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Impact of aspirin on fetal growth in diabetic pregnancies according to White classification
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Impact of aspirin on fetal growth in diabetic pregnancies according to White classification Q4
Katlynn Adkins, MD; Amanda A. Allshouse, MS; Torri D. Metz, MD, MS; Kent D. Heyborne, MD
BACKGROUND: Current US Preventive Services Task Force and other
RESULTS: All 444 women with pregestational diabetes and complete
guidelines recommend low-dose aspirin for all pregnant women with pregestational diabetes mellitus to prevent preeclampsia and small-forgestational-age birth. The Maternal-Fetal Medicine Units High-Risk Aspirin trial did not show a reduction in either preeclampsia or smallfor-gestational-age birth in diabetic women. OBJECTIVE: Our objective was to reassess the impact of aspirin on fetal growth in diabetic pregnancies overall and according to White classification. We hypothesized that aspirin improves fetal growth in pregnancies with vascular complications of diabetes at highest risk for poor fetal growth. STUDY DESIGN: We conducted secondary analysis of the cohort of diabetic women enrolled in the Maternal-Fetal Medicine Units High-Risk Aspirin trial. The impact of aspirin prophylaxis on birthweight was assessed in the overall cohort and in 2 groups categorized according to White classification as nonvascular (White class B, C, D) or vascular (White class R, F, RF). Birthweight was converted to Z-score normalized for gestational age at delivery and neonatal sex. Difference in birthweight Zscore between aspirin and placebo was tested with a 2-sample t test. The effect of vascular group, aspirin vs placebo randomization, and the interaction of the 2 on normalized birthweight percentile was estimated with linear regression with a multivariable model including covariates body mass index, tobacco use, race, and parity. The percentage of small and large-for-gestational-age newborns born to aspirin- vs placebo-treated women was compared between groups using Pearson exact c2 analysis, and an adjusted model was estimated by logistic regression.
outcome data were included (53 vascular, 391 nonvascular). Aspirin was significantly associated with a higher birthweight Z-score (0.283; 95% confidence interval, 0.023e0.544) in the overall cohort (P ¼ .03). In the adjusted model, the association of aspirin with higher birthweight Z-score was confined to neonates of women with nonvascular diabetes (0.341; 95% confidence interval, 0.677e0.006; P ¼ .044). An opposite but nonsignificant effect was observed among neonates from women with vascular diabetes (e0.416; 95% confidence interval, e1.335 to 0.503; P ¼ .6). This difference in the relationship of aspirin and birthweight Z-score by vascular group was significant at P ¼ .046. Aspirin-randomized women with nonvascular diabetes had more large-for-gestational-age births than those treated with placebo (40.2 vs 26.6%; P ¼ .005). Small-for-gestational-age births occurred at the same frequency with aspirin vs placebo randomization in the overall cohort (8% in each group) and in each vascular group. CONCLUSION: Inconsistent with our hypothesis, aspirin did not reduce small-for-gestational-age births in the overall cohort or either group. The increased incidence of large-for-gestational-age infants in aspirin-treated diabetic gestations is of potential concern given the known increased maternal and neonatal morbidity associated with macrosomia.
Introduction In late 2014, the US Preventive Services Task Force (USPSTF) recommended that low-dose aspirin (60-150 mg/d) be administered to all pregnant women with pregestational type 1 or type 2 diabetes in an effort to reduce the incidence of preeclampsia.1 Additional proposed benefits of aspirin administration are reductions in preterm birth and small-forgestational-age (SGA) birth. These USPSTF recommendations are in
Cite this article as: Adkins K, Allshouse AA, Metz TD, et al. Impact of aspirin on fetal growth in diabetic pregnancies according to White classification. Am J Obstet Gynecol 2017;volume:x.ex-x.ex. 0002-9378/$36.00 ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2017.05.062
Key words: aspirin, diabetes, fetal growth, large for gestational age,
macrosomia
agreement with previously published guidelines from the World Health Organization (WHO)2 and the National Institute for Health and Care Excellence,3 both of which also specifically recommend aspirin for pregnant women with pregestational diabetes (PGDM). The American Congress of Obstetricians and Gynecologists endorsed these guidelines in 2016.4 PGDM is a known risk factor for preeclampsia.5 The impact of PGDM on fetal growth is more complex and relates to White classification. For example, in a recent report, patients with vascular complications (White classifications R, F, RF, and H) were at increased risk for SGA births (17%), while those with White classification B, C, and D had increased rates of large-for-gestational-age (LGA)
newborns (34%, 28%, and 21%, respectively).6 While aspirin may reduce the risk of SGA in pregnancies at risk for preeclampsia in general, the impact of aspirin on fetal growth in diabetic pregnancies is not well understood. Of the 13 studies that formed the basis of the USPSTF conclusion that aspirin reduces SGA, only the Maternal-Fetal Medicine Units (MFMU) High-Risk Aspirin (HRA) trial enrolled women with PGDM.7 In this trial, aspirin was of no benefit in reducing either preeclampsia or SGA. Most other trials explicitly excluded women with PGDM. To better understand the possible impact of aspirin on fetal growth in patients with PGDM, we performed a secondary analysis of the MFMU HRA trial. Our hypothesis was that aspirin
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would reduce the risk of SGA in women with vascular complications of diabetes.
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Materials and Methods We performed a secondary analysis of the MFMU Network randomized controlled trial of aspirin (60 mg) for the prevention of preeclampsia in high-risk women.7 The original inclusion criteria were pregnancies with at least 1 risk factor for preeclampsia: preexisting insulin-dependent diabetes, chronic hypertension, multiple gestation, or preeclampsia in a previous pregnancy. Women were enrolled into 1 of 4 mutually exclusive high-risk groups defined as: (1) diabetes (with or without prior preeclampsia or chronic hypertension), (2) chronic hypertension (with or without prior preeclampsia), (3) multifetal gestation (with or without prior preeclampsia), and (4) previous preeclampsia (and no other risk factor). The protocol received institutional review board approval at each center, and all participating women provided written informed consent. This secondary analysis was considered exempt by the Colorado Multiple Institutional Review Board. Full details of the study design are available in the original article. Briefly, enrollment of eligible women occurred in the calendar years 1991 through 1995 during the 13th through 26th week of pregnancy. Women were randomized 1:1 to receive aspirin (60 mg) or placebo in a double-blind, randomized, placebocontrolled trial design to assess the impact of aspirin on the incidence of preeclampsia. Adherence to study drug regimen was measured by questioning of women, counting pills, and measuring thromboxane in serum. For this analysis, we included all women in the MFMU HRA study with PGDM for whom complete outcome data were available. Women with PGDM and chronic hypertension were class D in accordance with the revised White classification.8 Women were assigned to 1 of 2 mutually exclusive vascular groups: nonvascular (White class B, C, D) or vascular (White class R, F, RF). We used a previously published algorithm for
Patient selection from Maternal-Fetal Medicine Units High-Risk Aspirin trial. GA, gestational age; PGDM, pregestational diabetes. Adkins et al. Aspirin and fetal growth in diabetic pregnancies. Am J Obstet Gynecol 2017.
transforming birthweight into a normalized Z-score for gestational age at delivery and neonatal sex.9 From Zscores, neonates were categorized as SGA, average for gestational age, or LGA. Body mass index (BMI) calculated from prepregnancy weight was categorized according to WHO classifications with <18.5 kg/m2 underweight, 18.524.9 kg/m2 normal, 25.0-29.9 kg/m2 overweight, and 30 kg/m2 obese. For some analyses, underweight and normal BMI categories were combined because of the low frequency of women categorized as underweight.
Statistical Methods The success of randomization within this study population was assessed by comparing demographics between placebo- and aspirin-randomized women, with differences tested using c2 for
categorical and 2-sample t tests for continuous measures. The effect of vascular group, aspirin vs placebo randomization, and the interaction of the 2 on normalized birthweight percentile was estimated using linear regression with a multivariable model including covariates expected to impact birthweight based on clinical judgement: BMI category, tobacco use, race, and parity. The interaction of vascular group and randomization was parameterized as part of our primary hypothesis. The percentage of SGA and LGA newborns born to aspirin- vs placebo-treated women was compared between groups using Pearson exact c2 analysis, and a logistic regression model was estimated to adjust for covariates expected to impact birthweight based on clinical judgement: maternal BMI category, smoking, race, and parity. The adjusted estimates for the overall cohort include vascular group as a
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279 280 281 Demographic characteristics by randomization and vascular diabetes categorization 282 Vascular Nonvascular Aspirin Placebo 283 n ¼ 53 n ¼ 391 Characteristic n ¼ 221 n ¼ 223 P P 284 Parous 107 (48.4) 114 (51.1) .569 15 (28.3) 206 (52.7) <.001 285 286 Age, y 287 <35 204 (92.7) 197 (88.3) .115 50 (94.3) 351 (90.0) .312 288 35 16 (7.3) 26 (11.7) 3 (5.7) 39 (10.0) 289 Body mass index 290 291 Underweight 3 (1.4) 3 (1.4) .712 1 (1.9) 5 (1.3) .672 292 Normal 103 (46.8) 95 (43.2) 25 (47.2) 173 (44.7) 293 Overweight 44 (20.0) 54 (24.6) 14 (26.4) 84 (21.7) 294 Obese 70 (31.8) 68 (30.9) 13 (24.5) 125 (32.3) 295 296 Black race 89 (40.2) 86 (38.6) .713 13 (24.5) 162 (41.4) .018 297 Education 12 y 130 (58.8) 144 (64.6) .213 29 (54.7) 245 (62.7) .264 298 Gestational age, wk, at randomization, mean (SD) 18.5 (0.3) 18.1 (0.3) .329 18.4 (0.6) 18.3 (0.2) .878 299 Chronic hypertension 21 (9.5) 30 (13.5) .192 16 (30.2) 35 (9.0) <.001 300 301 Cigarette smoking 302 Never 155 (70.1) 150 (67.6) .626 39 (73.6) 266 (68.2) .564 303 Quit during pregnancy 18 (8.1) 24 (10.8) 3 (5.7) 39 (10.0) 304 Yes, current 48 (21.7) 48 (21.6) 11 (20.8) 85 (21.8) 305 306 White classification 307 B 78 (35.3) 74 (33.2) .783 0 (0.0) 152 (38.9) 308 C 94 (42.5) 92 (41.3) 0 (0.0) 186 (47.6) 309 D 27 (12.2) 26 (11.7) 0 (0.0) 53 (13.6) 310 311 F 15 (6.8) 20 (9.0) 35 (66.0) 0 (0.0) 312 R 7 (3.2) 11 (4.9) 18 (34.0) 0 (0.0) 313 Values are n (%) unless otherwise noted. 314 Adkins et al. Aspirin and fetal growth in diabetic pregnancies. Am J Obstet Gynecol 2017. 315 316 317 covariate but without an interaction with or RF) as shown in Figure 1. De- birthweight Z-score was confined to ½F1 318 randomization. mographics for randomization groups neonates of women with nonvascular 319 In a sensitivity analysis, we assessed and vascular and nonvascular groups are diabetes (0.341; 95% CI, 0.677e0.006; 320 the robustness of results on normalized tabulated in the Table. Women with P ¼ .044). An opposite but nonsignifi- ½T1 321 birthweight when gestational age at vascular diabetes were less likely to be cant effect was observed among neonates 322 randomization was week <17 vs week parous (P < .001). Black race was more from women with vascular diabetes 323 17. common among women with nonvas- (e0.416; 95% CI, e1.335 to 0.503; 324 All analyses were intent to treat, using cular PGDM. There were no significant P ¼ .6). This difference in the relation325 software (SAS 9.4; SAS Institute Inc, differences in other demographic char- ship of aspirin and birthweight Z-score 326 Cary, NC). Graphic results were created acteristics including age, BMI, and to- by vascular group was significant at 327 using software (GraphPad Prism 6.07; bacco use between vascular and P ¼ .046 (Figure 2). As 198 participants ½F2 328 GraphPad, La Jolla, CA). nonvascular groups (Table). (45%) were enrolled week <17, and 329 Aspirin was significantly associated 246 (55%) were enrolled week 17, 330 with a higher birthweight Z-score sensitivity analysis was conducted to Results 331 Of the 444 women with PGDM enrolled (0.283; 95% confidence interval [CI], explore the existence of an impact of 332 in the HRA trial, 391 had nonvascular 0.023e0.544) in the overall cohort gestational age at randomization on these 333 diabetes (White class B, C, or D) and 53 (P ¼ .03). In the adjusted model, the findings. There was a negligible difference 334 had vascular diabetes (White class R, F, association of aspirin with higher in the impact of aspirin on birthweight TABLE
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Effect of aspirin on adjusted birthweight Zscores for pregestational diabetic gestations overall and by vascular group. Adkins et al. Aspirin and fetal growth in diabetic pregnancies. Am J Obstet Gynecol 2017.
Z-score for vascular vs nonvascular diabetics who enrolled <17 vs 17 weeks; the 3-way interaction term was not significant (P ¼ .4, data not shown). Among all gestations included in the analysis, 32% (n ¼ 142) were LGA and 8% (n ¼ 36) were SGA. There were significantly more LGA births among aspirin-treated pregnancies as compared to those randomized to placebo (37% vs 27%, P ¼ .025). For the nonvascular diabetics, those treated with aspirin had significantly more LGA births (40.2%) compared to those in the placebo group (26.6%)
FIGURE 3 ---
Effect of aspirin on proportions of small-for-gestational-age (SGA), appropriatefor-gestational-age (AGA), and large-forgestational-age (LGA) infants in unadjusted model. Adkins et al. Aspirin and fetal growth in diabetic pregnancies. Am J Obstet Gynecol 2017.
(P ¼ .005). Among women with vascular diabetes, the difference in rates of LGA birth between the aspirin (9%) and placebo (29%) groups was not significant (P ¼ .10). Aspirin was not significantly associated with differences in SGA in the nonvascular group (8% with aspirin, 7% with placebo, P ¼ .70), the vascular group (9% with aspirin, 16% with placebo, P ¼ .69), or in the overall cohort (8% with both aspirin and placebo) (Figure 3). In a multivariate analysis adjusted for BMI, tobacco use, race, and parity, the association of aspirin with more LGA births persisted among women in the overall cohort (odds ratio [OR], 1.696; 95% CI, 1.096e2.625) and in the nonvascular group (OR, 2.09; 95% CI, 1.31e3.33). Aspirin was not associated with a significant difference in SGA in the overall cohort or within either vascular group in the adjusted analysis (overall cohort OR, 1.11; 95% CI, 0.54e2.28, nonvascular OR, 1.22; 95% CI, 0.55e2.69, vascular OR, 0.69; 95% CI, 0.113e4.22) (Figure 4).
Comment While aspirin was associated with an increase in fetal growth in this cohort of women with PGDM, this effect was due to an increase in LGA birth, and this effect was confined to women with nonvascular PGDM already at risk for fetal overgrowth. Contrary to our hypothesis, aspirin did not improve fetal growth in vascular PGDM pregnancies at highest risk for SGA, nor did it reduce SGA in the nonvascular group or the overall cohort. These observations have potential importance in further refining what populations might benefit from aspirin prophylaxis. Macrosomia is one of the central complications of diabetes in pregnancy. Given the increased maternal and neonatal morbidity associated with LGA birth these observations are of concern.10-13 The strengths of this study are the prospective data collection that occurred at the time of the original trial by trained research nurses. Our primary outcome of gestational agespecific birthweight percentiles that
391 392 393 --394 395 396 397 398 399 400 401 402 ½F3 403 404 405 Effect of aspirin on adjusted odds ratios for small-for-gestational-age (SGA) vs large-for406 gestational-age (LGA) infants overall and by 407 vascular group. 408 CI, confidence interval. 409 Adkins et al. Aspirin and fetal growth in diabetic pregnancies. 410 Am J Obstet Gynecol 2017. 411 412 413 relies on the objective measures of 414 gestational age at delivery and birth415 weight allows rigorous comparison. 416 Our results were robust to gestational 417 age at enrollment. We are limited in ½F4 418 assessing aspirin vs placebo within the 419 vascular diabetic group because of the 420 low frequency of vascular diabetes, 421 thus seemingly large trends towards 422 lower risk of both SGA and LGA with 423 aspirin occur in the absence of statis424 tical significance. 425 An additional limitation of our study 426 is our inability to report results for 427 women according to type 1 vs type 2 428 diabetes or according to medications 429 used to treat diabetes in pregnancy, as 430 these variables were not captured in the 431 original data set. Women with type 2 432 diabetes as a group may be more likely to 433 be obese, an additional risk factor for 434 LGA birth. However, we controlled for 435 maternal BMI in our adjusted analysis 436 and our findings persisted. In addition, 437 as a secondary analysis of a randomized 438 controlled trial, we would anticipate that 439 type 1 and type 2 diabetics would be 440 evenly allocated between treatment 441 groups. The recent study by Bennett 442 et al6 confirms the strong association 443 between birthweight and White classifi444 cation. Although not a primary outcome 445 of this study, we also found, among 446 placebo-randomized women, a higher FIGURE 4
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proportion of LGA births in the nonvascular group (26%) and a higher proportion of SGA births in the vascular group (16%). Together, these observations lend support to our vascular vs nonvascular grouping as biologically valid. We are unaware of similar data on abnormal growth as stratified by type 1 vs type 2 PGDM. The observation that aspirin increased the chance of LGA in the overall cohort and nonvascular PGDM gestations must be interpreted with caution. As an unplanned secondary analysis, such an observation should be viewed as hypothesis-generating. Is this a biologically plausible hypothesis? Fetal growth is a complex interaction of genetics, growth factors, substrate availability, and other factors. Given that PGDM pregnancies are at risk for preeclampsia,5 a disease characterized by altered placental perfusion,14,15 and given that aspirin acts by improving placental perfusion (among other mechanisms),16,17 we submit that aspirin could further augment the already increased substrate availability in PGDM pregnancies and further augment fetal growth. As aspirin has gained increased support as prophylaxis for preeclampsia, SGA and preterm birth, the inclusion criteria for prophylaxis have also broadened. However, the inclusion of women with PGDM in these recommendations may not be evidence-based, beyond the mere fact that PGDM patients are at increased risk for preeclampsia. The MFMU HRA trial is the only aspirin intervention study to specifically include women with PGDM, and most other trials specifically excluded these women. The MFMU HRA trial did not show a reduction in preeclampsia or SGA overall and there was no reduction in preeclampsia in the PGDM subgroup in particular. Our failure to detect a benefit (no reduction
in SGA) and finding of potential harm (increased risk of LGA) thus provide incremental information regarding the appropriate use of aspirin in pregnancy. These findings may warrant further investigation as well as consideration in future recommendations regarding the use of aspirin in pregnancy. n Acknowledgment The authors appreciate the assistance of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and Maternal-Fetal Medicine Units (MFMU) Network in making the database from the MFMU HighRisk Aspirin trial available for secondary analysis.
References 1. LeFevre ML; US Preventive Services Task Force. Low-dose aspirin use for the prevention of morbidity and mortality from preeclampsia: US Preventive Services Task Force recommendation statement. Ann Intern Med 2014;161: 819-26. 2. Organization WH. WHO recommendations for prevention and treatment of preeclampsia and eclampsia. Geneva: World Health Organization; 2014. 3. Redman CW. Hypertension in pregnancy: the NICE guidelines. Heart 2011;97:1967-9. 4. American College of Obstetricians and Gynecologists. Practice advisory on low-dose aspirin and prevention of preeclampsia: updated recommendations. 2016. 5. Henderson JT, Whitlock EP, O’Connor E, Senger CA, Thompson JH, Rowland MG. Lowdose aspirin for prevention of morbidity and mortality from preeclampsia: a systematic evidence review for the US Preventive Services Task Force. Ann Intern Med 2014;160:695-703. 6. Bennett SN, Tita A, Owen J, Biggio JR, Harper LM. Assessing White’s classification of pregestational diabetes in a contemporary diabetic population. Obstet Gynecol 2015;125: 1217-23. 7. Caritis S, Sibai B, Hauth J, et al. Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 1998;338:701-5. 8. Hare JW, White P. Gestational diabetes and the White classification. Diabetes Care 1980;3: 394. 9. Talge NM, Mudd LM, Sikorskii A, Basso O. United States birth weight reference corrected
for implausible gestational age estimates. Pediatrics 2014;133:844-53. 10. Nesbitt TS, Gilbert WM, Herrchen B. Shoulder dystocia and associated risk factors with macrosomic infants born in California. Am J Obstet Gynecol 1998;179: 476-80. 11. Oral E, Cagdas A, Gezer A, Kaleli S, Aydinli K, Ocer F. Perinatal and maternal outcomes of fetal macrosomia. Eur J Obstet Gynecol Reprod Biol 2001;99:167-71. 12. Stotland NE, Caughey AB, Breed EM, Escobar GJ. Risk factors and obstetric complications associated with macrosomia. Int J Gynaecol Obstet 2004;87:220-6. 13. Weissmann-Brenner A, Simchen MJ, Zilberberg E, et al. Maternal and neonatal outcomes of large for gestational age pregnancies. Acta Obstet Gynecol Scand 2012;91:844-9. 14. Campbell S. Placental vasculature as visualized by 3D power Doppler angiography and 3D color Doppler imaging. Ultrasound Obstet Gynecol 2007;30:917-20. 15. Fisher SJ. Why is placentation abnormal in preeclampsia? Am J Obstet Gynecol 2015;213: S115-22. 16. Dekker GA, Sibai BM. Etiology and pathogenesis of preeclampsia: current concepts. Am J Obstet Gynecol 1998;179:1359-75. 17. Walsh SW. Physiology of low-dose aspirin therapy for the prevention of preeclampsia. Semin Perinatol 1990;14:152-70.
Author and article information
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From the University of Colorado School of Medicine, Q1 Aurora, CO (Drs Adkins, Metz, and Heyborne); Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Denver, Denver, CO (Ms Allshouse); and Denver Health Medical Center, Denver, CO (Drs Metz and Heyborne). Received Feb. 21, 2017; revised May 18, 2017; accepted May 31, 2017. Dr Metz is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) under award no. 2K12HD001271-16. The contents of this report represent the views of the authors and do not necessarily represent the views of the NICHD Maternal-Fetal Medicine Units Network or the National Institutes of Health. The authors report no conflict of interest. Presented at poster session III of the 37th Annual Pregnancy Meeting of the Society for Maternal-Fetal Medicine, Las Vegas, NV, Jan. 27, 2017. Corresponding author: Kent D. Heyborne, MD. kent. [email protected]
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Impact of aspirin on fetal growth in diabetic pregnancies according to White classification Q4
Katlynn Adkins, MD; Amanda A. Allshouse, MS; Torri D. Metz, MD, MS; Kent D. Heyborne, MD
BACKGROUND: Current US Preventive Services Task Force and other
RESULTS: All 444 women with pregestational diabetes and complete
guidelines recommend low-dose aspirin for all pregnant women with pregestational diabetes mellitus to prevent preeclampsia and small-forgestational-age birth. The Maternal-Fetal Medicine Units High-Risk Aspirin trial did not show a reduction in either preeclampsia or smallfor-gestational-age birth in diabetic women. OBJECTIVE: Our objective was to reassess the impact of aspirin on fetal growth in diabetic pregnancies overall and according to White classification. We hypothesized that aspirin improves fetal growth in pregnancies with vascular complications of diabetes at highest risk for poor fetal growth. STUDY DESIGN: We conducted secondary analysis of the cohort of diabetic women enrolled in the Maternal-Fetal Medicine Units High-Risk Aspirin trial. The impact of aspirin prophylaxis on birthweight was assessed in the overall cohort and in 2 groups categorized according to White classification as nonvascular (White class B, C, D) or vascular (White class R, F, RF). Birthweight was converted to Z-score normalized for gestational age at delivery and neonatal sex. Difference in birthweight Zscore between aspirin and placebo was tested with a 2-sample t test. The effect of vascular group, aspirin vs placebo randomization, and the interaction of the 2 on normalized birthweight percentile was estimated with linear regression with a multivariable model including covariates body mass index, tobacco use, race, and parity. The percentage of small and large-for-gestational-age newborns born to aspirin- vs placebo-treated women was compared between groups using Pearson exact c2 analysis, and an adjusted model was estimated by logistic regression.
outcome data were included (53 vascular, 391 nonvascular). Aspirin was significantly associated with a higher birthweight Z-score (0.283; 95% confidence interval, 0.023e0.544) in the overall cohort (P ¼ .03). In the adjusted model, the association of aspirin with higher birthweight Z-score was confined to neonates of women with nonvascular diabetes (0.341; 95% confidence interval, 0.677e0.006; P ¼ .044). An opposite but nonsignificant effect was observed among neonates from women with vascular diabetes (e0.416; 95% confidence interval, e1.335 to 0.503; P ¼ .6). This difference in the relationship of aspirin and birthweight Z-score by vascular group was significant at P ¼ .046. Aspirin-randomized women with nonvascular diabetes had more large-for-gestational-age births than those treated with placebo (40.2 vs 26.6%; P ¼ .005). Small-for-gestational-age births occurred at the same frequency with aspirin vs placebo randomization in the overall cohort (8% in each group) and in each vascular group. CONCLUSION: Inconsistent with our hypothesis, aspirin did not reduce small-for-gestational-age births in the overall cohort or either group. The increased incidence of large-for-gestational-age infants in aspirin-treated diabetic gestations is of potential concern given the known increased maternal and neonatal morbidity associated with macrosomia.
Introduction In late 2014, the US Preventive Services Task Force (USPSTF) recommended that low-dose aspirin (60-150 mg/d) be administered to all pregnant women with pregestational type 1 or type 2 diabetes in an effort to reduce the incidence of preeclampsia.1 Additional proposed benefits of aspirin administration are reductions in preterm birth and small-forgestational-age (SGA) birth. These USPSTF recommendations are in
Cite this article as: Adkins K, Allshouse AA, Metz TD, et al. Impact of aspirin on fetal growth in diabetic pregnancies according to White classification. Am J Obstet Gynecol 2017;volume:x.ex-x.ex. 0002-9378/$36.00 ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2017.05.062
Key words: aspirin, diabetes, fetal growth, large for gestational age,
macrosomia
agreement with previously published guidelines from the World Health Organization (WHO)2 and the National Institute for Health and Care Excellence,3 both of which also specifically recommend aspirin for pregnant women with pregestational diabetes (PGDM). The American Congress of Obstetricians and Gynecologists endorsed these guidelines in 2016.4 PGDM is a known risk factor for preeclampsia.5 The impact of PGDM on fetal growth is more complex and relates to White classification. For example, in a recent report, patients with vascular complications (White classifications R, F, RF, and H) were at increased risk for SGA births (17%), while those with White classification B, C, and D had increased rates of large-for-gestational-age (LGA)
newborns (34%, 28%, and 21%, respectively).6 While aspirin may reduce the risk of SGA in pregnancies at risk for preeclampsia in general, the impact of aspirin on fetal growth in diabetic pregnancies is not well understood. Of the 13 studies that formed the basis of the USPSTF conclusion that aspirin reduces SGA, only the Maternal-Fetal Medicine Units (MFMU) High-Risk Aspirin (HRA) trial enrolled women with PGDM.7 In this trial, aspirin was of no benefit in reducing either preeclampsia or SGA. Most other trials explicitly excluded women with PGDM. To better understand the possible impact of aspirin on fetal growth in patients with PGDM, we performed a secondary analysis of the MFMU HRA trial. Our hypothesis was that aspirin
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would reduce the risk of SGA in women with vascular complications of diabetes.
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Materials and Methods We performed a secondary analysis of the MFMU Network randomized controlled trial of aspirin (60 mg) for the prevention of preeclampsia in high-risk women.7 The original inclusion criteria were pregnancies with at least 1 risk factor for preeclampsia: preexisting insulin-dependent diabetes, chronic hypertension, multiple gestation, or preeclampsia in a previous pregnancy. Women were enrolled into 1 of 4 mutually exclusive high-risk groups defined as: (1) diabetes (with or without prior preeclampsia or chronic hypertension), (2) chronic hypertension (with or without prior preeclampsia), (3) multifetal gestation (with or without prior preeclampsia), and (4) previous preeclampsia (and no other risk factor). The protocol received institutional review board approval at each center, and all participating women provided written informed consent. This secondary analysis was considered exempt by the Colorado Multiple Institutional Review Board. Full details of the study design are available in the original article. Briefly, enrollment of eligible women occurred in the calendar years 1991 through 1995 during the 13th through 26th week of pregnancy. Women were randomized 1:1 to receive aspirin (60 mg) or placebo in a double-blind, randomized, placebocontrolled trial design to assess the impact of aspirin on the incidence of preeclampsia. Adherence to study drug regimen was measured by questioning of women, counting pills, and measuring thromboxane in serum. For this analysis, we included all women in the MFMU HRA study with PGDM for whom complete outcome data were available. Women with PGDM and chronic hypertension were class D in accordance with the revised White classification.8 Women were assigned to 1 of 2 mutually exclusive vascular groups: nonvascular (White class B, C, D) or vascular (White class R, F, RF). We used a previously published algorithm for
Patient selection from Maternal-Fetal Medicine Units High-Risk Aspirin trial. GA, gestational age; PGDM, pregestational diabetes. Adkins et al. Aspirin and fetal growth in diabetic pregnancies. Am J Obstet Gynecol 2017.
transforming birthweight into a normalized Z-score for gestational age at delivery and neonatal sex.9 From Zscores, neonates were categorized as SGA, average for gestational age, or LGA. Body mass index (BMI) calculated from prepregnancy weight was categorized according to WHO classifications with <18.5 kg/m2 underweight, 18.524.9 kg/m2 normal, 25.0-29.9 kg/m2 overweight, and 30 kg/m2 obese. For some analyses, underweight and normal BMI categories were combined because of the low frequency of women categorized as underweight.
Statistical Methods The success of randomization within this study population was assessed by comparing demographics between placebo- and aspirin-randomized women, with differences tested using c2 for
categorical and 2-sample t tests for continuous measures. The effect of vascular group, aspirin vs placebo randomization, and the interaction of the 2 on normalized birthweight percentile was estimated using linear regression with a multivariable model including covariates expected to impact birthweight based on clinical judgement: BMI category, tobacco use, race, and parity. The interaction of vascular group and randomization was parameterized as part of our primary hypothesis. The percentage of SGA and LGA newborns born to aspirin- vs placebo-treated women was compared between groups using Pearson exact c2 analysis, and a logistic regression model was estimated to adjust for covariates expected to impact birthweight based on clinical judgement: maternal BMI category, smoking, race, and parity. The adjusted estimates for the overall cohort include vascular group as a
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279 280 281 Demographic characteristics by randomization and vascular diabetes categorization 282 Vascular Nonvascular Aspirin Placebo 283 n ¼ 53 n ¼ 391 Characteristic n ¼ 221 n ¼ 223 P P 284 Parous 107 (48.4) 114 (51.1) .569 15 (28.3) 206 (52.7) <.001 285 286 Age, y 287 <35 204 (92.7) 197 (88.3) .115 50 (94.3) 351 (90.0) .312 288 35 16 (7.3) 26 (11.7) 3 (5.7) 39 (10.0) 289 Body mass index 290 291 Underweight 3 (1.4) 3 (1.4) .712 1 (1.9) 5 (1.3) .672 292 Normal 103 (46.8) 95 (43.2) 25 (47.2) 173 (44.7) 293 Overweight 44 (20.0) 54 (24.6) 14 (26.4) 84 (21.7) 294 Obese 70 (31.8) 68 (30.9) 13 (24.5) 125 (32.3) 295 296 Black race 89 (40.2) 86 (38.6) .713 13 (24.5) 162 (41.4) .018 297 Education 12 y 130 (58.8) 144 (64.6) .213 29 (54.7) 245 (62.7) .264 298 Gestational age, wk, at randomization, mean (SD) 18.5 (0.3) 18.1 (0.3) .329 18.4 (0.6) 18.3 (0.2) .878 299 Chronic hypertension 21 (9.5) 30 (13.5) .192 16 (30.2) 35 (9.0) <.001 300 301 Cigarette smoking 302 Never 155 (70.1) 150 (67.6) .626 39 (73.6) 266 (68.2) .564 303 Quit during pregnancy 18 (8.1) 24 (10.8) 3 (5.7) 39 (10.0) 304 Yes, current 48 (21.7) 48 (21.6) 11 (20.8) 85 (21.8) 305 306 White classification 307 B 78 (35.3) 74 (33.2) .783 0 (0.0) 152 (38.9) 308 C 94 (42.5) 92 (41.3) 0 (0.0) 186 (47.6) 309 D 27 (12.2) 26 (11.7) 0 (0.0) 53 (13.6) 310 311 F 15 (6.8) 20 (9.0) 35 (66.0) 0 (0.0) 312 R 7 (3.2) 11 (4.9) 18 (34.0) 0 (0.0) 313 Values are n (%) unless otherwise noted. 314 Adkins et al. Aspirin and fetal growth in diabetic pregnancies. Am J Obstet Gynecol 2017. 315 316 317 covariate but without an interaction with or RF) as shown in Figure 1. De- birthweight Z-score was confined to ½F1 318 randomization. mographics for randomization groups neonates of women with nonvascular 319 In a sensitivity analysis, we assessed and vascular and nonvascular groups are diabetes (0.341; 95% CI, 0.677e0.006; 320 the robustness of results on normalized tabulated in the Table. Women with P ¼ .044). An opposite but nonsignifi- ½T1 321 birthweight when gestational age at vascular diabetes were less likely to be cant effect was observed among neonates 322 randomization was week <17 vs week parous (P < .001). Black race was more from women with vascular diabetes 323 17. common among women with nonvas- (e0.416; 95% CI, e1.335 to 0.503; 324 All analyses were intent to treat, using cular PGDM. There were no significant P ¼ .6). This difference in the relation325 software (SAS 9.4; SAS Institute Inc, differences in other demographic char- ship of aspirin and birthweight Z-score 326 Cary, NC). Graphic results were created acteristics including age, BMI, and to- by vascular group was significant at 327 using software (GraphPad Prism 6.07; bacco use between vascular and P ¼ .046 (Figure 2). As 198 participants ½F2 328 GraphPad, La Jolla, CA). nonvascular groups (Table). (45%) were enrolled week <17, and 329 Aspirin was significantly associated 246 (55%) were enrolled week 17, 330 with a higher birthweight Z-score sensitivity analysis was conducted to Results 331 Of the 444 women with PGDM enrolled (0.283; 95% confidence interval [CI], explore the existence of an impact of 332 in the HRA trial, 391 had nonvascular 0.023e0.544) in the overall cohort gestational age at randomization on these 333 diabetes (White class B, C, or D) and 53 (P ¼ .03). In the adjusted model, the findings. There was a negligible difference 334 had vascular diabetes (White class R, F, association of aspirin with higher in the impact of aspirin on birthweight TABLE
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Effect of aspirin on adjusted birthweight Zscores for pregestational diabetic gestations overall and by vascular group. Adkins et al. Aspirin and fetal growth in diabetic pregnancies. Am J Obstet Gynecol 2017.
Z-score for vascular vs nonvascular diabetics who enrolled <17 vs 17 weeks; the 3-way interaction term was not significant (P ¼ .4, data not shown). Among all gestations included in the analysis, 32% (n ¼ 142) were LGA and 8% (n ¼ 36) were SGA. There were significantly more LGA births among aspirin-treated pregnancies as compared to those randomized to placebo (37% vs 27%, P ¼ .025). For the nonvascular diabetics, those treated with aspirin had significantly more LGA births (40.2%) compared to those in the placebo group (26.6%)
FIGURE 3 ---
Effect of aspirin on proportions of small-for-gestational-age (SGA), appropriatefor-gestational-age (AGA), and large-forgestational-age (LGA) infants in unadjusted model. Adkins et al. Aspirin and fetal growth in diabetic pregnancies. Am J Obstet Gynecol 2017.
(P ¼ .005). Among women with vascular diabetes, the difference in rates of LGA birth between the aspirin (9%) and placebo (29%) groups was not significant (P ¼ .10). Aspirin was not significantly associated with differences in SGA in the nonvascular group (8% with aspirin, 7% with placebo, P ¼ .70), the vascular group (9% with aspirin, 16% with placebo, P ¼ .69), or in the overall cohort (8% with both aspirin and placebo) (Figure 3). In a multivariate analysis adjusted for BMI, tobacco use, race, and parity, the association of aspirin with more LGA births persisted among women in the overall cohort (odds ratio [OR], 1.696; 95% CI, 1.096e2.625) and in the nonvascular group (OR, 2.09; 95% CI, 1.31e3.33). Aspirin was not associated with a significant difference in SGA in the overall cohort or within either vascular group in the adjusted analysis (overall cohort OR, 1.11; 95% CI, 0.54e2.28, nonvascular OR, 1.22; 95% CI, 0.55e2.69, vascular OR, 0.69; 95% CI, 0.113e4.22) (Figure 4).
Comment While aspirin was associated with an increase in fetal growth in this cohort of women with PGDM, this effect was due to an increase in LGA birth, and this effect was confined to women with nonvascular PGDM already at risk for fetal overgrowth. Contrary to our hypothesis, aspirin did not improve fetal growth in vascular PGDM pregnancies at highest risk for SGA, nor did it reduce SGA in the nonvascular group or the overall cohort. These observations have potential importance in further refining what populations might benefit from aspirin prophylaxis. Macrosomia is one of the central complications of diabetes in pregnancy. Given the increased maternal and neonatal morbidity associated with LGA birth these observations are of concern.10-13 The strengths of this study are the prospective data collection that occurred at the time of the original trial by trained research nurses. Our primary outcome of gestational agespecific birthweight percentiles that
391 392 393 --394 395 396 397 398 399 400 401 402 ½F3 403 404 405 Effect of aspirin on adjusted odds ratios for small-for-gestational-age (SGA) vs large-for406 gestational-age (LGA) infants overall and by 407 vascular group. 408 CI, confidence interval. 409 Adkins et al. Aspirin and fetal growth in diabetic pregnancies. 410 Am J Obstet Gynecol 2017. 411 412 413 relies on the objective measures of 414 gestational age at delivery and birth415 weight allows rigorous comparison. 416 Our results were robust to gestational 417 age at enrollment. We are limited in ½F4 418 assessing aspirin vs placebo within the 419 vascular diabetic group because of the 420 low frequency of vascular diabetes, 421 thus seemingly large trends towards 422 lower risk of both SGA and LGA with 423 aspirin occur in the absence of statis424 tical significance. 425 An additional limitation of our study 426 is our inability to report results for 427 women according to type 1 vs type 2 428 diabetes or according to medications 429 used to treat diabetes in pregnancy, as 430 these variables were not captured in the 431 original data set. Women with type 2 432 diabetes as a group may be more likely to 433 be obese, an additional risk factor for 434 LGA birth. However, we controlled for 435 maternal BMI in our adjusted analysis 436 and our findings persisted. In addition, 437 as a secondary analysis of a randomized 438 controlled trial, we would anticipate that 439 type 1 and type 2 diabetics would be 440 evenly allocated between treatment 441 groups. The recent study by Bennett 442 et al6 confirms the strong association 443 between birthweight and White classifi444 cation. Although not a primary outcome 445 of this study, we also found, among 446 placebo-randomized women, a higher FIGURE 4
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proportion of LGA births in the nonvascular group (26%) and a higher proportion of SGA births in the vascular group (16%). Together, these observations lend support to our vascular vs nonvascular grouping as biologically valid. We are unaware of similar data on abnormal growth as stratified by type 1 vs type 2 PGDM. The observation that aspirin increased the chance of LGA in the overall cohort and nonvascular PGDM gestations must be interpreted with caution. As an unplanned secondary analysis, such an observation should be viewed as hypothesis-generating. Is this a biologically plausible hypothesis? Fetal growth is a complex interaction of genetics, growth factors, substrate availability, and other factors. Given that PGDM pregnancies are at risk for preeclampsia,5 a disease characterized by altered placental perfusion,14,15 and given that aspirin acts by improving placental perfusion (among other mechanisms),16,17 we submit that aspirin could further augment the already increased substrate availability in PGDM pregnancies and further augment fetal growth. As aspirin has gained increased support as prophylaxis for preeclampsia, SGA and preterm birth, the inclusion criteria for prophylaxis have also broadened. However, the inclusion of women with PGDM in these recommendations may not be evidence-based, beyond the mere fact that PGDM patients are at increased risk for preeclampsia. The MFMU HRA trial is the only aspirin intervention study to specifically include women with PGDM, and most other trials specifically excluded these women. The MFMU HRA trial did not show a reduction in preeclampsia or SGA overall and there was no reduction in preeclampsia in the PGDM subgroup in particular. Our failure to detect a benefit (no reduction
in SGA) and finding of potential harm (increased risk of LGA) thus provide incremental information regarding the appropriate use of aspirin in pregnancy. These findings may warrant further investigation as well as consideration in future recommendations regarding the use of aspirin in pregnancy. n Acknowledgment The authors appreciate the assistance of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and Maternal-Fetal Medicine Units (MFMU) Network in making the database from the MFMU HighRisk Aspirin trial available for secondary analysis.
References 1. LeFevre ML; US Preventive Services Task Force. Low-dose aspirin use for the prevention of morbidity and mortality from preeclampsia: US Preventive Services Task Force recommendation statement. Ann Intern Med 2014;161: 819-26. 2. Organization WH. WHO recommendations for prevention and treatment of preeclampsia and eclampsia. Geneva: World Health Organization; 2014. 3. Redman CW. Hypertension in pregnancy: the NICE guidelines. Heart 2011;97:1967-9. 4. American College of Obstetricians and Gynecologists. Practice advisory on low-dose aspirin and prevention of preeclampsia: updated recommendations. 2016. 5. Henderson JT, Whitlock EP, O’Connor E, Senger CA, Thompson JH, Rowland MG. Lowdose aspirin for prevention of morbidity and mortality from preeclampsia: a systematic evidence review for the US Preventive Services Task Force. Ann Intern Med 2014;160:695-703. 6. Bennett SN, Tita A, Owen J, Biggio JR, Harper LM. Assessing White’s classification of pregestational diabetes in a contemporary diabetic population. Obstet Gynecol 2015;125: 1217-23. 7. Caritis S, Sibai B, Hauth J, et al. Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 1998;338:701-5. 8. Hare JW, White P. Gestational diabetes and the White classification. Diabetes Care 1980;3: 394. 9. Talge NM, Mudd LM, Sikorskii A, Basso O. United States birth weight reference corrected
for implausible gestational age estimates. Pediatrics 2014;133:844-53. 10. Nesbitt TS, Gilbert WM, Herrchen B. Shoulder dystocia and associated risk factors with macrosomic infants born in California. Am J Obstet Gynecol 1998;179: 476-80. 11. Oral E, Cagdas A, Gezer A, Kaleli S, Aydinli K, Ocer F. Perinatal and maternal outcomes of fetal macrosomia. Eur J Obstet Gynecol Reprod Biol 2001;99:167-71. 12. Stotland NE, Caughey AB, Breed EM, Escobar GJ. Risk factors and obstetric complications associated with macrosomia. Int J Gynaecol Obstet 2004;87:220-6. 13. Weissmann-Brenner A, Simchen MJ, Zilberberg E, et al. Maternal and neonatal outcomes of large for gestational age pregnancies. Acta Obstet Gynecol Scand 2012;91:844-9. 14. Campbell S. Placental vasculature as visualized by 3D power Doppler angiography and 3D color Doppler imaging. Ultrasound Obstet Gynecol 2007;30:917-20. 15. Fisher SJ. Why is placentation abnormal in preeclampsia? Am J Obstet Gynecol 2015;213: S115-22. 16. Dekker GA, Sibai BM. Etiology and pathogenesis of preeclampsia: current concepts. Am J Obstet Gynecol 1998;179:1359-75. 17. Walsh SW. Physiology of low-dose aspirin therapy for the prevention of preeclampsia. Semin Perinatol 1990;14:152-70.
Author and article information
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From the University of Colorado School of Medicine, Q1 Aurora, CO (Drs Adkins, Metz, and Heyborne); Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Denver, Denver, CO (Ms Allshouse); and Denver Health Medical Center, Denver, CO (Drs Metz and Heyborne). Received Feb. 21, 2017; revised May 18, 2017; accepted May 31, 2017. Dr Metz is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) under award no. 2K12HD001271-16. The contents of this report represent the views of the authors and do not necessarily represent the views of the NICHD Maternal-Fetal Medicine Units Network or the National Institutes of Health. The authors report no conflict of interest. Presented at poster session III of the 37th Annual Pregnancy Meeting of the Society for Maternal-Fetal Medicine, Las Vegas, NV, Jan. 27, 2017. Corresponding author: Kent D. Heyborne, MD. kent. [email protected]
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