syndrome diagnosis was made based on chest radiograph findings of reticulogranular appearance and need for supplemental oxygen. A diagnosis of transient tachypnea of the newborn was made by chest radiograph finding of perihilar linear streaking. Those neonates requiring oxygen, but with normal chest radiograph findings were individually reviewed for a diagnosis by a
neonatologist. As respiratory distress syndrome and transient tachypnea are rare outcomes in the late-preterm period, we also considered a respiratory composite outcome that included respiratory distress syndrome, transient tachypnea, or receipt of surfactant. First, to evaluate implementation of the protocol, the frequency of adherence to the protocol in the postprotocol cohort was calculated on a monthly basis and plotted on a run chart. Each data point represents the proportion of women in a given month who received care adherent to the protocol out of all women meeting inclusion criteria in that month. Adherent care was defined as appropriately receiving corticosteroids or not receiving corticosteroids per the new protocol. Next, to evaluate outcomes associated with implementation of the protocol, we first compared maternal baseline characteristics and neonatal outcomes in the preprotocol period to MONTH 2019 AJOG MFM
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279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334
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
391 392 393 Neonatal outcomes among neonates in the preprotocol cohort compared to those in the postprotocol cohort 394 Unadjusted regression Adjusted regression 395 Preprotocol Postprotocol a (n ¼ 452) (n ¼ 451) 396 OR/b 95% CI aOR/ab 95% CI 397 Hypoglycemia <40 mg/dL 113 (25.0) 122 (27.1) 1.11 0.83 to 1.50 1.14 0.84 to 1.53 398 Hypoglycemia <50 mg/dL 233 (51.6) 264 (58.5) 1.33 1.02 to 1.73 1.37 1.05 to 1.80 399 Dextrose administration 58 (12.8) 66 (14.6) 1.16 0.80 to 1.70 1.25 0.85 to 1.86 400 401 Birthweight, grams 2672 485 2740 473 0.07 0.004 to 0.13 0.06 0.01 to 0.11 402 5-min Apgar < 7 16 (3.5) 12 (2.7) 0.74 0.35 to 1.59 0.80 0.37 to 1.71 403 Surfactant 16 (3.5) 10 (2.2) 0.62 0.28 to 1.38 0.66 0.29 to 1.48 404 Respiratory distress 21 (4.7) 24 (5.32) 1.15 0.63 to 2.10 1.24 0.67 to 2.29 405 406 Transient tachypnea 38 (8.4) 39 (8.7) 1.03 0.65 to 1.65 1.11 0.69 to 1.78 407 Respiratory compositeb 60 (13.3) 63 (14.0) 1.06 0.73 to 1.55 1.15 0.78 to 1.71 408 NICU length of stay, days 4.0 7.3 4.0 6.6 0.02 -0.92 to 0.97 -0.07 -0.94 to 0.81 409 Intraventricular hemorrhage 2 (0.4) 1 (0.2) 0.50 0.05 to 5.53 0.52 0.05 to 5.83 410 411 Necrotizing enterocolitis 1 (0.2) 1 (0.2) 1.00 0.06 to 16.07 0.93 0.06 to 15.23 412 Culture positive sepsis 2 (0.4) 4 (0.9) 2.01 0.37 to 11.05 1.85 0.33 to 10.24 413 Bronchopulmonary 0 (0) 0 (0) 414 dysplasia 415 Death 0 (0) 0 (0) 416 417 Data presented as mean standard deviation and prevalence (%). 418 ab, adjusted beta coefficient; aOR, adjusted odds ratio; b, beta coefficient; CI, confidence interval; NICU, neonatal intensive care unit; OR, odds ratio. a 419 Logistic and linear regressions adjusting for gestational age at delivery and nulliparity; preprotocol cohort as referent.; b Respiratory composite ¼ surfactant, respiratory distress, transient tachypnea. 420 Badreldin et al. Antenatal late-preterm corticosteroid protocol. AJOG MFM 2019. 421 422 423 424 all of those in the postprotocol period. significance in the bivariable models, demonstrating overall rapid uptake of 425 Second, because women who were given the importance of association of the new practice. The majority of the 426 eligible but did not receive cortico- gestational age with neonatal out- postprotocol women (n ¼ 366, 81.2%) 427 steroids may differ from the total comes. A P value of <.05 was used to received care that was adherent with the 428 cohort in unmeasured ways, we then define statistical significance and all protocol. 429 performed a “per-protocol” analysis, tests were 2-tailed. Statistical analyses Women in the preprotocol and post430 comparing maternal baseline charac- were performed with Stata v. 15 (Sta- protocol cohorts were similar with re431 teristics and neonatal outcomes for all taCorp, College Station, Texas). This gard to age, race and ethnicity, body 432 neonates in the preprotocol period study was approved by the Institu- mass index, rates of hypertensive disor(none of whom had received late- tional Review Board at Northwestern ders, and mode of delivery (Table 1). The ½T1 433 434 preterm corticosteroids) with only University. gestational age at admission (35.7 vs 35.7 435 those neonates in the postprotocol weeks; P ¼ .710) and gestational age at 436 period who received care adherent Results delivery (36.1 vs 36.1 weeks; P ¼ .237) 437 with the new protocol. c2, Wilcoxon A total of 903 women met inclusion were similar between the 2 cohorts. 438 rank sum, and t tests were performed, criteria and were included in analysis. Women in the postprotocol period were, 439 as appropriate. Multivariable logistic Of these, 452 (50.1%) were cared for however, significantly more likely to be 440 and linear regression models were before and 451 (49.9%) were cared for nulliparous (54.7% vs 62.8%; P ¼ .013). 441 constructed adjusting for gestational after implementation of the protocol. In the postprotocol cohort, women who 442 age and those maternal and pregnancy Adherence to the new protocol changed received corticosteroids received them at 443 factors that were significant on over the first year after implementation. a mean gestational age of 35.6 weeks ( bivariable models. An a priori decision The Figure illustrates the monthly 0.8 weeks). ½F1 444 445 In unadjusted analysis comparing was made to include gestational age at adherence rates to the late-preterm 446 birth in the models regardless of antenatal corticosteroid protocol, outcomes of neonates in the TABLE 2
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Original Research 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 ½T2 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502
503 504 505 Characteristics of women in the preprotocol cohort compared to those of women in the postprotocol period who 506 received adherent care 507 Preprotocol (n ¼ 452) Postprotocol (n ¼ 366) P value 508 Maternal age, years 31.9 5.3 32.3 5.0 .264 509 510 Race/ethnicity .079 511 White/non-Hispanic 228 (50.4) 207 (56.6) 512 Black/non-Hispanic 43 (9.5) 40 (10.9) 513 Hispanic 86 (19.0) 47 (12.8) 514 515 Asian 33 (7.3) 32 (8.7) 516 Other 62 (13.7) 40 (10.9) 517 BMI, kg/m2 30.2 5.7 30.4 9.0 .569 518 Nulliparous 247 (54.7) 233 (63.7) .009 519 520 Chronic hypertension 15 (3.3) 16 (4.4) .433 521 Preeclampsia 9 (2.0) 9 (2.5) .650 522 Cesarean delivery 130 (28.8) 122 (33.3) .159 523 524 Gestational age at admission, weeks 35.7 0.8 35.7 0.8 .489 525 Gestational age at delivery, weeks 36.1 1.2 35.9 1.0 .162 526 Female neonate 199 (44.0) 148 (40.4) .302 527 Received betamethasone 302 (82.5) 528 529 Gestational age at betamethasone, weeks 35.6 0.8 530 Data presented as mean standard deviation and prevalence (%). 531 BMI, body mass index. 532 Badreldin et al. Antenatal late-preterm corticosteroid protocol. AJOG MFM 2019. 533 534 535 Next, we evaluated women in the CI, 1.20 to 2.11), which persisted in preprotocol cohort to those of the 536 postprotocol cohort, the odds of hypo- preprotocol cohort compared to only multivariable analysis adjusting for 537 glycemia with a glucose value of <40 those women in the postprotocol cohort gestational age at delivery and nulliparity 538 mg/dL were not significantly different in who received care adherent to the pro- (adjusted OR, 1.52; 95% CI, 1.14 to 539 the postprotocol cohort (odds ratio tocol (Table 3). Women in the post- 2.03). The adherent postprotocol cohort ½T3 540 [OR], 1.11; 95% confidence interval protocol cohort who received adherent was not significantly more likely to 541 [CI], 0.83e1.50) compared to the pre- care were again significantly more likely require dextrose administration 542 protocol cohort (Table 2). However, to be nulliparous than those in the pre- (adjusted OR, 1.37; 95% CI, 0.92e2.05). 543 when hypoglycemia was defined as a protocol cohort (54.7% vs 63.7%; P ¼ Again, respiratory outcomes did not 544 glucose value of <50 mg/dL, neonates .009), but the 2 cohorts were otherwise differ between neonates in the pre545 of women in the postprotocol cohort similar in terms of age, race and protocol cohort and those in the post546 were significantly more likely to expe- ethnicity, body mass index, hypertensive protocol cohort who received adherent 547 rience hypoglycemia (OR, 1.33; 95% CI, disorders, mode of delivery, and gesta- care. 548 1.02e1.73). This finding remained sig- tional ages at admission and delivery. In 549 nificant (adjusted OR, 1.37; 95% CI, unadjusted analysis, the odds of hypo- Comment 550 1.05e1.80) in multivariable analysis glycemia of <40 mg/dL were not signif- Principal findings 551 after adjusting for gestational age at icantly different in the adherent Since the publication of a sentinel 552 delivery and nulliparity. Five-minute postprotocol cohort compared to the placebo-controlled randomized clin553 Apgar <7, birthweight, and neonatal preprotocol cohort (OR, 1.31; 95% CI, ical trial showing improved neonatal 554 intensive care unit length of stay did not 0.96e1.78) (Table 4). However, hypo- respiratory outcomes in women ½T4 555 differ between the 2 cohorts. Notably, glycemia of <50 mg/dL was again receiving antenatal corticosteroids in 556 neither dextrose administration nor significantly more likely in neonates of the late-preterm time period, many 557 respiratory outcomes were significantly women in the postprotocol cohort who providers and institutions have adop558 different between the 2 cohorts. received adherent care (OR, 1.59; 95% ted protocols for administration. At TABLE 3
MONTH 2019 AJOG MFM FLA 5.6.0 DTD AJOGMF100076_proof 27 December 2019 3:53 pm ce
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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
Neonatal outcomes among women in the preprotocol cohort compared to women in the postprotocol cohort who received adherent care Unadjusted regression
Adjusted regression
OR/b
aOR/aba
Preprotocol (n ¼ 452)
Postprotocol (n ¼ 366)
Hypoglycemia <40 mg/dL
113 (25.0)
111 (30.3)
1.31
0.96 to 1.78
1.29
0.94 to 1.76
Hypoglycemia <50 mg/dL
233 (51.6)
230 (62.8)
1.59
1.20 to 2.11
1.52
1.14 to 2.03
58 (12.8)
62 (16.9)
1.39
0.94 to 2.04
1.37
0.92 to 2.05
2672 485
Dextrose administration
95% CI
95% CI
2692 469
0.92
-0.05 to 0.09
0.05
-0.01 to 0.11
5-min Apgar < 7
16 (3.5)
9 (2.5)
0.69
0.30 to 1.57
0.69
0.30 to 1.60
Surfactant
16 (3.5)
10 (2.7)
0.77
0.34 to 1.71
0.77
0.34 to 1.74
Respiratory distress
21 (4.7)
22 (6.0)
1.31
0.70 to 2.46
1.31
0.70 to 2.46
Transient tachypnea
38 (8.4)
36 (9.8)
1.19
0.73 to 1.95
1.19
0.73 to 1.95
Respiratory compositeb
60 (13.3)
58 (15.8)
1.23
0.83 to 1.82
1.25
0.83 to 1.88
4.0 7.3
3.9 6.7
-0.08
-1.05 to 0.89
-0.28
-1.18 to 0.61
Intraventricular hemorrhage
2 (0.4)
1 (0.3)
0.50
0.05 to 5.53
0.52
0.05 to 5.83
Necrotizing enterocolitis
1 (0.2)
1 (0.3)
1.00
0.06 to 16.07
0.93
0.06 to 15.23
Culture-positive sepsis
2 (0.4)
4 (0.9)
2.01
0.37 to 11.05
1.85
0.33 to 10.24
Bronchopulmonary dysplasia
0 (0)
0 (0)
Death
0 (0)
0 (0)
Birthweight, grams
NICU length of stay, days
Data presented as mean standard deviation and prevalence (%). ab, adjusted beta coefficient; aOR, adjusted odds ratio; b, beta coefficient; CI, confidence interval; NICU, neonatal intensive care unit; OR, odds ratio. Logistic and linear regressions adjusting for gestational age at delivery and nulliparity; preprotocol cohort as referent.; b Respiratory composite ¼ surfactant, respiratory distress, transient tachypnea. Badreldin et al. Antenatal late-preterm corticosteroid protocol. AJOG MFM 2019. a
this high volume, tertiary care maternal center uptake of the new protocol was high in the first year after implementation. Our data suggest that neonates of women who received care after implementation of the new protocol had increased odds of hypoglycemia compared to neonates of women in the preprotocol cohort, but had no other significant differences in clinical outcomes.
Results Unlike the randomized clinical trial, we did not identify improvement in neonatal respiratory outcomes. However, our study was designed to assess implementation over a short period of time immediately after release of the new protocol, and thus was of limited size. As this analysis had inadequate power to identify differences in these infrequent
events, the lack of demonstrated reduction in respiratory outcomes should not be considered rationale for not giving antenatal late-preterm corticosteroids. We did, however, identify a statistically significant increase in the odds of neonatal hypoglycemia in neonates born in the postprotocol period, both as a whole and when limiting analysis to only neonates in the postprotocol period who received adherent care. These findings stress the importance of continued evaluation of protocols in real-world settings.
Clinical implications Neonatal hypoglycemia after maternal steroid administration requires careful consideration. Normal term neonatal glucose values in the first day of life are greater than 55e60 mg/dL.8 Although the precise definition of clinically
significant hypoglycemia is debated in the pediatric literature, neonatal hypoglycemia is recognized to be associated with adverse neonatal outcomes such as seizures and long-term neurologic deficits.9e11 The American Academy of Pediatrics and Pediatric Endocrine Society recommend that neonates in the late-preterm period maintain glucose values above 40e50 mg/dL in the first 1e2 days of life.12 Our study found that neonates of women born following implementation of an antenatal latepreterm corticosteroid protocol were more likely to experience hypoglycemia <50 mg/dL. Notably, although neonatal hypoglycemia was more common, invasive treatment with dextrose admission did not increase, suggesting that hypoglycemia improved with oral feeds in this population. However, literature suggests that even transient
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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
neonatal hypoglycemia may be associated with poorer academic achievement, and thus this finding warrants attention as we continue to improve care for women and neonates delivered in the late-preterm period.11,13
Research implications Further evaluation of implementation of this practice into diverse clinical settings, including beyond academic medical centers, will be beneficial. Additionally, further work on the application of this clinical practice to previously excluded populations, particularly women with diabetes, will be essential to understanding how best to provide care for all women at risk of delivering in the latepreterm period.
Strengths and limitations Major strengths of this study include the large study cohort, the institution-wide implementation of the new practice shortly after the ALPS trial was published, and the detailed medical data available from individual records. In addition, the diversity in provider types allows our study to evaluate implementation of this new protocol in a reallife setting. However, this study is subject to several limitations. Primarily, this is a retrospective analysis, which is susceptible to ascertainment bias and unmeasured confounding, and although we did not find a difference in measured factors between groups, it is possible that unmeasured factors aside from steroids may contribute to the findings of neonatal hypoglycemia. Importantly, this study was performed at an institution that participated in the ALPS trial, and thus providers are likely to be more familiar with the study protocol, more
comfortable with its implementation, and overall faster to uptake this practice. While this study site’s involvement in ALPS recruitment and its academic tertiary nature may limit generalizability regarding implementation, findings with regards to neonatal outcomes remain relevant. Finally, the relatively small sample size may not have the power to identify differences in the less common outcomes that were studied in the primary ALPS study.
Conclusion In conclusion, we noted high adherence to a new institutional protocol for antenatal late-preterm corticosteroids. Although neonatal respiratory outcomes in this real-life setting did not mirror those of the randomized clinical trial, there was an increase in the frequency of neonatal hypoglycemia less than 50 mg/ dL in those neonates in the postprotocol cohort. n
References 1. Creanga AA, Syverson C, Seed K, Callaghan WM. Pregnancy-related mortality in the United States, 2011-2013. Obstet Gynecol 2017;130:366–73. 2. Consortium on Safe Labor, Hibbard JU, Wilkins I, et al. Respiratory morbidity in late preterm births. JAMA 2010;304:419–25. 3. Gyamfi-Bannerman C, Thom EA, Blackwell SC, et al. Antenatal betamethasone for women at risk for late preterm delivery. N Engl J Med 2016;374:1311–20. 4. American College of Obstetricians and Gynecologists (ACOG). Practice Bulletin No. 171: Management of Preterm Labor. Obstet Gynecol 2016;128:e155–64. 5. Battarbee AN, Clapp MA, Boggess KA, et al. Practice variation in antenatal steroid administration for anticipated late preterm birth: a physician survey. Am J Perinatol 2019;36: 200–4.
6. ACOG Committee on Patient Safety and Quality Improvement. ACOG Committee Opinion No. 526: Standardization of practice to improve outcomes. Obstet Gynecol 2012;119: 1081–2. 7. Adamkin DH. Neonatal hypoglycemia. Semin Fetal Neonatal Med 2017;22:36–41. 8. Stanley CA, Rozance PJ, Thornton PS, et al. Re-evaluating “transitional neonatal hypoglycemia”: mechanism and implications for management. J Pediatr 2015;166: 1520–5 e1. 9. Cornblath M, Odell GB, Levin EY. Symptomatic neonatal hypoglycemia associated with toxemia of pregnancy. J Pediatr 1959;55: 545–62. 10. Qiao LX, Wang J, Yan JH, et al. Follow-up Q6 study of neurodevelopment in 2-year-old infants who had suffered from neonatal hypoglycemia. BMC Pediatr 2019;19:133. 11. Kaiser JR, Bai S, Gibson N, et al. Association between transient newborn hypoglycemia and fourth-grade achievement test proficiency: a population-based study. JAMA Pediatr 2015;169:913–21. 12. Adamkin DH, Committee on Fetus and Newborn. Postnatal glucose homeostasis in late-preterm and term infants. Pediatrics 2011;127:575–9. 13. Kerstjens JM, Bocca-Tjeertes IF, de Winter AF, Reijneveld SA, Bos AF. Neonatal morbidities and developmental delay in moderately preterm-born children. Pediatrics 2012;130:e265–72.
Author and article information From the Department of Obstetrics and Gynecology, Division of MaternaleFetal Medicine (Drs Badreldin, Henricks, Peaceman, and Yee, and Ms Willert), and Department of Pediatrics, Division of Neonatology (Ms Caldarelli), Northwestern University Feinberg School of Q3 Medicine, Chicago, Illinois. Received Aug. 26, 2019; revised Nov. 18, 2019; accepted Dec. 2, 2019. The authors report no conflicts of interest. L.M.Y. is supported by NICHD K12 HD050121-11. This paper was presented at the 2018 Society for MaternaleFetal Medicine Annual Meeting (Dallas, TX) as a poster presentation (Jan. 29 e Feb. 3, 2018). Correspondence: Nevert Badreldin, MD. nevert. [email protected]
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Q1 Q7 Q2
Implementation of an antenatal late-preterm corticosteroid protocol at a high-volume tertiary care center Nevert Badreldin, MD; Grace G. Willert, BS; Andrea A. Henricks, BS, MD; Alan Peaceman, MD; Leslie A. Caldarelli; Lynn M. Yee, MD, MPH
BACKGROUND: Since publication of the sentinel antenatal late-
preterm steroids clinical trial, the use of antenatal steroids has become a routine aspect of the management of pregnancies at risk for late-preterm delivery. However, in practice, the administration of antenatal corticosteroids in the late-preterm period is widely varied across provider and institution, and the process of implementation of this new practice as well as outcomes associated with implementation are not well understood. OBJECTIVE: The objective was to evaluate institutional adherence to an antenatal late-preterm corticosteroid protocol and to assess neonatal outcomes associated with its introduction. STUDY DESIGN: This is a retrospective cohort study of all women with singleton pregnancies admitted between 34 and 36 5/7 weeks’ who presented in the year before (“preprotocol”: November 2012 to October 2013) and after implementation (“postprotocol”: April 2016 to March 2017). The protocol recommends corticosteroid administration to women 34 to 36 5/7 weeks’ gestation at risk for preterm birth who have not received prior corticosteroids. Women with fetal anomalies or pregestational or gestational diabetes were excluded from analysis. The frequency with which eligible women received corticosteroids and ineligible women were appropriately excluded (adherence) was calculated on a monthly basis. Neonatal outcomes of interest were hypoglycemia, receipt of dextrose, birthweight, 5-minute Apgar less than 7, receipt of surfactant, respiratory distress syndrome, transient tachypnea of the newborn, neonatal intensive care unit length of stay, intraventricular hemorrhage, necrotizing enterocolitis, culture-positive sepsis, bronchopulmonary dysplasia, and death. Bivariable and multivariable analyses were used to
T
he majority of preterm neonates are born in the late-preterm period (>34 weeks), with infants born between 34 and 37 weeks comprising 8% of all deliveries nationwide.1 These neonates are at increased risk for respiratory morbidity compared to neonates born at term.2 Although administration of antenatal corticosteroids has long been a mainstay of obstetrical practice for pregnancies at risk for preterm birth
Q4
Cite this article as: Badreldin N, Willert GG, Henricks AA, et al. Implementation of an antenatal late-preterm corticosteroid protocol at a high-volume tertiary care center. 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.2019.100076
compare neonatal outcomes between (1) all women in the postprotocol cohort to those in the preprotocol cohort and (2) only women who received adherent care in the postprotocol cohort to all women in the preprotocol cohort. RESULTS: A total of 452 women were included in the preprotocol cohort and 451 in the postprotocol cohort. The majority of the postprotocol women (n ¼ 366, 81.2%) received adherent care. Women in both cohorts were similar, with the exception that women in the postprotocol cohort were more likely to be nulliparous (P ¼ .013). Compared to the preprotocol period, neonates of women in the postprotocol period had significantly higher odds of hypoglycemia <50 mg/dL in the first 24 hours of life (adjusted odds ratio, 1.37; 95% confidence interval, 1.05e1.80), without improvements in respiratory outcomes. Results were similar when restricting the analysis to only women in the postprotocol cohort who received adherent care (glucose <50 mg/dL: adjusted odds ratio, 1.52; 95% confidence interval, 1.14e2.03). No differences in composite respiratory morbidity or other neonatal outcomes were observed. CONCLUSION: Uptake of a new institutional protocol for antenatal late-preterm corticosteroids was rapid. Compared with historic controls, neonates exposed to antenatal late-preterm corticosteroid experienced increased odds of hypoglycemia, without significant improvements in respiratory morbidities. Key words: antenatal late-preterm steroids, corticosteroids, late-preterm
delivery, neonatal hypoglycemia, neonatal respiratory outcomes, protocol implementation
before 34 weeks, in 2016 a sentinel multisite, placebo-controlled randomized trial demonstrated the benefits of use of betamethasone for women with singleton gestations at risk for latepreterm birth.3 The Antenatal Late Preterm Steroids (ALPS) trial showed a significant reduction in neonatal respiratory complications with administration of betamethasone for women at high risk of preterm delivery between 34 and 36 6/7 weeks of gestation. Since publication of this clinical trial, the use of antenatal steroids in this population has become a routine aspect of the management of pregnancies at risk for late-preterm delivery.4 In practice, the administration of antenatal corticosteroids in the latepreterm period varies widely across
provider and institution, drawing into question if findings from a randomized trial are demonstrable in clinical practice.5,6 Furthermore, in centers where protocols have been implemented, uptake of the protocol and associated outcomes remain poorly understood. Therefore, the objectives of this study were (1) to evaluate implementation of an institutional antenatal late-preterm corticosteroids protocol and (2) to investigate neonatal outcomes associated with implementation.
Materials and Methods This is a retrospective cohort study of all women with singleton gestations admitted to Northwestern Memorial Hospital between 34 weeks 0 days and 36 weeks 5 days of gestation. MONTH 2019 AJOG MFM
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Original Research AJOG MFM at a Glance Why was this study conducted? This study was conducted to evaluate institutional adherence to an antenatal latepreterm corticosteroid protocol and to assess neonatal outcomes associated with its introduction. Key findings Neonates exposed to antenatal late-preterm corticosteroid experienced increased odds of hypoglycemia, without significant improvements in respiratory morbidities. What does this add to what is known? Unlike the randomized clinical trial, we did not identify improvement in neonatal respiratory outcomes. We did, however, identify an increase in the odds of neonatal hypoglycemia in neonates born in the postprotocol period.
Northwestern Memorial Hospital is a large tertiary hospital with approximately 11,500 births per year. The hospital is a member of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network and participated in recruitment for the ALPS trial during the trial period (October 2010 to November 2012, November 2013 to February 2015). For this analysis, women were eligible for inclusion if they presented to care during the
1-year gap in recruitment for the ALPS trial (preprotocol: November 1, 2012, to October 1, 2013) or the 1 year after (postprotocol: April 1, 2016, to March 30, 2017) implementation of the institutional antenatal late-preterm corticosteroids protocol (described below). The preprotocol period represents a period of time during which women did not receive antenatal latepreterm corticosteroids. Women were excluded if they received antenatal corticosteroids as an outpatient or received a prior course of antenatal
FIGURE
Adherence to antenatal late-preterm corticosteroid protocol web 4C=FPO
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
Badreldin et al. Antenatal late-preterm corticosteroid protocol. AJOG MFM 2019.
corticosteroids. Although our institutional protocol allows for administration of corticosteroids to women with a multiple gestation, pregestational or gestational diabetes, or major fetal anomalies, these women were excluded from this analysis in order to better mirror the ALPS trial criteria. All data were abstracted from the electronic medical record used for clinical care and thus the data are fully inclusive of all eligible patients; data were reviewed by the research team for accuracy. The institution’s protocol was implemented in March 2016 following publication of the ALPS study. Mirroring the trial protocol, our institutional protocol recommends that women who present between 34 weeks 0 days and 36 weeks 5 days receive betamethasone if delivery is planned or if there is substantial risk for delivery prior to 37 weeks 0 days in women who have not previously received a course of corticosteroids. Indications for corticosteroids included signs or symptoms demonstrating risk for late-preterm birth (eg, preterm labor, premature rupture of membranes, new-onset hypertensive disorder) or delivery scheduled prior to 37 weeks (eg, growth restriction, nonreassuring fetal status, abnormal placentation). Health care provider types at Northwestern Memorial Hospital include maternalefetal medicine physicians, general obstetrics and gynecology physicians, and certified nurse-midwives. Women who require evaluation present to a hospital-based obstetrical triage unit and are evaluated by institutionally hired nurses, certified nurse-midwives, and attending physicians. Following evaluation, an antenatal management plan is formed in conjunction with the patient’s primary obstetrical provider. Women may be admitted to the inpatient antepartum service, admitted to labor and delivery, observed in triage, or discharged to home, depending on the clinical circumstances. The institutional protocol was disseminated to clinicians using education sessions, including grand rounds, resident and fellow lectures, labor and delivery unit lectures,
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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 225Q5 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278
TABLE 1
Characteristics of women in the preprotocol cohort compared to all women the postprotocol period Maternal age, years
Preprotocol (n ¼ 452)
Postprotocol (n ¼ 451)
P value
31.9 5.3
32.2 5.1
.347
Race/ethnicity
.193
White/non-Hispanic
228 (50.4)
251 (55.7)
Black/non-Hispanic
43 (9.5)
50 (11.1)
Hispanic
86 (19.0)
62 (13.8)
Asian
33 (7.3)
34 (7.5)
62 (13.7)
54 (12.0)
Other BMI, kg/m
30.2 5.7
30.4 8.5
.638
Nulliparous
257 (54.7)
283 (62.8)
.013
15 (3.3)
20 (4.4)
.385
9 (2.0)
13 (2.9)
.385
130 (28.8)
142 (31.5)
.372
2
Chronic hypertension Preeclampsia Cesarean delivery Gestational age at admission, weeks
35.7 0.8
35.7 0.8
.710
Gestational age at delivery, weeks
36.1 1.2
36.1 1.2
.237
Female neonate
199 (44.0)
191 (42.35)
.611
Received betamethasone
304 (67.4)
Gestational age at betamethasone, weeks
35.6 0.8
Data presented as mean standard deviation and prevalence (%). BMI, body mass index. Badreldin et al. Antenatal late-preterm corticosteroid protocol. AJOG MFM 2019.
and e-mail reminders. Additionally, a member of the maternalefetal medicine division oversees the obstetrical units each day and these faculty provided inperson re-education and reminders throughout the first year of implementation. Maternal characteristics of interest included age, race and ethnicity, parity, and body mass index. Pregnancy characteristics such as gestational age at admission and delivery, mode of delivery, fetal sex, and existence of hypertensive disorders of pregnancy were abstracted from inpatient records. Neonatal outcomes of interest included hypoglycemia, receipt of dextrose, birthweight, 5-minute Apgar less than 7, receipt of surfactant, respiratory distress syndrome, transient tachypnea of the newborn, neonatal intensive care unit length of stay, intraventricular hemorrhage, necrotizing enterocolitis, culturepositive sepsis, bronchopulmonary dysplasia, and death. Neonatal
hypoglycemia was defined as a glucose of less than 40 mg/dL in the first 24 hours; additionally, we also investigated a threshold of less than 50 mg/dL. Two values of glucose were used as a proxy for hypoglycemia, as controversy exists as to the precise numerical threshold at which to intervene.7 At this institution, asymptomatic late-preterm neonates with glucose values of <40e50 mg/dL (depending on age in hours) are treated with an oral feeding and glucose values are repeated in 1 hour. Neonates whose glucose values do not improve with oral feeding are given dextrose. Respiratory distress syndrome diagnosis was made based on chest radiograph findings of reticulogranular appearance and need for supplemental oxygen. A diagnosis of transient tachypnea of the newborn was made by chest radiograph finding of perihilar linear streaking. Those neonates requiring oxygen, but with normal chest radiograph findings were individually reviewed for a diagnosis by a
neonatologist. As respiratory distress syndrome and transient tachypnea are rare outcomes in the late-preterm period, we also considered a respiratory composite outcome that included respiratory distress syndrome, transient tachypnea, or receipt of surfactant. First, to evaluate implementation of the protocol, the frequency of adherence to the protocol in the postprotocol cohort was calculated on a monthly basis and plotted on a run chart. Each data point represents the proportion of women in a given month who received care adherent to the protocol out of all women meeting inclusion criteria in that month. Adherent care was defined as appropriately receiving corticosteroids or not receiving corticosteroids per the new protocol. Next, to evaluate outcomes associated with implementation of the protocol, we first compared maternal baseline characteristics and neonatal outcomes in the preprotocol period to MONTH 2019 AJOG MFM
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279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334
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
391 392 393 Neonatal outcomes among neonates in the preprotocol cohort compared to those in the postprotocol cohort 394 Unadjusted regression Adjusted regression 395 Preprotocol Postprotocol a (n ¼ 452) (n ¼ 451) 396 OR/b 95% CI aOR/ab 95% CI 397 Hypoglycemia <40 mg/dL 113 (25.0) 122 (27.1) 1.11 0.83 to 1.50 1.14 0.84 to 1.53 398 Hypoglycemia <50 mg/dL 233 (51.6) 264 (58.5) 1.33 1.02 to 1.73 1.37 1.05 to 1.80 399 Dextrose administration 58 (12.8) 66 (14.6) 1.16 0.80 to 1.70 1.25 0.85 to 1.86 400 401 Birthweight, grams 2672 485 2740 473 0.07 0.004 to 0.13 0.06 0.01 to 0.11 402 5-min Apgar < 7 16 (3.5) 12 (2.7) 0.74 0.35 to 1.59 0.80 0.37 to 1.71 403 Surfactant 16 (3.5) 10 (2.2) 0.62 0.28 to 1.38 0.66 0.29 to 1.48 404 Respiratory distress 21 (4.7) 24 (5.32) 1.15 0.63 to 2.10 1.24 0.67 to 2.29 405 406 Transient tachypnea 38 (8.4) 39 (8.7) 1.03 0.65 to 1.65 1.11 0.69 to 1.78 407 Respiratory compositeb 60 (13.3) 63 (14.0) 1.06 0.73 to 1.55 1.15 0.78 to 1.71 408 NICU length of stay, days 4.0 7.3 4.0 6.6 0.02 -0.92 to 0.97 -0.07 -0.94 to 0.81 409 Intraventricular hemorrhage 2 (0.4) 1 (0.2) 0.50 0.05 to 5.53 0.52 0.05 to 5.83 410 411 Necrotizing enterocolitis 1 (0.2) 1 (0.2) 1.00 0.06 to 16.07 0.93 0.06 to 15.23 412 Culture positive sepsis 2 (0.4) 4 (0.9) 2.01 0.37 to 11.05 1.85 0.33 to 10.24 413 Bronchopulmonary 0 (0) 0 (0) 414 dysplasia 415 Death 0 (0) 0 (0) 416 417 Data presented as mean standard deviation and prevalence (%). 418 ab, adjusted beta coefficient; aOR, adjusted odds ratio; b, beta coefficient; CI, confidence interval; NICU, neonatal intensive care unit; OR, odds ratio. a 419 Logistic and linear regressions adjusting for gestational age at delivery and nulliparity; preprotocol cohort as referent.; b Respiratory composite ¼ surfactant, respiratory distress, transient tachypnea. 420 Badreldin et al. Antenatal late-preterm corticosteroid protocol. AJOG MFM 2019. 421 422 423 424 all of those in the postprotocol period. significance in the bivariable models, demonstrating overall rapid uptake of 425 Second, because women who were given the importance of association of the new practice. The majority of the 426 eligible but did not receive cortico- gestational age with neonatal out- postprotocol women (n ¼ 366, 81.2%) 427 steroids may differ from the total comes. A P value of <.05 was used to received care that was adherent with the 428 cohort in unmeasured ways, we then define statistical significance and all protocol. 429 performed a “per-protocol” analysis, tests were 2-tailed. Statistical analyses Women in the preprotocol and post430 comparing maternal baseline charac- were performed with Stata v. 15 (Sta- protocol cohorts were similar with re431 teristics and neonatal outcomes for all taCorp, College Station, Texas). This gard to age, race and ethnicity, body 432 neonates in the preprotocol period study was approved by the Institu- mass index, rates of hypertensive disor(none of whom had received late- tional Review Board at Northwestern ders, and mode of delivery (Table 1). The ½T1 433 434 preterm corticosteroids) with only University. gestational age at admission (35.7 vs 35.7 435 those neonates in the postprotocol weeks; P ¼ .710) and gestational age at 436 period who received care adherent Results delivery (36.1 vs 36.1 weeks; P ¼ .237) 437 with the new protocol. c2, Wilcoxon A total of 903 women met inclusion were similar between the 2 cohorts. 438 rank sum, and t tests were performed, criteria and were included in analysis. Women in the postprotocol period were, 439 as appropriate. Multivariable logistic Of these, 452 (50.1%) were cared for however, significantly more likely to be 440 and linear regression models were before and 451 (49.9%) were cared for nulliparous (54.7% vs 62.8%; P ¼ .013). 441 constructed adjusting for gestational after implementation of the protocol. In the postprotocol cohort, women who 442 age and those maternal and pregnancy Adherence to the new protocol changed received corticosteroids received them at 443 factors that were significant on over the first year after implementation. a mean gestational age of 35.6 weeks ( bivariable models. An a priori decision The Figure illustrates the monthly 0.8 weeks). ½F1 444 445 In unadjusted analysis comparing was made to include gestational age at adherence rates to the late-preterm 446 birth in the models regardless of antenatal corticosteroid protocol, outcomes of neonates in the TABLE 2
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Original Research 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 ½T2 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502
503 504 505 Characteristics of women in the preprotocol cohort compared to those of women in the postprotocol period who 506 received adherent care 507 Preprotocol (n ¼ 452) Postprotocol (n ¼ 366) P value 508 Maternal age, years 31.9 5.3 32.3 5.0 .264 509 510 Race/ethnicity .079 511 White/non-Hispanic 228 (50.4) 207 (56.6) 512 Black/non-Hispanic 43 (9.5) 40 (10.9) 513 Hispanic 86 (19.0) 47 (12.8) 514 515 Asian 33 (7.3) 32 (8.7) 516 Other 62 (13.7) 40 (10.9) 517 BMI, kg/m2 30.2 5.7 30.4 9.0 .569 518 Nulliparous 247 (54.7) 233 (63.7) .009 519 520 Chronic hypertension 15 (3.3) 16 (4.4) .433 521 Preeclampsia 9 (2.0) 9 (2.5) .650 522 Cesarean delivery 130 (28.8) 122 (33.3) .159 523 524 Gestational age at admission, weeks 35.7 0.8 35.7 0.8 .489 525 Gestational age at delivery, weeks 36.1 1.2 35.9 1.0 .162 526 Female neonate 199 (44.0) 148 (40.4) .302 527 Received betamethasone 302 (82.5) 528 529 Gestational age at betamethasone, weeks 35.6 0.8 530 Data presented as mean standard deviation and prevalence (%). 531 BMI, body mass index. 532 Badreldin et al. Antenatal late-preterm corticosteroid protocol. AJOG MFM 2019. 533 534 535 Next, we evaluated women in the CI, 1.20 to 2.11), which persisted in preprotocol cohort to those of the 536 postprotocol cohort, the odds of hypo- preprotocol cohort compared to only multivariable analysis adjusting for 537 glycemia with a glucose value of <40 those women in the postprotocol cohort gestational age at delivery and nulliparity 538 mg/dL were not significantly different in who received care adherent to the pro- (adjusted OR, 1.52; 95% CI, 1.14 to 539 the postprotocol cohort (odds ratio tocol (Table 3). Women in the post- 2.03). The adherent postprotocol cohort ½T3 540 [OR], 1.11; 95% confidence interval protocol cohort who received adherent was not significantly more likely to 541 [CI], 0.83e1.50) compared to the pre- care were again significantly more likely require dextrose administration 542 protocol cohort (Table 2). However, to be nulliparous than those in the pre- (adjusted OR, 1.37; 95% CI, 0.92e2.05). 543 when hypoglycemia was defined as a protocol cohort (54.7% vs 63.7%; P ¼ Again, respiratory outcomes did not 544 glucose value of <50 mg/dL, neonates .009), but the 2 cohorts were otherwise differ between neonates in the pre545 of women in the postprotocol cohort similar in terms of age, race and protocol cohort and those in the post546 were significantly more likely to expe- ethnicity, body mass index, hypertensive protocol cohort who received adherent 547 rience hypoglycemia (OR, 1.33; 95% CI, disorders, mode of delivery, and gesta- care. 548 1.02e1.73). This finding remained sig- tional ages at admission and delivery. In 549 nificant (adjusted OR, 1.37; 95% CI, unadjusted analysis, the odds of hypo- Comment 550 1.05e1.80) in multivariable analysis glycemia of <40 mg/dL were not signif- Principal findings 551 after adjusting for gestational age at icantly different in the adherent Since the publication of a sentinel 552 delivery and nulliparity. Five-minute postprotocol cohort compared to the placebo-controlled randomized clin553 Apgar <7, birthweight, and neonatal preprotocol cohort (OR, 1.31; 95% CI, ical trial showing improved neonatal 554 intensive care unit length of stay did not 0.96e1.78) (Table 4). However, hypo- respiratory outcomes in women ½T4 555 differ between the 2 cohorts. Notably, glycemia of <50 mg/dL was again receiving antenatal corticosteroids in 556 neither dextrose administration nor significantly more likely in neonates of the late-preterm time period, many 557 respiratory outcomes were significantly women in the postprotocol cohort who providers and institutions have adop558 different between the 2 cohorts. received adherent care (OR, 1.59; 95% ted protocols for administration. At TABLE 3
MONTH 2019 AJOG MFM FLA 5.6.0 DTD AJOGMF100076_proof 27 December 2019 3:53 pm ce
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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
Neonatal outcomes among women in the preprotocol cohort compared to women in the postprotocol cohort who received adherent care Unadjusted regression
Adjusted regression
OR/b
aOR/aba
Preprotocol (n ¼ 452)
Postprotocol (n ¼ 366)
Hypoglycemia <40 mg/dL
113 (25.0)
111 (30.3)
1.31
0.96 to 1.78
1.29
0.94 to 1.76
Hypoglycemia <50 mg/dL
233 (51.6)
230 (62.8)
1.59
1.20 to 2.11
1.52
1.14 to 2.03
58 (12.8)
62 (16.9)
1.39
0.94 to 2.04
1.37
0.92 to 2.05
2672 485
Dextrose administration
95% CI
95% CI
2692 469
0.92
-0.05 to 0.09
0.05
-0.01 to 0.11
5-min Apgar < 7
16 (3.5)
9 (2.5)
0.69
0.30 to 1.57
0.69
0.30 to 1.60
Surfactant
16 (3.5)
10 (2.7)
0.77
0.34 to 1.71
0.77
0.34 to 1.74
Respiratory distress
21 (4.7)
22 (6.0)
1.31
0.70 to 2.46
1.31
0.70 to 2.46
Transient tachypnea
38 (8.4)
36 (9.8)
1.19
0.73 to 1.95
1.19
0.73 to 1.95
Respiratory compositeb
60 (13.3)
58 (15.8)
1.23
0.83 to 1.82
1.25
0.83 to 1.88
4.0 7.3
3.9 6.7
-0.08
-1.05 to 0.89
-0.28
-1.18 to 0.61
Intraventricular hemorrhage
2 (0.4)
1 (0.3)
0.50
0.05 to 5.53
0.52
0.05 to 5.83
Necrotizing enterocolitis
1 (0.2)
1 (0.3)
1.00
0.06 to 16.07
0.93
0.06 to 15.23
Culture-positive sepsis
2 (0.4)
4 (0.9)
2.01
0.37 to 11.05
1.85
0.33 to 10.24
Bronchopulmonary dysplasia
0 (0)
0 (0)
Death
0 (0)
0 (0)
Birthweight, grams
NICU length of stay, days
Data presented as mean standard deviation and prevalence (%). ab, adjusted beta coefficient; aOR, adjusted odds ratio; b, beta coefficient; CI, confidence interval; NICU, neonatal intensive care unit; OR, odds ratio. Logistic and linear regressions adjusting for gestational age at delivery and nulliparity; preprotocol cohort as referent.; b Respiratory composite ¼ surfactant, respiratory distress, transient tachypnea. Badreldin et al. Antenatal late-preterm corticosteroid protocol. AJOG MFM 2019. a
this high volume, tertiary care maternal center uptake of the new protocol was high in the first year after implementation. Our data suggest that neonates of women who received care after implementation of the new protocol had increased odds of hypoglycemia compared to neonates of women in the preprotocol cohort, but had no other significant differences in clinical outcomes.
Results Unlike the randomized clinical trial, we did not identify improvement in neonatal respiratory outcomes. However, our study was designed to assess implementation over a short period of time immediately after release of the new protocol, and thus was of limited size. As this analysis had inadequate power to identify differences in these infrequent
events, the lack of demonstrated reduction in respiratory outcomes should not be considered rationale for not giving antenatal late-preterm corticosteroids. We did, however, identify a statistically significant increase in the odds of neonatal hypoglycemia in neonates born in the postprotocol period, both as a whole and when limiting analysis to only neonates in the postprotocol period who received adherent care. These findings stress the importance of continued evaluation of protocols in real-world settings.
Clinical implications Neonatal hypoglycemia after maternal steroid administration requires careful consideration. Normal term neonatal glucose values in the first day of life are greater than 55e60 mg/dL.8 Although the precise definition of clinically
significant hypoglycemia is debated in the pediatric literature, neonatal hypoglycemia is recognized to be associated with adverse neonatal outcomes such as seizures and long-term neurologic deficits.9e11 The American Academy of Pediatrics and Pediatric Endocrine Society recommend that neonates in the late-preterm period maintain glucose values above 40e50 mg/dL in the first 1e2 days of life.12 Our study found that neonates of women born following implementation of an antenatal latepreterm corticosteroid protocol were more likely to experience hypoglycemia <50 mg/dL. Notably, although neonatal hypoglycemia was more common, invasive treatment with dextrose admission did not increase, suggesting that hypoglycemia improved with oral feeds in this population. However, literature suggests that even transient
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neonatal hypoglycemia may be associated with poorer academic achievement, and thus this finding warrants attention as we continue to improve care for women and neonates delivered in the late-preterm period.11,13
Research implications Further evaluation of implementation of this practice into diverse clinical settings, including beyond academic medical centers, will be beneficial. Additionally, further work on the application of this clinical practice to previously excluded populations, particularly women with diabetes, will be essential to understanding how best to provide care for all women at risk of delivering in the latepreterm period.
Strengths and limitations Major strengths of this study include the large study cohort, the institution-wide implementation of the new practice shortly after the ALPS trial was published, and the detailed medical data available from individual records. In addition, the diversity in provider types allows our study to evaluate implementation of this new protocol in a reallife setting. However, this study is subject to several limitations. Primarily, this is a retrospective analysis, which is susceptible to ascertainment bias and unmeasured confounding, and although we did not find a difference in measured factors between groups, it is possible that unmeasured factors aside from steroids may contribute to the findings of neonatal hypoglycemia. Importantly, this study was performed at an institution that participated in the ALPS trial, and thus providers are likely to be more familiar with the study protocol, more
comfortable with its implementation, and overall faster to uptake this practice. While this study site’s involvement in ALPS recruitment and its academic tertiary nature may limit generalizability regarding implementation, findings with regards to neonatal outcomes remain relevant. Finally, the relatively small sample size may not have the power to identify differences in the less common outcomes that were studied in the primary ALPS study.
Conclusion In conclusion, we noted high adherence to a new institutional protocol for antenatal late-preterm corticosteroids. Although neonatal respiratory outcomes in this real-life setting did not mirror those of the randomized clinical trial, there was an increase in the frequency of neonatal hypoglycemia less than 50 mg/ dL in those neonates in the postprotocol cohort. n
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6. ACOG Committee on Patient Safety and Quality Improvement. ACOG Committee Opinion No. 526: Standardization of practice to improve outcomes. Obstet Gynecol 2012;119: 1081–2. 7. Adamkin DH. Neonatal hypoglycemia. Semin Fetal Neonatal Med 2017;22:36–41. 8. Stanley CA, Rozance PJ, Thornton PS, et al. Re-evaluating “transitional neonatal hypoglycemia”: mechanism and implications for management. J Pediatr 2015;166: 1520–5 e1. 9. Cornblath M, Odell GB, Levin EY. Symptomatic neonatal hypoglycemia associated with toxemia of pregnancy. J Pediatr 1959;55: 545–62. 10. Qiao LX, Wang J, Yan JH, et al. Follow-up Q6 study of neurodevelopment in 2-year-old infants who had suffered from neonatal hypoglycemia. BMC Pediatr 2019;19:133. 11. Kaiser JR, Bai S, Gibson N, et al. Association between transient newborn hypoglycemia and fourth-grade achievement test proficiency: a population-based study. JAMA Pediatr 2015;169:913–21. 12. Adamkin DH, Committee on Fetus and Newborn. Postnatal glucose homeostasis in late-preterm and term infants. Pediatrics 2011;127:575–9. 13. Kerstjens JM, Bocca-Tjeertes IF, de Winter AF, Reijneveld SA, Bos AF. Neonatal morbidities and developmental delay in moderately preterm-born children. Pediatrics 2012;130:e265–72.
Author and article information From the Department of Obstetrics and Gynecology, Division of MaternaleFetal Medicine (Drs Badreldin, Henricks, Peaceman, and Yee, and Ms Willert), and Department of Pediatrics, Division of Neonatology (Ms Caldarelli), Northwestern University Feinberg School of Q3 Medicine, Chicago, Illinois. Received Aug. 26, 2019; revised Nov. 18, 2019; accepted Dec. 2, 2019. The authors report no conflicts of interest. L.M.Y. is supported by NICHD K12 HD050121-11. This paper was presented at the 2018 Society for MaternaleFetal Medicine Annual Meeting (Dallas, TX) as a poster presentation (Jan. 29 e Feb. 3, 2018). Correspondence: Nevert Badreldin, MD. nevert. [email protected]
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