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Childhood neurodevelopment after spontaneous versus indicated preterm birth
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
Childhood neurodevelopment after spontaneous versus indicated preterm birth Q4
Emily E. Nuss, MD; Jessica Spiegelman, MD; Amy L. Turitz, MD; Cynthia Gyamfi-Bannerman, MD, MSc
BACKGROUND: Preterm birth is the leading cause of neonatal morbidity and mortality. Individuals who survive preterm birth are at a higher risk for many long-term adverse effects, including neurodevelopmental deficits. There are many well-established risk factors for worse neurologic outcomes spanning the prenatal and postnatal periods; however, investigators have yet to assess whether the cause of preterm birth has an impact on neurodevelopment. OBJECTIVE: Our objective was to assess whether neurologic outcomes differ by children born via indicated versus spontaneous preterm birth. STUDY DESIGN: We performed secondary analysis of a multicenter trial assessing magnesium for neuroprotection in women at risk for preterm delivery from 24 to 31 weeks. We included women with live, nonanomalous, singleton gestations who delivered preterm; we excluded women whose children were missing 2-year follow-up information for reasons other than perinatal demise. The primary exposure was type of preterm birth: (1) spontaneous if the child’s mother presented with preterm labor or ruptured membranes, or (2) indicated if the child was delivered preterm iatrogenically. The primary outcome was death (including stillbirths, neonatal intensive care unit deaths, and deaths after discharge) or an abnormal Bayley II score by 2 years of age, defined as a Mental Developmental Index score or Psychomotor Developmental Index score 2 standard deviations below the mean. Secondary outcomes included death or Mental Developmental Index and Psychomotor Developmental Index scores 1 standard deviation or less, and neonatal morbidities associated with prematurity. Bivariate analyses of baseline characteristics by exposure were conducted. A logistic regression model was fitted to adjust for confounders. RESULTS: Of 1678 subjects, 1631 (97.2%) underwent spontaneous preterm birth and 47 (2.8%) underwent indicated preterm birth. Baseline maternal demographics and gestational age at delivery were
P
reterm birth, the leading cause of neonatal morbidity and mortality, occurs in approximately 10% of all pregnancies in the United States.1 However, with advancements in technology and collaboration among obstetricians and neonatologists, survival rates of preterm infants, especially those bordering viability, have been
Cite this article as: Nuss EE, Spiegelman J, Turitz AL, et al. Childhood neurodevelopment after spontaneous versus indicated preterm birth. Am J Obstet Gynecol MFM 2019;XX:x.ex-x.ex. 2589-9333/$36.00 Published by Elsevier Inc. https://doi.org/10.1016/j.ajogmf.2019.100082
similar between groups (29.6 weeks 7.8 versus 28.8 weeks 2.5, P ¼ .07). A Psychomotor Developmental Index score 2 standard deviations or less below the mean or death occurred in 340 (20.9%) spontaneous preterm birth subjects and 17 (36.2%) indicated preterm birth subjects (P ¼ .01). When adjusting for confounders, there remained an increased probability of a Psychomotor Developmental Index scores 2 standard deviations or less or death in indicated preterm birth subjects (P ¼ .02). Although not statistically significant, indicated preterm birth was also associated with higher odds of Mental Developmental Index scores 2 standard deviations or less or death, Psychomotor Developmental scores 1 standard deviation or less or death, and Mental Developmental Index scores 1 standard deviation or less or death (1.76, 1.59, and 1.45, respectively). Limiting the analysis to small for gestational age infants, there was no difference in neurologic outcomes. The same was true for when we excluded small for gestational age infants from our analysis. However, after adjusting for small for gestational age, the odds of a Psychomotor Developmental Index score 2 standard deviations or less or death remained significant higher in the indicated preterm birth group (adjusted odds ratio, 1.98; 95% confidence interval, 1.013.88). CONCLUSION: In this cohort of pregnant women who delivered preterm, indicated deliveries were associated with worse psychomotor development than were spontaneous deliveries. Other outcomes appeared to be poor, but our numbers were limited. This finding should be confirmed in a larger cohort of women undergoing medically indicated preterm deliveries. Key words: Bayley Scales of Infant Development, BEAM, indicated
preterm birth, neurodevelopment, preterm birth, spontaneous preterm birth
increasing.2e6 As such, clinicians and researchers alike are becoming more familiar with survivors of preterm birth and the lifelong morbidities know to affect this population. Individuals who are born preterm compared to those who are born at term are at an increased risk for neurodevelopmental deficits, including cerebral palsy,7e9 motor and cognitive impairments,10e12 visual and auditory deficits,13 and behavioral problems.14e16 Furthermore, risks of these deficits appear to increase with decreasing gestational age (GA).11,13,16,17 Among individuals who are born preterm, dozens of risk factors for worse neurodevelopmental outcomes exist, from
maternal factors that exist prior to conception, through pregnancy, and even into the postnatal period. Yet few studies, if any, have examined the relationship between the cause of preterm birth and longterm neurodevelopmental outcomes. Broadly, there are 3 main causes of preterm birth: (1) spontaneous preterm labor with intact membranes; (2) preterm premature rupture of membranes; and (3) labor induction or cesarean delivery for maternal or fetal indications. These 3 main etiologies are commonly classified into 2 functional groups: the first 2 etiologies are collectively referred to as spontaneous preterm birth (SPTB), and the last MONTH 2020 AJOG MFM
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AJOG MFM at a Glance Why was this study conducted? This study aimed to determine whether long-term neurodevelopmental outcomes differ by spontaneous vs indicated preterm birth. Key findings In this cohort of pregnancies, indicated preterm birth was associated with worse psychomotor development than spontaneous preterm birth in infants assessed at 2 years of age. What does this add to what is known? This study contributes to the growing body of literature regarding the adverse impact of preterm delivery on neurodevelopment, and is the first to look at how the cause of preterm birth affects long-term neurodevelopment.
etiology is referred to as indicated preterm birth (IPTB). Our objective was to determine whether long-term neurodevelopmental outcomes, as measured by the Bayley Scales of Infant Development II, would differ based on spontaneous vs indicated preterm birth. If IPTB is associated with worse neurodevelopmental outcomes, as is hypothesized, further studies examining the mechanism for this relationship as well as possible ways to mitigate this outcome may be warranted.
Materials and Methods This is a secondary analysis of the Beneficial Effects of Antenatal Magnesium Sulfate (BEAM) randomized controlled trial conducted through the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s MaternalFetal Medicine Units Network. This multicenter, randomized, placebo-controlled trial was conducted from 1997 to 2004 at 20 institutions across the United States. It tested the hypothesis that the administration of antenatal magnesium sulfate to women at high risk for early preterm delivery (2431 weeks’ gestation) would reduce the risk of moderate to severe cerebral palsy or death in their children. To be eligible for the parent trial, there had to be a high likelihood of preterm delivery, skewing the cohort toward more spontaneous preterm deliveries. Comprehensive details of the study design and methods have been previously reported.18
The current study is a retrospective observational cohort study. From the parent study, we included women with live, nonanomalous, singleton gestations who delivered preterm (<37 weeks’ gestation) and excluded women whose children were missing outcome data at 2 years of age for reasons other than perinatal demise. Gestational age was established by the last menstrual period and the earliest ultrasonogram date before randomization, in accordance with a standardized algorithm.18 The primary exposure was type of preterm birth: spontaneous preterm birth (SPTB) or indicated preterm birth (IPTB). Women who presented with preterm premature rupture of membranes (PPROM) or preterm labor were considered to be part of the SPTB group. PPROM was diagnosed if any of the 2 following criteria were met: pooling of the amniotic fluid in the vaginal vault; positive Nitrazine test result; or ferning of vaginal fluid. Alternatively, PPROM could also be diagnosed if 1 of the following criteria was met: indigo carmine pooling in the vagina after amnioinfusion; or visible leakage of amniotic fluid from the cervix. In addition in the SPTB group was preterm labor, defined as 6 contractions per hour and cervical dilation of 4 cm or more. If neither PPROM or preterm labor was present and delivery was planned for within 24 hours, then subjects and their children were considered to be part of the IPTB group. If subjects who initially
presented with PPROM or preterm labor later underwent iatrogenic delivery for various maternal or fetal indications, then these subjects were still considered to be a part of the SPTB group. Our primary outcome was the composite of death (including stillbirths, neonatal intensive care unit deaths, and deaths after discharge) or an abnormal Bayley Scales of Infant Development II (Bayley) score at 2 years of age, defined as a Mental Developmental Index (MDI) score or Psychomotor Developmental Index (PDI) score of less than 2 standard deviations (SD) below the mean. Bayley scores are a standardized series of measurements performed by a trained psychologist or psychometrist that are designed to assess for motor and cognitive developmental delay in children aged 0e3 years. The MDI score assesses sensory perception, knowledge, memory, problem solving, and early language. The PDI score assesses degree of control of the body, coordination of the large muscles, dexterity of the hands and fingers, dynamic movement, dynamic praxis, postural imitation, and stereognosis. The standardized mean Bayley II score is 100 with a standard deviation (SD) of 15. Death was included, as this is a competing outcome. Our secondary outcomes included the composite frequency of death or Bayley scores less than 1 SD below the mean, and various maternal and neonatal out- Q1 comes and morbidities associated with prematurity. Maternal baseline characteristics and secondary outcomes were compared using the Student t test for continuous variables, the c2 test or Fisher exact test for categorical variables, and the Wilcoxon rank-sum test for nonparametric data to assess for group differences. Our primary outcome was compared between groups, and unadjusted odds ratios with 95% confidence intervals were estimated. A logistic regression model was generated, adjusting for confounders based on either historical importance or significant correlation
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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 254½F1 255 256 257 258 259 260 261 262 263 264 265 266 267 268½T1 269 270½T2 271 272 273 274 275 276 277 278
on bivariate analysis, including the following: maternal magnesium exposure, race/ethnicity, years of education, diabetes, drug use during pregnancy, alcohol use during pregnancy, multiple courses of steroids, and whether prenatal care was received (P < .05). Our sample size was fixed by the parent trial and by our exclusions. Setting the power at 80% and a type 1 error rate of 5%, we would be able to detect a relative risk of 1.85 or greater, or 0.3 or less. SAS software, version 9.4 (SAS Institute, Cary, NC) was used for analysis. This analysis was considered exempt by the Institutional Review Board at Columbia University Irving Medical Center because the study data is publicly available and de-identified.
Results Of the 2444 subjects in the parent study, we sequentially excluded 406 twin gestations, 83 gestations with major congenital malformations, 156 gestations for missing outcome data at 2 years age not due to death, 84 gestations with missing information on death status, and 37 gestations that resulted in term neonates (Figure 1). This left 1678 women and their offspring eligible for inclusion in our analysis. The majority of gestations in this study (1,631, 97.2%) resulted in SPTB, whereas the remaining resulted in IPTB (47, 2.8%) (Figure 1). Analysis of maternal baseline characteristics by exposure showed that the 2 groups differed in years of education but were similar across all other fronts including age, body mass index, race/ ethnicity, diabetes, substance use during pregnancy, and exposure to magnesium sulfate (Table 1). Analysis of our primary outcome (Table 2) revealed that PDI scores 2 SD from the mean or death occurred significantly more frequently in IPTB subjects than in SPTB subjects (17 [36.2%] compared to 340 [20.9%], P ¼ .01). However, the frequency of MDI scores 2 SD or death were similar between groups (16 [34.0%] compared to 386 [23.7%], P ¼ .10). We then fit a log-linear regression
279 280 281 Flow diagram of study participants 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 Nuss et al. Neurodevelopment of spontaneous vs indicated preterm infants. AJOG MFM 2019. 298 299 300 model and adjusted for maternal race/ preterm labor and subsequently un301 ethnicity, diabetes, antenatal magne- derwent indicated deliveries, intra302 sium, and steroid exposure, drug and amniotic infection was the most 303 alcohol use during pregnancy, years of common cause. Among the subjects 304 education, and whether or not pre- originally in the IPTB group whose 305 natal care was received. In this delivery had been planned, many 306 adjusted model, there remained an different indications were represented, 307 increased probability of PDI scores 2 such as placental abruptions, placental 308 SD from the mean or death in IPTB previas, fetal distress, and intrauterine 309 subjects (adjusted odds ratio [OR], growth restriction. Subjects in the 310 2.21; 95% confidence interval [CI], IPTB group were more likely to have 311 1.15e4.23, P ¼ 0.02). Although not received multiple courses of steroids 312 statistically significant, higher rates of and antibiotics and to undergo cesar313 MDI 2 SD from the mean or death, ean deliveries. There were no differ314 PDI 1 SD or death, and MDI 1 SD ences in incidences of preeclampsia, 315 or death (1.76, 1.59, and 1.45, chorioamnionitis, and postpartum 316 respectively) occurred in IPTB sub- endometritis among women in the 2 317 jects. Sensitivity analyses were per- groups. 318 formed, showing that when limiting Analysis of neonatal secondary out319 the analysis to only small for gesta- comes (Table 3) showed that neonates 320 tional age (SGA) infants, there was no who underwent IPTB had decreased 321 difference in neurologic outcomes. birthweights and smaller head circum322 The same was true after excluding ferences, and were more likely to be 323 SGA infants from our analysis. How- small for SGA. Compared to their 324 ever, after adjusting for SGA, the odds counterparts, IPTB infants had higher 325 of a PDI score 2 SD from the mean incidences of respiratory distress syn326 or death remained significantly higher drome and sepsis and a lower incidence 327 in the IPTB group (aOR, 1.98; 95% of transient tachypnea of the newborn 328 CI, 1.013.88). Apgar scores at 1 and 5 minutes, 329 Analysis of maternal secondary admission rates to the neonatal intensive 330 outcomes (Table 3) showed that the care unit, and incidences of both ½T3 331 average gestational ages between necrotizing enterocolitis and intraven332 groups were similar. The indications tricular hemorrhage were similar be333 for delivery varied: among the women tween groups. Between groups, there 334 who presented in spontaneous was no significant difference in the mean FIGURE 1
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TABLE 1
Maternal demographics based on indicated or spontaneous preterm birth Characteristic
Spontaneous preterm birth (n ¼ 1631)
Indicated preterm birth (n ¼ 47)
P value
Age, mean SD
26.37 5.76
26.76 6.57
.66
AMA (35 y)
169 (10.36%)
5 (10.64%)
.95
2
BMI (kg/m )
.93
<18.5
279 (17.11%)
7 (14.89%)
18.524.9
662 (40.59%)
18 (38.30%)
2529.9
330 (20.23%)
11 (23.40%)
>30
360 (22.07%)
11 (23.40%)
African American
732 (44.88%)
24 (51.06%)
Caucasian/white
580 (35.56%)
19 (40.43%)
Hispanic
287 (17.60%)
4 (8.51%)
Race/ethnicity
.44
Asian
13 (0.80%)
0
Native American/other
19 (1.16%)
0 <.0001a,b
Education, y 25% Q1
11
11
50% Median
12
12
75% Q3
13
12
Marital status
.82
Married
790 (48.50%)
22 (46.81%)
Single
839 (51.50%)
25 (53.19%)
88 (5.40%)
4 (8.51%)
.32c
1517 (93.01%)
41 (87.23%)
.13
Smoking
436 (26.73%)
17 (36.17%)
.15
Alcohol use
143 (8.77%)
5 (10.64%)
.66
Recreational drug use
161 (9.87%)
7 (14.89%)
.26
Magnesium sulfate
805 (49.36%)
22 (46.81%)
.73
Diabetes Received prenatal care
Data are presented as frequency (%) unless otherwise indicated. AMA, advanced maternal age; BMI, body mass index; SD, standard deviation. KruskalWallis test for comparison of variances; b P < .001; c Fisher exact test for frequencies <5. Nuss et al. Neurodevelopment of spontaneous vs indicated preterm infants. AJOG MFM 2019.
a
PDI and MDI scores; however, the incidence of a PDI score 2 SD from the mean was higher among IPTB infants. There was no difference in mortality rates between groups.
Discussion Principal findings In this cohort of pregnancies who delivered preterm, indicated deliveries were associated with worse psychomotor development than spontaneous deliveries in children at age 2 years.
Our findings contribute to the growing body of literature regarding the adverse impact of preterm delivery on neurodevelopment, and may offer improved patient counseling in the setting of IPTB.
Results in the context what is known Few studies have examined the immediate postnatal impact of IPTBs vs SPTBs19,20; however, their short followup periods limit our understanding of
the more permanent, indelible effects of the different causes of preterm delivery in this patient population. Therefore, our present study has broadened its scope beyond the neonatal population to examine how type of preterm delivery affects 2-yearold children as well.
Clinical implications Appropriate indications for indicated or iatrogenic preterm delivery are actively debated in obstetrics. In
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Original Research 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502
TABLE 2
Adjusted model of adverse Bayley II scores in infants born via indicated compared to spontaneous preterm birth Unadjusted OR (95% CI)
Adjusted OR (95% CI)
P valuea
PDI 2 SD or death
2.15 (1.17e3.95)
2.21 (1.15e4.23)
.02
MDI 2 SD or death
1.66 (0.90e3.08)
1.76 (0.91e3.40)
.10
PDI 1 SD or death
1.45 (0.81e2.59)
1.59 (0.86e2.96)
.14
MDI 1 SD or death
1.29 (0.72e2.31)
1.45 (0.77e2.75)
.25
Standard deviations refer to standard deviations from the mean. CI, confidence interval; MDI, Mental Developmental Index; OR, odds ratio; PDI, Psychomotor Developmental Index; SD, standard deviation. a
Adjusted for magnesium exposure, race/ethnicity, years of education, diabetes, drug use during pregnancy, alcohol use during pregnancy, multiple courses of steroids, and whether prenatal care was received. Nuss et al. Neurodevelopment of spontaneous vs indicated preterm infants. AJOG MFM 2019.
conjunction with the Society for Maternal-Fetal Medicine, the American College of Obstetricians and
Gynecologists published their committee opinion on appropriate indications for late-preterm and early-term birth.21
This committee opinion was recently updated to include a few more diagnoses while changing delivery timing
TABLE 3
Secondary outcomes based on indicated or spontaneous preterm birtha Spontaneous preterm birth (n ¼ 1631)
Characteristic
Indicated preterm birth (n ¼ 47)
P value
Maternal Membranes ruptured
1452 (98.91%)
Cesarean section
580 (35.56%)
0 32 (68.09%)
<.0001b,c <.0001d <.0001d
Primary indication for delivery Fetal stress/distress
9 (17.65%)
6 (13.04%)
IUGR
1 (1.96%)
9 (19.57%)
Intra-amniotic infection
33 (64.71%)
9 (19.57%)
Placental abruption/previa
4 (7.84%)
12 (26.09%)
Other reason
4 (7.74%)
10 (21.74%)
61 (3.84%)
5 (11.63%)
71 (4.35%)
18 (38.30%)
1499 (91.91%)
25 (53.19%)
61 (3.74%)
4 (8.51%)
12 (0.74%)
1 (2.13%)
.31c
Chorioamnionitis
203 (12.45%)
8 (17.02%)
.35
Postpartum endometritis
105 (6.44%)
3 (6.38)
1.00c
29.59 7.80
28.83 2.53
Multiple courses of steroids
.011e
Antibiotics No antibiotics Ampicillin and erythromycin Other antibiotics Preeclampsia
EGA at delivery (wk), mean SD Very preterm
a
1532 (93.93%)
46 (97.87%)
<.0001d
.07 .52c
Neonatal .0003d,f
Birthweight (g) 25% Q1
1000
748
50% Median
1370
1110
Nuss et al. Neurodevelopment of spontaneous vs indicated preterm infants. AJOG MFM 2019.
(continued)
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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 3
Secondary outcomes based on indicated or spontaneous preterm birtha (continued) Characteristic 75% Q3 Head circumference (cm)b
Spontaneous preterm birth (n ¼ 1631)
Indicated preterm birth (n ¼ 47)
1755
1380
26.95 3.04
25.87 2.83
Small for gestational age
31 (1.90%)
10 (21.28%)
1-min Apgar score < 5
402 (24.68%)
9 (19.15%)
5-min Apgar score < 7
P value .02e <.0001d .39
305 (18.72%)
8 (17.02%)
.77
1546 (95.37%)
47 (100.00%)
.27a
Respiratory distress syndrome
811 (50.03%)
33 (70.21%)
.006b
Transient tachypnea of the newborn
264 (16.29%)
2 (4.26%)
.02c,e
Necrotizing enterocolitis
143 (8.82%)
5 (10.64%)
.67
Intraventricular hemorrhage
325 (20.85%)
9 (20.00%)
.89
Sepsis
272 (16.78%)
14 (29.79%)
.02e
85.72 17.53
83.78 20.40
.49
MDI < 2 SD
255 (17.00%)
9 (22.50%)
.36
MDI < 1 SD
668 (44.53%)
19 (47.50%)
.71 .17
Admission to NICU
MDI score, mean SD
PDI score, mean SD
90.90 17.86
86.98 22.66
PDI < 2 SD
209 (13.93%)
10 (25.00%)
<.05e
PDI < 1 SD
485 (32.33%)
15 (37.50%)
.49
131 (8.03%)
7 (14.89%)
.09
Death Data are presented as frequency (%) unless otherwise indicated
EGA, estimated gestational age; IUGR, intrauterine growth restriction; MDI, Mental Developmental Index; PDI, Psychomotor Developmental Index; SD, standard deviation. Very preterm defined as <34 weeks’ EGA; b P < .01; c Fisher exact test for frequencies <5; d P < .001; e P < .05; f KruskalWallis test for comparison of variances. Nuss et al. Neurodevelopment of spontaneous vs indicated preterm infants. AJOG MFM 2019. a
for others.22 Prior to these recommendations, Gyamfi-Bannerman et al showed that there were a variety of reasons for late preterm iatrogenic delivery that were not evidence based.23 Our findings show an association between indicated preterm delivery and adverse neurodevelopment, and provide further evidence that initiation of iatrogenic preterm delivery should be truly indicated.
Research implications Based on the inclusion criteria of the parent trial, our cohort was skewed toward spontaneous preterm deliveries. Because of the small number of indicated preterm deliveries, it is difficult to draw meaningful conclusions by specific indication. The next steps in this area of research would include to confirm our findings in a larger or prospective cohort
and to examine our findings by indication for delivery.
Strengths and limitations There are several important limitations to this study. From a statistical standpoint, there was a large discrepancy in the sizes of the exposure groups, and the small size of the IPTB group introduced the risk of sampling bias and limited the generalizability of our analysis. However, after adjusting for potential confounders, we were still able to detect a difference, which should be considered hypothesis generating. In addition, this is a secondary analysis of a randomized controlled trial specifically designed for a different outcome related to magnesium and cerebral palsy. Although completion of Bayley II testing at age 2 years was part of
the parent study protocol, we had to exclude a proportion of patients who were lost to follow-up, and although we do not know how this would influence our findings, we do not have a reason to suspect differential loss to follow-up between groups. Moreover, limitations of the parent study should be considered, as their effects may be inherited in our current secondary analysis. For example, the subjects who were included in the original BEAM trial were deemed to have a high likelihood of delivering preterm based on PPROM or preterm labor. Because of the strict inclusion criteria for preterm labor, the sample was heavily skewed toward women presenting with PPROM (89.4%). Our SPTB cohort was similarly skewed toward PPROM and thus limits the generalizability of our results.
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Therefore, the neurodevelopmental outcomes of the SPTB group may more accurately represent those who undergo SPTB following PPROM versus preterm labor. Finally, because of the small number of indicated preterm deliveries, we are unable to draw conclusions by specific indication in the IPTB group. It is possible that the specific indication, rather than all IPTB, is related to our findings. Our study also has several strengths. First, we examined data from a large, multicenter, randomized controlled trial with long-term follow-up. A large sample size was achieved, and data on a wide range of variables were rigorously collected and entered by trained and credentialed study staff. This allows for a more granular analysis of risk factors than insurance or International Classification of Diseases (ICD) ninth or tenth revision data can achieve. In addition, our findings were based on a widely used standardized scale, the Bayley Scales of Infant Development II, to measure neurodevelopmental deficits. Although the Bayley III scale now exists, at the time of data collection in the parent trial, it had not yet been developed.
Conclusion In conclusion, our study demonstrates that indicated preterm birth is associated with worse psychomotor outcomes, as assessed by Bayley II scores at 2 years of age. Future research should look to corroborate these findings and to evaluate the impact of specific indications’ on neurodevelopment to aid in clinical decision making and patient counseling. n Acknowledgments This article could not have been completed without the assistance of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the Maternal-Fetal Medicine Units Network, and the study Protocol Subcommittee. However, the contents of this report represent the views of the authors and do
not represent the views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the Maternal-Fetal Medicine Units Network, or the National Institutes of Health.
References 1. Purisch SE, Gyamfi-Bannerman C. Epidemiology of preterm birth. Semin Perinatol 2017;41: 387–91. 2. Vohr BR, Wright LL, Poole WK, McDonald SA. Neurodevelopmental outcomes of extremely low birth weight infants <32 weeks’ gestation between 1993 and 1998. Pediatrics 2005;116:635–43. 3. Stoll BJ, Hansen NI, Bell EF, et al. Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993-2012. JAMA 2015;314:1039–51. 4. Garcia-Munoz Rodrigo F, Diez Recinos AL, Garcia-Alix Perez A, Figueras Aloy J, Vento Torres M. Changes in perinatal care and outcomes in newborns at the limit of viability in Spain: the EPI-SEN Study. Neonatology 2015;107:120–9. 5. Zeitlin J, Mortensen L, Cuttini M, et al. Declines in stillbirth and neonatal mortality rates in Europe between 2004 and 2010: results from the Euro-Peristat project. J Epidemiol Community Health 2016;70:609–15. 6. Gonzalez R, Merialdi M, Lincetto O, et al. Reduction in neonatal mortality in Chile between 1990 and 2000. Pediatrics 2006;117:e949–54. 7. Petrini JR, Dias T, McCormick MC, Massolo ML, Green NS, Escobar GJ. Increased risk of adverse neurological development for late preterm infants. J Pediatr 2009;154:169–76. 8. Himpens E, Van den Broeck C, Oostra A, Calders P, Vanhaesebrouck P. Prevalence, type, distribution, and severity of cerebral palsy in relation to gestational age: a meta-analytic review. Dev Med Child Neurol 2008;50:334–40. 9. Hirvonen M, Ojala R, Korhonen P, et al. Cerebral palsy among children born moderately and late preterm. Pediatrics 2014;134: e1584–93. 10. Twilhaar ES, Wade RM, de Kieviet JF, van Goudoever JB, van Elburg RM, Oosterlaan J. Cognitive outcomes of children born extremely or very preterm since the 1990s and associated risk factors: a meta-analysis and meta-regression. JAMA Pediatr 2018;172:361–7. 11. Kerr-Wilson CO, Mackay DF, Smith GC, Pell JP. Meta-analysis of the association between preterm delivery and intelligence. J Public Health (Oxf) 2012;34:209–16. 12. de Kieviet JF, Piek JP, AarnoudseMoens CS, Oosterlaan J. Motor development in very preterm and very low-birth-weight children from birth to adolescence: a meta-analysis. JAMA 2009;302:2235–42.
13. Hirvonen M, Ojala R, Korhonen P, et al. Visual and hearing impairments after preterm birth. Pediatrics 2018;142. 14. Arpi E, Ferrari F. Preterm birth and behaviour problems in infants and preschool-age children: a review of the recent literature. Dev Med Child Neurol 2013;55:788–96. 15. de Jong M, Verhoeven M, van Baar AL. School outcome, cognitive functioning, and behaviour problems in moderate and late preterm children and adults: a review. Semin Fetal Neonatal Med 2012;17:163–9. 16. Newman L, Judd F, Olsson CA, et al. Early origins of mental disordererisk factors in the perinatal and infant period. BMC Psychiatry 2016;16:270. 17. Hafstrom M, Kallen K, Serenius F, et al. Cerebral palsy in extremely preterm infants. Pediatrics 2018;141. 18. 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;359:895–905. 19. Bouchet N, Gayet-Ageron A, Lumbreras Areta M, Pfister RE, Martinez de Tejada B. Avoiding late preterm deliveries to reduce neonatal complications: an 11-year cohort study. BMC Pregnancy Childbirth 2018;18:17. 20. Pinto S, Malheiro MF, Vaz A, Rodrigues T, Montenegro N, Guimaraes H. Neonatal outcome in preterm deliveries before 34-week gestationethe influence of the mechanism of labor onset. J Matern Fetal Neonatal Med 2018: 1–7. 21. American College of Obtetricians and Gynecologists. ACOG committee opinion no. 560: medically indicated late-preterm and early-term deliveries. Obstet Gynecol 2013;121:908–10. 22. ACOG committee opinion no. 764: medically indicated late-preterm and early-term deliveries. Obstet Gynecol 2019;133:e151–5. 23. Gyamfi-Bannerman C, Fuchs KM, Young OM, Hoffman MK. Nonspontaneous late preterm birth: etiology and outcomes. Am J Obstet Gynecol 2011;205:456.
Author and article information From the Division of Maternal-Fetal Medicine (Drs Nuss, Spiegelman, Turitz, and Gyamfi-Bannerman) and Department of Obstetrics and Gynecology (Drs Nuss, Spiegelman, Turitz, and Gyamfi-Bannerman), Columbia University Irving Medical Center, New York, NY Received Aug. 20, 2019; revised Dec. 18, 2019; accepted Dec. 20, 2019. The authors report no conflict of interest. Presented at the 39th Annual Society for Maternal Fetal Medicine Pregnancy Meeting, Las Vegas, Nevada, Feb. 11-16, 2019. Corresponding author: Emily Nuss, MD. emilynuss1@ gmail.com
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Childhood neurodevelopment after spontaneous versus indicated preterm birth Q4
Emily E. Nuss, MD; Jessica Spiegelman, MD; Amy L. Turitz, MD; Cynthia Gyamfi-Bannerman, MD, MSc
BACKGROUND: Preterm birth is the leading cause of neonatal morbidity and mortality. Individuals who survive preterm birth are at a higher risk for many long-term adverse effects, including neurodevelopmental deficits. There are many well-established risk factors for worse neurologic outcomes spanning the prenatal and postnatal periods; however, investigators have yet to assess whether the cause of preterm birth has an impact on neurodevelopment. OBJECTIVE: Our objective was to assess whether neurologic outcomes differ by children born via indicated versus spontaneous preterm birth. STUDY DESIGN: We performed secondary analysis of a multicenter trial assessing magnesium for neuroprotection in women at risk for preterm delivery from 24 to 31 weeks. We included women with live, nonanomalous, singleton gestations who delivered preterm; we excluded women whose children were missing 2-year follow-up information for reasons other than perinatal demise. The primary exposure was type of preterm birth: (1) spontaneous if the child’s mother presented with preterm labor or ruptured membranes, or (2) indicated if the child was delivered preterm iatrogenically. The primary outcome was death (including stillbirths, neonatal intensive care unit deaths, and deaths after discharge) or an abnormal Bayley II score by 2 years of age, defined as a Mental Developmental Index score or Psychomotor Developmental Index score 2 standard deviations below the mean. Secondary outcomes included death or Mental Developmental Index and Psychomotor Developmental Index scores 1 standard deviation or less, and neonatal morbidities associated with prematurity. Bivariate analyses of baseline characteristics by exposure were conducted. A logistic regression model was fitted to adjust for confounders. RESULTS: Of 1678 subjects, 1631 (97.2%) underwent spontaneous preterm birth and 47 (2.8%) underwent indicated preterm birth. Baseline maternal demographics and gestational age at delivery were
P
reterm birth, the leading cause of neonatal morbidity and mortality, occurs in approximately 10% of all pregnancies in the United States.1 However, with advancements in technology and collaboration among obstetricians and neonatologists, survival rates of preterm infants, especially those bordering viability, have been
Cite this article as: Nuss EE, Spiegelman J, Turitz AL, et al. Childhood neurodevelopment after spontaneous versus indicated preterm birth. Am J Obstet Gynecol MFM 2019;XX:x.ex-x.ex. 2589-9333/$36.00 Published by Elsevier Inc. https://doi.org/10.1016/j.ajogmf.2019.100082
similar between groups (29.6 weeks 7.8 versus 28.8 weeks 2.5, P ¼ .07). A Psychomotor Developmental Index score 2 standard deviations or less below the mean or death occurred in 340 (20.9%) spontaneous preterm birth subjects and 17 (36.2%) indicated preterm birth subjects (P ¼ .01). When adjusting for confounders, there remained an increased probability of a Psychomotor Developmental Index scores 2 standard deviations or less or death in indicated preterm birth subjects (P ¼ .02). Although not statistically significant, indicated preterm birth was also associated with higher odds of Mental Developmental Index scores 2 standard deviations or less or death, Psychomotor Developmental scores 1 standard deviation or less or death, and Mental Developmental Index scores 1 standard deviation or less or death (1.76, 1.59, and 1.45, respectively). Limiting the analysis to small for gestational age infants, there was no difference in neurologic outcomes. The same was true for when we excluded small for gestational age infants from our analysis. However, after adjusting for small for gestational age, the odds of a Psychomotor Developmental Index score 2 standard deviations or less or death remained significant higher in the indicated preterm birth group (adjusted odds ratio, 1.98; 95% confidence interval, 1.013.88). CONCLUSION: In this cohort of pregnant women who delivered preterm, indicated deliveries were associated with worse psychomotor development than were spontaneous deliveries. Other outcomes appeared to be poor, but our numbers were limited. This finding should be confirmed in a larger cohort of women undergoing medically indicated preterm deliveries. Key words: Bayley Scales of Infant Development, BEAM, indicated
preterm birth, neurodevelopment, preterm birth, spontaneous preterm birth
increasing.2e6 As such, clinicians and researchers alike are becoming more familiar with survivors of preterm birth and the lifelong morbidities know to affect this population. Individuals who are born preterm compared to those who are born at term are at an increased risk for neurodevelopmental deficits, including cerebral palsy,7e9 motor and cognitive impairments,10e12 visual and auditory deficits,13 and behavioral problems.14e16 Furthermore, risks of these deficits appear to increase with decreasing gestational age (GA).11,13,16,17 Among individuals who are born preterm, dozens of risk factors for worse neurodevelopmental outcomes exist, from
maternal factors that exist prior to conception, through pregnancy, and even into the postnatal period. Yet few studies, if any, have examined the relationship between the cause of preterm birth and longterm neurodevelopmental outcomes. Broadly, there are 3 main causes of preterm birth: (1) spontaneous preterm labor with intact membranes; (2) preterm premature rupture of membranes; and (3) labor induction or cesarean delivery for maternal or fetal indications. These 3 main etiologies are commonly classified into 2 functional groups: the first 2 etiologies are collectively referred to as spontaneous preterm birth (SPTB), and the last MONTH 2020 AJOG MFM
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AJOG MFM at a Glance Why was this study conducted? This study aimed to determine whether long-term neurodevelopmental outcomes differ by spontaneous vs indicated preterm birth. Key findings In this cohort of pregnancies, indicated preterm birth was associated with worse psychomotor development than spontaneous preterm birth in infants assessed at 2 years of age. What does this add to what is known? This study contributes to the growing body of literature regarding the adverse impact of preterm delivery on neurodevelopment, and is the first to look at how the cause of preterm birth affects long-term neurodevelopment.
etiology is referred to as indicated preterm birth (IPTB). Our objective was to determine whether long-term neurodevelopmental outcomes, as measured by the Bayley Scales of Infant Development II, would differ based on spontaneous vs indicated preterm birth. If IPTB is associated with worse neurodevelopmental outcomes, as is hypothesized, further studies examining the mechanism for this relationship as well as possible ways to mitigate this outcome may be warranted.
Materials and Methods This is a secondary analysis of the Beneficial Effects of Antenatal Magnesium Sulfate (BEAM) randomized controlled trial conducted through the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s MaternalFetal Medicine Units Network. This multicenter, randomized, placebo-controlled trial was conducted from 1997 to 2004 at 20 institutions across the United States. It tested the hypothesis that the administration of antenatal magnesium sulfate to women at high risk for early preterm delivery (2431 weeks’ gestation) would reduce the risk of moderate to severe cerebral palsy or death in their children. To be eligible for the parent trial, there had to be a high likelihood of preterm delivery, skewing the cohort toward more spontaneous preterm deliveries. Comprehensive details of the study design and methods have been previously reported.18
The current study is a retrospective observational cohort study. From the parent study, we included women with live, nonanomalous, singleton gestations who delivered preterm (<37 weeks’ gestation) and excluded women whose children were missing outcome data at 2 years of age for reasons other than perinatal demise. Gestational age was established by the last menstrual period and the earliest ultrasonogram date before randomization, in accordance with a standardized algorithm.18 The primary exposure was type of preterm birth: spontaneous preterm birth (SPTB) or indicated preterm birth (IPTB). Women who presented with preterm premature rupture of membranes (PPROM) or preterm labor were considered to be part of the SPTB group. PPROM was diagnosed if any of the 2 following criteria were met: pooling of the amniotic fluid in the vaginal vault; positive Nitrazine test result; or ferning of vaginal fluid. Alternatively, PPROM could also be diagnosed if 1 of the following criteria was met: indigo carmine pooling in the vagina after amnioinfusion; or visible leakage of amniotic fluid from the cervix. In addition in the SPTB group was preterm labor, defined as 6 contractions per hour and cervical dilation of 4 cm or more. If neither PPROM or preterm labor was present and delivery was planned for within 24 hours, then subjects and their children were considered to be part of the IPTB group. If subjects who initially
presented with PPROM or preterm labor later underwent iatrogenic delivery for various maternal or fetal indications, then these subjects were still considered to be a part of the SPTB group. Our primary outcome was the composite of death (including stillbirths, neonatal intensive care unit deaths, and deaths after discharge) or an abnormal Bayley Scales of Infant Development II (Bayley) score at 2 years of age, defined as a Mental Developmental Index (MDI) score or Psychomotor Developmental Index (PDI) score of less than 2 standard deviations (SD) below the mean. Bayley scores are a standardized series of measurements performed by a trained psychologist or psychometrist that are designed to assess for motor and cognitive developmental delay in children aged 0e3 years. The MDI score assesses sensory perception, knowledge, memory, problem solving, and early language. The PDI score assesses degree of control of the body, coordination of the large muscles, dexterity of the hands and fingers, dynamic movement, dynamic praxis, postural imitation, and stereognosis. The standardized mean Bayley II score is 100 with a standard deviation (SD) of 15. Death was included, as this is a competing outcome. Our secondary outcomes included the composite frequency of death or Bayley scores less than 1 SD below the mean, and various maternal and neonatal out- Q1 comes and morbidities associated with prematurity. Maternal baseline characteristics and secondary outcomes were compared using the Student t test for continuous variables, the c2 test or Fisher exact test for categorical variables, and the Wilcoxon rank-sum test for nonparametric data to assess for group differences. Our primary outcome was compared between groups, and unadjusted odds ratios with 95% confidence intervals were estimated. A logistic regression model was generated, adjusting for confounders based on either historical importance or significant correlation
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on bivariate analysis, including the following: maternal magnesium exposure, race/ethnicity, years of education, diabetes, drug use during pregnancy, alcohol use during pregnancy, multiple courses of steroids, and whether prenatal care was received (P < .05). Our sample size was fixed by the parent trial and by our exclusions. Setting the power at 80% and a type 1 error rate of 5%, we would be able to detect a relative risk of 1.85 or greater, or 0.3 or less. SAS software, version 9.4 (SAS Institute, Cary, NC) was used for analysis. This analysis was considered exempt by the Institutional Review Board at Columbia University Irving Medical Center because the study data is publicly available and de-identified.
Results Of the 2444 subjects in the parent study, we sequentially excluded 406 twin gestations, 83 gestations with major congenital malformations, 156 gestations for missing outcome data at 2 years age not due to death, 84 gestations with missing information on death status, and 37 gestations that resulted in term neonates (Figure 1). This left 1678 women and their offspring eligible for inclusion in our analysis. The majority of gestations in this study (1,631, 97.2%) resulted in SPTB, whereas the remaining resulted in IPTB (47, 2.8%) (Figure 1). Analysis of maternal baseline characteristics by exposure showed that the 2 groups differed in years of education but were similar across all other fronts including age, body mass index, race/ ethnicity, diabetes, substance use during pregnancy, and exposure to magnesium sulfate (Table 1). Analysis of our primary outcome (Table 2) revealed that PDI scores 2 SD from the mean or death occurred significantly more frequently in IPTB subjects than in SPTB subjects (17 [36.2%] compared to 340 [20.9%], P ¼ .01). However, the frequency of MDI scores 2 SD or death were similar between groups (16 [34.0%] compared to 386 [23.7%], P ¼ .10). We then fit a log-linear regression
279 280 281 Flow diagram of study participants 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 Nuss et al. Neurodevelopment of spontaneous vs indicated preterm infants. AJOG MFM 2019. 298 299 300 model and adjusted for maternal race/ preterm labor and subsequently un301 ethnicity, diabetes, antenatal magne- derwent indicated deliveries, intra302 sium, and steroid exposure, drug and amniotic infection was the most 303 alcohol use during pregnancy, years of common cause. Among the subjects 304 education, and whether or not pre- originally in the IPTB group whose 305 natal care was received. In this delivery had been planned, many 306 adjusted model, there remained an different indications were represented, 307 increased probability of PDI scores 2 such as placental abruptions, placental 308 SD from the mean or death in IPTB previas, fetal distress, and intrauterine 309 subjects (adjusted odds ratio [OR], growth restriction. Subjects in the 310 2.21; 95% confidence interval [CI], IPTB group were more likely to have 311 1.15e4.23, P ¼ 0.02). Although not received multiple courses of steroids 312 statistically significant, higher rates of and antibiotics and to undergo cesar313 MDI 2 SD from the mean or death, ean deliveries. There were no differ314 PDI 1 SD or death, and MDI 1 SD ences in incidences of preeclampsia, 315 or death (1.76, 1.59, and 1.45, chorioamnionitis, and postpartum 316 respectively) occurred in IPTB sub- endometritis among women in the 2 317 jects. Sensitivity analyses were per- groups. 318 formed, showing that when limiting Analysis of neonatal secondary out319 the analysis to only small for gesta- comes (Table 3) showed that neonates 320 tional age (SGA) infants, there was no who underwent IPTB had decreased 321 difference in neurologic outcomes. birthweights and smaller head circum322 The same was true after excluding ferences, and were more likely to be 323 SGA infants from our analysis. How- small for SGA. Compared to their 324 ever, after adjusting for SGA, the odds counterparts, IPTB infants had higher 325 of a PDI score 2 SD from the mean incidences of respiratory distress syn326 or death remained significantly higher drome and sepsis and a lower incidence 327 in the IPTB group (aOR, 1.98; 95% of transient tachypnea of the newborn 328 CI, 1.013.88). Apgar scores at 1 and 5 minutes, 329 Analysis of maternal secondary admission rates to the neonatal intensive 330 outcomes (Table 3) showed that the care unit, and incidences of both ½T3 331 average gestational ages between necrotizing enterocolitis and intraven332 groups were similar. The indications tricular hemorrhage were similar be333 for delivery varied: among the women tween groups. Between groups, there 334 who presented in spontaneous was no significant difference in the mean FIGURE 1
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TABLE 1
Maternal demographics based on indicated or spontaneous preterm birth Characteristic
Spontaneous preterm birth (n ¼ 1631)
Indicated preterm birth (n ¼ 47)
P value
Age, mean SD
26.37 5.76
26.76 6.57
.66
AMA (35 y)
169 (10.36%)
5 (10.64%)
.95
2
BMI (kg/m )
.93
<18.5
279 (17.11%)
7 (14.89%)
18.524.9
662 (40.59%)
18 (38.30%)
2529.9
330 (20.23%)
11 (23.40%)
>30
360 (22.07%)
11 (23.40%)
African American
732 (44.88%)
24 (51.06%)
Caucasian/white
580 (35.56%)
19 (40.43%)
Hispanic
287 (17.60%)
4 (8.51%)
Race/ethnicity
.44
Asian
13 (0.80%)
0
Native American/other
19 (1.16%)
0 <.0001a,b
Education, y 25% Q1
11
11
50% Median
12
12
75% Q3
13
12
Marital status
.82
Married
790 (48.50%)
22 (46.81%)
Single
839 (51.50%)
25 (53.19%)
88 (5.40%)
4 (8.51%)
.32c
1517 (93.01%)
41 (87.23%)
.13
Smoking
436 (26.73%)
17 (36.17%)
.15
Alcohol use
143 (8.77%)
5 (10.64%)
.66
Recreational drug use
161 (9.87%)
7 (14.89%)
.26
Magnesium sulfate
805 (49.36%)
22 (46.81%)
.73
Diabetes Received prenatal care
Data are presented as frequency (%) unless otherwise indicated. AMA, advanced maternal age; BMI, body mass index; SD, standard deviation. KruskalWallis test for comparison of variances; b P < .001; c Fisher exact test for frequencies <5. Nuss et al. Neurodevelopment of spontaneous vs indicated preterm infants. AJOG MFM 2019.
a
PDI and MDI scores; however, the incidence of a PDI score 2 SD from the mean was higher among IPTB infants. There was no difference in mortality rates between groups.
Discussion Principal findings In this cohort of pregnancies who delivered preterm, indicated deliveries were associated with worse psychomotor development than spontaneous deliveries in children at age 2 years.
Our findings contribute to the growing body of literature regarding the adverse impact of preterm delivery on neurodevelopment, and may offer improved patient counseling in the setting of IPTB.
Results in the context what is known Few studies have examined the immediate postnatal impact of IPTBs vs SPTBs19,20; however, their short followup periods limit our understanding of
the more permanent, indelible effects of the different causes of preterm delivery in this patient population. Therefore, our present study has broadened its scope beyond the neonatal population to examine how type of preterm delivery affects 2-yearold children as well.
Clinical implications Appropriate indications for indicated or iatrogenic preterm delivery are actively debated in obstetrics. In
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Original Research 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502
TABLE 2
Adjusted model of adverse Bayley II scores in infants born via indicated compared to spontaneous preterm birth Unadjusted OR (95% CI)
Adjusted OR (95% CI)
P valuea
PDI 2 SD or death
2.15 (1.17e3.95)
2.21 (1.15e4.23)
.02
MDI 2 SD or death
1.66 (0.90e3.08)
1.76 (0.91e3.40)
.10
PDI 1 SD or death
1.45 (0.81e2.59)
1.59 (0.86e2.96)
.14
MDI 1 SD or death
1.29 (0.72e2.31)
1.45 (0.77e2.75)
.25
Standard deviations refer to standard deviations from the mean. CI, confidence interval; MDI, Mental Developmental Index; OR, odds ratio; PDI, Psychomotor Developmental Index; SD, standard deviation. a
Adjusted for magnesium exposure, race/ethnicity, years of education, diabetes, drug use during pregnancy, alcohol use during pregnancy, multiple courses of steroids, and whether prenatal care was received. Nuss et al. Neurodevelopment of spontaneous vs indicated preterm infants. AJOG MFM 2019.
conjunction with the Society for Maternal-Fetal Medicine, the American College of Obstetricians and
Gynecologists published their committee opinion on appropriate indications for late-preterm and early-term birth.21
This committee opinion was recently updated to include a few more diagnoses while changing delivery timing
TABLE 3
Secondary outcomes based on indicated or spontaneous preterm birtha Spontaneous preterm birth (n ¼ 1631)
Characteristic
Indicated preterm birth (n ¼ 47)
P value
Maternal Membranes ruptured
1452 (98.91%)
Cesarean section
580 (35.56%)
0 32 (68.09%)
<.0001b,c <.0001d <.0001d
Primary indication for delivery Fetal stress/distress
9 (17.65%)
6 (13.04%)
IUGR
1 (1.96%)
9 (19.57%)
Intra-amniotic infection
33 (64.71%)
9 (19.57%)
Placental abruption/previa
4 (7.84%)
12 (26.09%)
Other reason
4 (7.74%)
10 (21.74%)
61 (3.84%)
5 (11.63%)
71 (4.35%)
18 (38.30%)
1499 (91.91%)
25 (53.19%)
61 (3.74%)
4 (8.51%)
12 (0.74%)
1 (2.13%)
.31c
Chorioamnionitis
203 (12.45%)
8 (17.02%)
.35
Postpartum endometritis
105 (6.44%)
3 (6.38)
1.00c
29.59 7.80
28.83 2.53
Multiple courses of steroids
.011e
Antibiotics No antibiotics Ampicillin and erythromycin Other antibiotics Preeclampsia
EGA at delivery (wk), mean SD Very preterm
a
1532 (93.93%)
46 (97.87%)
<.0001d
.07 .52c
Neonatal .0003d,f
Birthweight (g) 25% Q1
1000
748
50% Median
1370
1110
Nuss et al. Neurodevelopment of spontaneous vs indicated preterm infants. AJOG MFM 2019.
(continued)
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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 3
Secondary outcomes based on indicated or spontaneous preterm birtha (continued) Characteristic 75% Q3 Head circumference (cm)b
Spontaneous preterm birth (n ¼ 1631)
Indicated preterm birth (n ¼ 47)
1755
1380
26.95 3.04
25.87 2.83
Small for gestational age
31 (1.90%)
10 (21.28%)
1-min Apgar score < 5
402 (24.68%)
9 (19.15%)
5-min Apgar score < 7
P value .02e <.0001d .39
305 (18.72%)
8 (17.02%)
.77
1546 (95.37%)
47 (100.00%)
.27a
Respiratory distress syndrome
811 (50.03%)
33 (70.21%)
.006b
Transient tachypnea of the newborn
264 (16.29%)
2 (4.26%)
.02c,e
Necrotizing enterocolitis
143 (8.82%)
5 (10.64%)
.67
Intraventricular hemorrhage
325 (20.85%)
9 (20.00%)
.89
Sepsis
272 (16.78%)
14 (29.79%)
.02e
85.72 17.53
83.78 20.40
.49
MDI < 2 SD
255 (17.00%)
9 (22.50%)
.36
MDI < 1 SD
668 (44.53%)
19 (47.50%)
.71 .17
Admission to NICU
MDI score, mean SD
PDI score, mean SD
90.90 17.86
86.98 22.66
PDI < 2 SD
209 (13.93%)
10 (25.00%)
<.05e
PDI < 1 SD
485 (32.33%)
15 (37.50%)
.49
131 (8.03%)
7 (14.89%)
.09
Death Data are presented as frequency (%) unless otherwise indicated
EGA, estimated gestational age; IUGR, intrauterine growth restriction; MDI, Mental Developmental Index; PDI, Psychomotor Developmental Index; SD, standard deviation. Very preterm defined as <34 weeks’ EGA; b P < .01; c Fisher exact test for frequencies <5; d P < .001; e P < .05; f KruskalWallis test for comparison of variances. Nuss et al. Neurodevelopment of spontaneous vs indicated preterm infants. AJOG MFM 2019. a
for others.22 Prior to these recommendations, Gyamfi-Bannerman et al showed that there were a variety of reasons for late preterm iatrogenic delivery that were not evidence based.23 Our findings show an association between indicated preterm delivery and adverse neurodevelopment, and provide further evidence that initiation of iatrogenic preterm delivery should be truly indicated.
Research implications Based on the inclusion criteria of the parent trial, our cohort was skewed toward spontaneous preterm deliveries. Because of the small number of indicated preterm deliveries, it is difficult to draw meaningful conclusions by specific indication. The next steps in this area of research would include to confirm our findings in a larger or prospective cohort
and to examine our findings by indication for delivery.
Strengths and limitations There are several important limitations to this study. From a statistical standpoint, there was a large discrepancy in the sizes of the exposure groups, and the small size of the IPTB group introduced the risk of sampling bias and limited the generalizability of our analysis. However, after adjusting for potential confounders, we were still able to detect a difference, which should be considered hypothesis generating. In addition, this is a secondary analysis of a randomized controlled trial specifically designed for a different outcome related to magnesium and cerebral palsy. Although completion of Bayley II testing at age 2 years was part of
the parent study protocol, we had to exclude a proportion of patients who were lost to follow-up, and although we do not know how this would influence our findings, we do not have a reason to suspect differential loss to follow-up between groups. Moreover, limitations of the parent study should be considered, as their effects may be inherited in our current secondary analysis. For example, the subjects who were included in the original BEAM trial were deemed to have a high likelihood of delivering preterm based on PPROM or preterm labor. Because of the strict inclusion criteria for preterm labor, the sample was heavily skewed toward women presenting with PPROM (89.4%). Our SPTB cohort was similarly skewed toward PPROM and thus limits the generalizability of our results.
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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 717Q3 718 719 720 721 722 723 724 725 726
Therefore, the neurodevelopmental outcomes of the SPTB group may more accurately represent those who undergo SPTB following PPROM versus preterm labor. Finally, because of the small number of indicated preterm deliveries, we are unable to draw conclusions by specific indication in the IPTB group. It is possible that the specific indication, rather than all IPTB, is related to our findings. Our study also has several strengths. First, we examined data from a large, multicenter, randomized controlled trial with long-term follow-up. A large sample size was achieved, and data on a wide range of variables were rigorously collected and entered by trained and credentialed study staff. This allows for a more granular analysis of risk factors than insurance or International Classification of Diseases (ICD) ninth or tenth revision data can achieve. In addition, our findings were based on a widely used standardized scale, the Bayley Scales of Infant Development II, to measure neurodevelopmental deficits. Although the Bayley III scale now exists, at the time of data collection in the parent trial, it had not yet been developed.
Conclusion In conclusion, our study demonstrates that indicated preterm birth is associated with worse psychomotor outcomes, as assessed by Bayley II scores at 2 years of age. Future research should look to corroborate these findings and to evaluate the impact of specific indications’ on neurodevelopment to aid in clinical decision making and patient counseling. n Acknowledgments This article could not have been completed without the assistance of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the Maternal-Fetal Medicine Units Network, and the study Protocol Subcommittee. However, the contents of this report represent the views of the authors and do
not represent the views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the Maternal-Fetal Medicine Units Network, or the National Institutes of Health.
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Author and article information From the Division of Maternal-Fetal Medicine (Drs Nuss, Spiegelman, Turitz, and Gyamfi-Bannerman) and Department of Obstetrics and Gynecology (Drs Nuss, Spiegelman, Turitz, and Gyamfi-Bannerman), Columbia University Irving Medical Center, New York, NY Received Aug. 20, 2019; revised Dec. 18, 2019; accepted Dec. 20, 2019. The authors report no conflict of interest. Presented at the 39th Annual Society for Maternal Fetal Medicine Pregnancy Meeting, Las Vegas, Nevada, Feb. 11-16, 2019. Corresponding author: Emily Nuss, MD. emilynuss1@ gmail.com
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