Original Research ajog.

org

1 OBSTETRICS 56
2 57
3 Esomeprazole to treat women with preterm 58
4
5
preeclampsia: a randomized placebo controlled trial 59
60
6 Q18 Catherine A. Cluver, MMed; Natalie J. Hannan, PhD; Erika van Papendorp, BN; Richard Hiscock, MBBS; Sally Beard, BSc; 61
7 Ben W. Mol, PhD; Gerhard B. Theron, MD; David R. Hall, MD; Eric H. Decloed, MMed; Marietjie Stander, PhD; 62
8 Q1 Kim T. Adams,



; Megan Rensburg, MMed; Pawel Schubert,



; Susan P. Walker, MD; Stephen Tong, PhD 63
9 Q2 64
10 65
11 BACKGROUND: Preterm preeclampsia has a high rate of fetal death or was 29þ4 weeks gestation. There were no between-group differences in 66
12 disability. There is no treatment to slow the disease, except delivery. Pre- median time from randomization to delivery: 11.4 days (interquartile 67
13 clinical studies have identified proton pump inhibitors as a possible treatment. range, 3.6e19.7 days) in the esomeprazole group and 8.3 days (inter- 68
14 OBJECTIVE: The purpose of this study was to examine whether eso- quartile range, 3.8e19.6 days) in the placebo group (3 days longer in the 69
15 meprazole could prolong pregnancy in women who have received a esomeprazole arm; 95% confidence interval, e2.9e8.8; P¼.31). There 70
16 diagnosis of preterm preeclampsia. were no placental abruptions in the esomeprazole group and 6 (10%) in 71
17 STUDY DESIGN: We performed a double-blind, randomized controlled the placebo group (P¼.01, P¼.14 adjusted). There were no differences in 72
18 trial at Tygerberg Hospital in South Africa. Women with preterm pre- other maternal or neonatal outcomes or markers of endothelial dysfunc- 73
19 eclampsia (gestational age 26 weeksþ0 days to 31 weeksþ6 days) were tion. Esomeprazole and its metabolites were detected in maternal blood 74
assigned randomly to 40-mg daily esomeprazole or placebo. The primary among those treated with esomeprazole, but only trace amounts in the 75
20
outcome was a prolongation of gestation of 5 days. Secondary outcomes umbilical cord blood.
21 76
were maternal and neonatal outcomes. We compared circulating markers CONCLUSION: Daily esomeprazole (40 mg) did not prolong gestation
22 77
of endothelial dysfunction that was associated with preeclampsia and in pregnancies with preterm preeclampsia or decrease circulating soluble
23 78
performed pharmacokinetic studies. fms-like tyrosine kinase 1concentrations. Higher levels in the maternal
24 RESULTS: Between January 2016 and April 2017, we recruited 120 circulation may be needed for clinical effect.
79
25 participants. One participant was excluded because of incorrect 80
26 randomization, which left 59 participants in the esomeprazole and 60 Key words: esomeprazole, trial, preterm preeclampsia, sFlt1, 81
27 participants in the placebo group. Median gestational age at enrolment pharmacokinetics 82
28 83
29 84

P
30 85
reeclampsia is 1 of the most serious available that temporizes disease pro- and preeclamptic pregnancies. Second,
31 86
complications of pregnancy. It af- gression, it could be used to safely delay esomeprazole was able to dilate whole
32 87
fects 3e8 % of pregnancies and is a delivery to gain gestation, thereby human vessels from both normal preg-
33 88
leading cause of maternal, fetal, and decreasing the degree of prematurity and nancies treated with a constrictor and
34 89
neonatal morbidity.1,2 There is no improving perinatal outcomes. vessels that were obtained from women
35 90
treatment that can slow disease pro- The preeclamptic placenta releases with preeclampsia. The preclinical
36 91
gression, and the only treatment option elevated levels of soluble fms-like tyro- studies also showed that esomeprazole
37 92
is to deliver the pregnancy. For pre- sine kinase 1 (sFlt1) and soluble endo- decreased endothelial dysfunction by
38 93
eclampsia that occurs at preterm gesta- glin into the maternal circulation.4 These mitigating tumor necrosis aeinduced
39 94
tions, clinicians are often required to antiangiogenic factors cause maternal endothelial injury, as demonstrated by
40 95
deliver the fetus early, which results in endothelial dysfunction, hypertension, reducing expression of endothelial
41 96
iatrogenic prematurity with a risk of and multiorgan injury.5 Esomeprazole is vascular cell adhesion molecule-1 and
42 97
major disability that includes cerebral a proton pump inhibitor (PPI) that is reduced leucocyte adhesion to the
43 98
palsy, intracerebral bleeding, retinopathy prescribed widely in pregnancy to relieve endothelium. Last, important animal
44 99
of prematurity, chronic lung disease, and symptomatic gastric reflux. Members of studies clearly show that esomeprazole
45 100
death. The risks of these complications our team have performed preclinical reduces blood pressure in a transgenic
46 101
are higher if pregnancies are delivered at laboratory studies that have shown that mouse model of preeclampsia in which
47 102
earlier gestations.3 If a treatment were PPIs such as esomeprazole are a candi- human sFlt1 is overexpressed in the
48 103
date therapeutic for preeclampsia.6 placenta and released in excess into the
49 104
50 Cite this article as: Cluver CA, Hannan NJ, van Esomeprazole, in particular, has been maternal blood, as seen in women with
105
Papendorp E, et al. Esomeprazole to treat women with shown to have diverse biologic actions. preeclampsia.6 Others subsequently have
51 106
preterm preeclampsia: a randomized placebo controlled First, esomeprazole decreases sFlt1 and found decreased circulating sFlt1 and
52 trial. Am J Obstet Gynecol 2018;


:



.
107
soluble endoglin production and release soluble endoglin levels in an existing
53 108
0002-9378/$36.00 from primary trophoblast cells and cohort of bloods of women with sus-
54 109
ª 2018 Published by Elsevier Inc. placental tissue explants and primary pected or confirmed preeclampsia that
55 https://doi.org/10.1016/j.ajog.2018.07.019 110
endothelial cells/tissues in both normal were coincidentally taking PPIs.7

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111 167
112 blood pressure measurement, twice daily 168
AJOG at a Glance clinical assessments, daily urinalysis, and
113 169
114 Why was this study conducted? twice weekly biochemical testing. Fetal 170
115 Preeclampsia has high rates of fetal death or disability. There is no treatment to surveillance involved 6 hourly car- 171
116 slow the disease, except delivery. Preclinical studies have identified proton pump diotocography and ultrasound assess- 172
117 inhibitors as a possible treatment. ments every 2 weeks or more frequently, if 173
118 indicated. To enhance fetal lung maturity, Q3 174
Key findings all participants received 2 doses of beta-
119 175
Daily oral esomeprazole (40 mg) did not prolong gestation in pregnancies with methasone that were given 24 hours apart,
120 176
preterm preeclampsia or decrease circulating soluble fms-like tyrosine kinase followed by a single repeat dose 1 week
121 177
1concentrations. later if not delivered, as per local proto-
122 178
123 col.13 Expectant management ended at 34 179
What does this add to what is known? weeks gestation; women who reached this
124 This is the first trial for preterm preeclampsia that has integrated clinical out- 180
125 gestation were delivered. Delivery at <34 181
comes, mechanistic studies, and pharmacokinetics. Oral esomeprazole (40 mg) weeks gestation was a clinical decision
126 may be too low a dose to treat preterm preeclampsia; higher doses may still be 182
127 made by the patient’s treating team. 183
effective. This may be the fastest completed randomized clinical trial of a treat- The study participants provided
128 ment for preterm preeclampsia. It is possible to complete clinical trials for pre- 184
129 written informed consent. The study had 185
term preeclampsia in a reasonable timeframe by running the trials in settings in Health Research Ethics Committee
130 which the incidence of disease is high. 186
131 (HREC) approval, was approved by the 187
132 South African Medicines Control 188
133 These promising preclinical data examination. Both the managing perina- Council. Study data were collected and 189
134 suggest that esomeprazole is a potential tologist and neonatologist had to agree managed with the use of REDCap elec- 190
135 candidate treatment; we therefore set out that expectant management could benefit tronic data capture tools.14 191
136 to examine whether oral esomeprazole the fetus. 192
137 may be an effective treatment for pre- Women were not eligible if they had an Randomization and masking 193
138 term preeclampsia. indication for immediate delivery because Randomization was performed in a 1:1 194
139 they could not be treated expectantly to ratio with the use of an online, web- 195
140 Methods gain further fetal maturity. Exclusion based sequence generator. Because 196
141 Trial design criteria therefore included established gestation at randomization could 197
142 In this single-site phase II double-blind, maternal or fetal compromise that possibly impact the length of pregnancy 198
143 randomized, placebo-controlled clinical necessitated delivery, the current use or prolongation, randomization was strati- 199
144 trial, we compared oral esomeprazole contraindications to the use of PPIs, and fied (strata 1 was 28þ6 weeks; strata 2 200
145 with placebo. A 40-mg daily dose was the use of medications that could interact was 29þ0 until 31þ6 weeks gestation). 201
146 selected based on pharmacokinetic data with PPIs (which included warfarin, ke- Randomization was done within blocks 202
147 that showed effective suppression of toconazole, voriconazole, atazanavir, nel- of random size within 4e6. The tablets 203
148 gastrointestinal symptoms in nonpreg- finavir, saquinavir, digoxin, St John’s and treatment packs were manufactured, 204
149 nant patients and on reassuring data that Wort, rifampin, cilostazol, diazepam, packed, and labelled by the Institute of 205
150 showed no adverse effects if taken during tacrolimus, erlotinib, methotrexate, and Drug Technology Limited (en.idtaus.- 206
151 pregnancy.8-11 The trial site was Tyger- clopidogrel). Specific clinical exclusion com.au) in Victoria, Australia, and were 207
152 berg Hospital, Cape Town, South Africa, criteria included eclampsia, severe hyper- identical with respect to variables such as 208
153 which is a large academic referral center tension not be controlled within 48 hours size, thickness, physical properties, and 209
154 that is situated in a region with high rates of admission, a cerebrovascular event, appearance. The investigators had no 210
155 of preeclampsia. We have published the posterior reversible encephalopathy syn- access to the randomization list, and 211
156 protocol,12 and the trial was registered drome, severe renal impairment with a allocation concealment was maintained 212
157 with the Pan African Clinical Trials creatinine >125 mmol/L, pulmonary throughout the trial. 213
158 Registry (PACTR201 504000771349). edema, disseminated intravascular coag- 214
159 Pregnant women with singleton preg- ulation, hemolysis, elevated liver enzymes Placental and blood collection to 215
160 nancies were invited to participate if they and low platelets (HELLP) syndrome, measure angiogenic markers of 216
161 had been diagnosed with preterm pre- liver hematoma or rupture, severe ascites preeclampsia and endothelial 217
162 eclampsia between 26þ0 and 31þ6 weeks on ultrasound examination. We excluded dysfunction and to perform 218
163 gestation. The gestation at enrolment was pregnancies with a suspicion of a major pharmacokinetics 219
164 determined by either menstrual dates (if fetal anomaly or malformation. Expectant Plasma samples to measure circulating 220
165 the women was certain of her last men- management involved hospital admission preeclampsia and angiogenic biomarkers 221
166 strual period) or by an early or mid- with close maternal and fetal surveillance. were collected at randomization and twice 222
trimester pregnancy ultrasound Maternal surveillance involved 4 hourly weekly until delivery. Placental tissue

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223 279
224 FIGURE 1 280
225 Flowchart of the preeclampsia intervention with esomeprazole trial protocol 281
226 282
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262 318
263 The flowchart that summarizes the preeclampsia intervention with esomeprazole trial protocol shows the number of women who were eligible for 319
264 inclusion, decline in participation, randomization, allocation to placebo vs esomeprazole, additional complications, and exclusion from the study. 320
265Q11 SLE, systemic lupus erythematosus. 321
Cluver et al. Esomeprazole to treat preterm preeclampsia. Am J Obstet Gynecol 2018.
266 322
267 323
268 324
269 samples and umbilical artery cord blood forearm vein at the following dosing in- to show a prolongation of 5 days. Sec- 325
270 were collected at delivery when possible. terval: predose, at 15, 30, and 45 minutes; ondary outcomes included composite 326
271 After recruitment was completed, circu- postdose, at 1, 1.5, 2, 4, 8, and 24 hours. and individual maternal, fetal, and 327
272 lating concentrations and placental Levels were measured in batch after the neonatal outcomes, maternal bio- 328
273 expression of molecules that are markers trial was completed (the Supplemental markers, pharmacokinetics, and 329
274 of preeclampsia and endothelial dysfunc- Material provides further details on how placental samples. 330
275 tion were measured. the esomeprazole was measured). After completion of the trial, we 331
276 Pharmacokinetics was performed in a measured the plasma circulating con- 332
277 subgroup of patients who had been Outcome measures centrations of the following markers of 333
278 administered esomeprazole. Plasma The primary outcome was prolongation preeclampsia: sFlt1, soluble endoglin, 334
samples were drawn from a catheter in a of pregnancy, and the study was powered placental growth factor (PlGF) with the

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335 391
336 TABLE 1 392
337 Characteristics of trial participants at enrolment 393
338 394
339 Characteristics Esomeprazole (n¼59) Placebo (n¼60) 395
340 Q12 Gestation at randomization, wkþd 396
341 Median [interquartile range] 29þ4 [27þ6e30þ6] 29þ5 [28þ1e30þ5] 397
342 398
Mean (standard deviation) 29.4 (1.65) 29.4 (1.66)
343 399
344 Gestation <29 weeks at randomization, n (%) a
20 (33.9) 20 (33.3) 400
345 Maternal age (y), median [interquartile range] 24 [21e31] 30 [25e34] 401
346 2
Body mass index (kg/m ), median [interquartile range] 29.4 [24.8e33.3] 29.0 [24.0e35.2] 402
347 403
Race or ethnicity, n (%)
348 404
349 Black 34 (57.6) 33 (55) 405
350 Q13 Colored 25 (42.4) 27 (45.0) 406
351 Smoking, n (%) 8 (13.6) 4 (6.7) 407
352 408
Aspirin use, n (%) 1 (1.7) 0
353 409
354 Calcium use, n (%) 1 (1.7) 0 410
355 HIV positive, n (%) 8 (13.6) 12 (20.0) 411
356 412
Chronic hypertension, n (%) 13 (22.0) 21 (35.0)
357 413
358 Nulliparous, n (%) 26 (44.1) 12 (20) 414
359 Multiparous, n (%) 415
360 Without hypertension in a previous pregnancy 25 (42.4) 27 (45) 416
361 417
With hypertension in a previous pregnancy 8 (13.6) 21 (34.9)
362 418
363 New paternity in current pregnancy, n (%) 11/37 (29.7) 17/48 (35.4) 419
364 Highest systolic blood pressure before randomization 166 (17.5) 168 (16.4) 420
365 (mm Hg), mean (standard deviation) 421
366 Highest diastolic blood pressure before randomization 103 (13.4) 103 (11.4) 422
367 (mm Hg), mean (standard deviation) 423
368 24-Hour protein creatinine ratio at enrolment (g/24 hr), 1.46 [0.62-3.16] 1.06 [0.57-16.86] 424
369 median [interquartile range] 425
370 Hemoglobin (g/dL), mean (standard deviation) 12.3 (1.5) 11.6 (1.4) 426
371 9
427
Platelet count (10 /L), mean (standard deviation) 207 (59.9) 222 (67.2)
372 428
373 Urea (mmol/L), mean (standard deviation) 4.0 (1.64) 3.7 (1.4) 429
374 Creatinine (mg/dL), mean (standard deviation) 0.05 (0.015) 0.05 (0.013) 430
375 Estimated fetal weight (g), mean (standard deviation) 1153 (300.4) 1153 (217.7)
431
376 432
377 Fetal weight percentile, median [interquartile range] 6.0 [2.1-24.8] 9.5 [1.7-22.5] 433
378 Absent blood flow on umbilical artery Doppler, n (%) 2 (3.4) 4 (6.7) 434
379 a
Percentage of each group. 435
380 Cluver et al. Esomeprazole to treat preterm preeclampsia. Am J Obstet Gynecol 2018. 436
381 437
382 438
383 use of commercially available enzyme- sFlt1, PlGF, vascular endothelial growth were collected, and the remaining tablets 439
384 linked immunosorbent assays. We also factor-1, and the anti-oxidant molecule were counted. The trial midwife 440
385 measured markers of endothelial heme oxygenase-1 was measured by reviewed participants daily for adverse 441
386 dysfunction: endothelin-1, vascular polymerase chain reaction events. Serious adverse events were re- 442
387 endothelial cell adhesion molecule-1 (Supplemental Material). ported to the Data Monitoring and 443
388 (VCAM-1). Safety Committee and Health Research 444
389 Total RNA was extracted from the Adherence and adverse events Ethics Committee and were handled in 445
390 placental biopsy specimens that were Medication adherence was checked accordance with Good Clinical Practice 446
collected at delivery; the expression of daily. After delivery, the treatment packs guidelines.

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 ajog.org OBSTETRICS Original Research
447 503
448 FIGURE 2 504
449 Survival curve 505
print & web 4C=FPO

450 506
451 507
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480 536
481 Survival curve shows the proportion of trial participants who remained undelivered, graphed against the number of days of gestation after randomization. 537
482 Blue indicates the women who were treated with esomeprazole; red indicates the women who were treated with placebo. 538
483 Cluver et al. Esomeprazole to treat preterm preeclampsia. Am J Obstet Gynecol 2018. 539
484 540
485 541
Statistical analysis treatment group and gestational strata as correlation and missing samples. Graphic
486 covariates. Results are presented as me- presentation used median, 25th, and 75th 542
The sample size was based on data on the
487 dian group difference with 95% confi- percentiles that were calculated from 543
duration of expectant management at
488 544
Tygerberg Hospital.15 To identify a gain in dence interval (95% CI). Survival analyses samples that were available at each day
489 were done with Cox proportional hazards after random assignment. A smoothed 545
gestation of 5 days, we needed to recruit
490 regression and graphed with Kaplan- scatterplot of these quantiles was con- 546
86 women (90% power, 2-sided alpha
491 Meier survivorship curves. Continuous structed with the use of kernel-weighted 547
0.05). This sample size was multiplied by
492 variables were compared with either t-test local polynomial regression over a pre- 548
1.15 to statistically correct for non-
493 (normally distributed variables) or Mann- specified number of time units each side of 549
normality. An additional 10 per arm were
494 Whitney U (nonnormally distributed the time of interest. The analysis used an 550
added to account for anticipated drop-
495 data). Categoric values were compared Epanechnikov kernel function, automatic 551
outs. Thus, a total of 120 participants
496 with the use of the Fisher’s exact test. optimization of the degree of polynomials, 552
(60 per arm) had to be recruited.
497 For circulating biomarker studies, and a bandwidth of 4 days. 553
Statistical analyses were performed on
498 between-group comparisons of circulating 554
an intention-to-treat principle. A 2-sided
499 555
P-value <.05 was considered to indicate analyte concentrations were performed by Results
500 a marginal mean model that was estimated Trial participants 556
statistical significance. The primary
501 with the use of generalized estimating Participants were recruited from 557
outcome was tested with the use of
502 equations to allow for both within patient January 2016 until April 2017 558
quantile regression analysis with the

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 Original Research OBSTETRICS ajog.org

559 615
560 TABLE 2 616
561 Outcomes according to trial group 617
562 618
563 Outcome Esomeprazole (n¼59) Placebo (n¼60) P value 619
564 Primary 620
565 Prolongation of gestation, d 621
566 622
Median [interquartile range] 11.4 [3.6e19.7] 8.3 [3.8e19.6] .31
567 623
568 Mean (standard deviation) 12.9 (10.8) 13.1(12.2) 624
569 Q14 Gestation at delivery (wkþd), median [interquartile range] 31þ2 [29þ3e33þ3] 31þ3 [29þ3e33þ4] .93 625
570 Secondary 626
571 627
Composite maternal outcome, n (%)a 1 (1.7) 4 (6.7) .36
572 628
573 Individual maternal outcomes 629
574 Eclampsia, n (%) 0 3 (5.0) .24 630
575 Pulmonary edema, n (%) 1 (1.7) 1 (1.7) .99 631
576 632
Admission to high care unit or intensive care unit, n (%) 3 (5.1) 6 (10.0) .49
577 633
578 Proteinuria 3g/24h, n (%) 22 (37.3) 24 (40) .85 634
579 Systolic blood pressure >160 mm Hg, n (%) 29 (49.2) 24 (40.0) .36 635
580 Diastolic blood pressure >110 mm Hg, n (%) 13 (22.0) 8 (13.3) .24 636
581 637
Highest systolic blood pressure during trial (mm Hg), mean 160 (11.9) 160 (12.3) .91
582 (standard deviation) 638
583 639
Highest diastolic blood pressure during trial (mm Hg), mean 102 (10.6) 101 (8.7) .57
584 (standard deviation) 640
585 641
Platelet count <50109, n (%) 0 1 (1.7) .99
586 642
587 HELLP (hemolysis, elevated liver enzymes, and low platelet count) 5 (8.5) 3 (5.0) .49 643
588 syndrome, n (%) 644
589 Aspartate aminotransferase (level) >60 m/L, n (%) 3 (5.1) 1 (1.7) .30 645
590Q15 Hemolysis (LDH >600 m/L) or hemolysis on peripheral blood smear 2 (3.4) 3 (5.0) .99 646
591 or decreased haptoglobin, n (%) 647
592 Placental abruption, n (%) 0 6 (10.0) .03 648
593 649
Major postpartum hemorrhage, n (%) 0 3 (5.0) .24
594 650
595 Thromboembolic disease, n (%) 1 (1.7) 0 .99 651
596 Moderate-to-severe ascites, n (%) 7 (11.9) 4 (6.7) .36 652
597 Composite fetal outcome, n (%) b
49 (83.1) 45 (75) .37 653
598 654
Individual fetal outcomes
599 655
600 Persistent absent flow in umbilical artery Doppler, n (%) 4 (6.8) 7 (11.7) .53 656
601 Redistribution in the middle cerebral artery, n (%) 28 (47.5) 27 (45) .85 657
602 Growth restriction (estimated fetal weight <10th percentile), n (%) 38 (64.4) 30 (50) .14 658
603 659
Significant changes in fetal heart rate pattern necessitating delivery, 28 (47.5) 26 (43.3) .74
604 n (%) 660
605 661
Intrauterine death, n (%) 1 (1.7) 1 (1.7) .99
606 662
c
607 Neonatal composite outcome, n (%) 11 (18.6) 11 (18.3) .99 663
608 Cluver et al. Esomeprazole to treat preterm preeclampsia. Am J Obstet Gynecol 2018. (continued) 664
609 665
610½F1 (Figure 1). Of 124 women who were esomeprazole group was excluded after significant hypertension and protein- 666
611 admitted with preterm preeclampsia randomization because it was later uria. This left 59 women in the eso- 667
612 who were considered eligible, 4 women discovered that she did not meet the meprazole group. Two participants in 668
613 declined to participate (96.7% recruit- trial criteria for a diagnosis of pre- this group were given the incorrect 669
614 ment rate). One participant in the eclampsia because she did not have treatment pack and received placebo. 670

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671 727
672 TABLE 2 728
673 Outcomes according to trial group (continued) 729
674 730
675 Outcome Esomeprazole (n¼59) Placebo (n¼60) P value 731
676 Individual neonatal outcomes 732
677 Neonatal death within 6 weeks after the due date, n (%) 8 (13.6) 9 (15.0) .99 733
678 734
Grade III or IV intraventricular hemorrhage, n (%) 2 (3.4) 0 .24
679 735
680 Necrotizing enterocolitis, n (%) 4 (6.8) 3 (5.0) .72 736
681 Bronchopulmonary dysplasia, n (%) 1 (1.7) 0 .50 737
682 Apgar score <7 at 5 minutes, n (%) 1 (1.7) 7 (11.7) .06 738
683 739
Umbilical artery pH <7.05, n (%) 1/35 (2.9) 2/34 (5.9) .61
684 740
685 Surfactant use, n (%) 14 (23.7) 9 (15.0) .25 741
686 Neonatal intensive care unit admission, n (%) 8 (13.6) 4 (6.7) .24 742
687 High care unit admission, n (%) 53 (89.8) 45 (75.0) .05 743
688 744
Intubation and mechanical ventilation, n (%) 6 (10.2) 6 (10.0) .99
689 745
690 Continuous positive airway pressure support, n (%) 46 (78.0) 39 (65.0) .16 746
691 Grade III or IV hyaline membrane disease, n (%) 7 (11.9) 9 (15.0) .79 747
692 Retinopathy of prematurity, n (%) 2 (3.4) 0 .24 748
693 749
Neonatal sepsis, n (%) 9 (15.3) 5 (8.3) .27
694 750
695 Birthweight (g), mean (standard deviation) 1343 (466.5) 1379 (441.3) .54 751
696 Discharge time (d), median [interquartile range] 3 (3e5) 3 (3e4) .24 752
697 NOTE: No participant had any of the following outcomes: maternal death, severe renal impairment, cerebral vascular event, liver hematoma or rupture, posterior reversible encephalopathy syndrome, 753
698 left ventricular failure, serum creatinine >125 mmol, disseminated intravascular coagulation, home oxygen support, persistent reversed flow in the umbilical artery Doppler. 754
699
a
Included the occurrence of any of the following serious maternal outcomes: maternal death, eclampsia, pulmonary edema (oxygen saturation 90%, with clinical signs and symptoms that required 755
treatment), severe renal impairment or the need for dialysis, a cerebral vascular event, and liver hematoma or rupture; b Reversed a-wave in the ductus venosus, significant changes in fetal heart
700 rate pattern that necessitated delivery, intrauterine fetal death, fetal growth restriction, persistent reversed flow in the umbilical artery, redistribution in the middle cerebral artery Doppler, reversed 756
701 a-wave in the ductus venosus Doppler; c Neonatal death within 6 weeks after the expected due date, grade III or IV intraventricular hemorrhage, necrotizing enterocolitis; and bronchopulmonary 757
dysplasia.
702 Cluver et al. Esomeprazole to treat preterm preeclampsia. Am J Obstet Gynecol 2018. 758
703 759
704 760
705 One participant in this group declined underlying hypertension, and women time, between the 2 treatment arms for 761
706 hospital treatment 1 week after who had a previous pregnancy compli- either stratum (Figure 2). The estimated ½F2 762
707 randomization, left the hospital, and cated by hypertension in the placebo hazard ratio was 1.13 (95% CI, 763
708 returned with a stillbirth. Sixty women group. 0.70e2.17; P¼.70) for <29 weeks and 764
709 were allocated to placebo, and all were 1.07 (95% CI, 0.68e1.68; P¼.78) for 765
710 included in the analysis. One partici- Primary outcome 29 weeks. 766
711 pant delivered before taking her trial The median time from randomization to 767
712 medication, and 1 participant was delivery was 11.4 days (mean, 12.9 days) in Secondary outcomes 768
713 diagnosed with systemic lupus erythe- the esomeprazole group vs 8.3 days (mean, There were no significant differences 769
714 matosus after randomization. One 13.1 days) in the placebo group. There was between treatment groups for any of the 770
715 participant in this group stopped taking no significant difference in median pro- maternal, fetal, and neonatal composite 771
716 her medication a few days before de- longation between treatment groups or individual outcomes (Table 2), except ½T2 772
717 livery. The maternal characteristics and either unadjusted (median difference, 3.0; for placental abruption. There were no 773
718 obstetrics history of the cohort are 95% CI, 2.9e8.8; P¼.31) or adjusted for placental abruptions (0/59) in the eso- 774
719½T1 shown in Table 1. gestational age strata (median difference, meprazole group and 10% (6/60) in the Q16 775
720 The median gestational age at 0.81; 95% CI, 5.1e6.7; P¼.79). There was placebo group (P¼.01), which was not 776
721 randomization was 29 weeks 4 days in also no difference in the median prolon- significant when we adjusted for the fact 777
722 the esomeprazole group and 29 weeks 5 gation between strata when adjusted for that we performed multiple compari- 778
723 days in the placebo group. The placebo treatment group (median difference, 3.0; sons for other secondary outcomes 779
724 group had a higher median maternal age 95% CI, 3.2e9.2; P¼.34) days. (P¼.14). Q4 780
725 at enrolment. There were also more There was no difference in the SFlt1 and soluble endoglin are anti- 781
726 multiparous women, women with instantaneous hazard of delivery, at any angiogenic factors that are increased 782

MONTH 2018 American Journal of Obstetrics & Gynecology 1.e7

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783 839
784 FIGURE 3 840
785 Circulating plasma levels of antiangiogenic factors in women who were treated with either placebo or esomeprazole 841
786 842
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832 A, Median circulating plasma soluble fms-like tyrosine kinase 1 concentrations (solid lines) and 25th and 75th percentiles (dotted lines) among participants 888
833 administered placebo (red) or esomeprazole (blue). There were no differences in circulating soluble fms-like tyrosine kinase 1 levels between groups. 889
834 B, Median circulating plasma soluble endoglin concentrations (solid line), and 25th and 75th percentiles (dotted line) among participants administered 890
835 placebo (red) or esomeprazole (blue). There were no differences in circulating soluble endoglin levels between groups. Numbers that were still undelivered at 891
836 each 5-day time point and that could have contributed to the data for soluble fms-like tyrosine kinase 1 or soluble endoglin are shown in A. 892
837 sENG, soluble endoglin; sFlt1, soluble fms-like tyrosine kinase 1. 893
838 Cluver et al. Esomeprazole to treat preterm preeclampsia. Am J Obstet Gynecol 2018. 894

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895 951
896 FIGURE 4 952
897 Circulating plasma levels of antiangiogenic factors in women who were treated with either placebo or esomeprazole 953
898 954
web 4C=FPO

899 955
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943 The graphs show analyte concentrations among the subcohorts of women who were either under (A and B) or over (C and D) 29 weeks gestation at 999
944 recruitment. All graphs depict median circulating plasma concentrations (solid lines) of analytes and the 25th and 75th percentiles (dotted lines). None of 1000
945 the comparisons between esomeprazole (blue) and placebo (red) were significant. Numbers that were still undelivered at each 5-day time point and that 1001
946 could have contributed to the data are shown in A and C for soluble fms-like tyrosine kinase 1. The numbers that were left undelivered for soluble endoglin 1002
947 for B are the same as that shown in A for soluble fms-like tyrosine kinase 1; and the numbers that were left undelivered for D are the same as that shown 1003
948 in C for soluble fms-like tyrosine kinase 1. 1004
949 sENG, soluble endoglin; sFlt1, soluble fms-like tyrosine kinase 1. 1005
Cluver et al. Esomeprazole to treat preterm preeclampsia. Am J Obstet Gynecol 2018.
950 1006

MONTH 2018 American Journal of Obstetrics & Gynecology 1.e9

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1007 1063
1008 FIGURE 5 1064
1009 Circulating plasma levels of placental growth factor in women who were treated with either placebo or esomeprazole 1065
1010 1066
web 4C=FPO

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1055 1111
1056 1112
1057 The graphs show analyte for A, the entire cohort or the entire cohort split according to whether women were B, under or C, over 29 weeks gestation at 1113
1058 recruitment. All graphs depict median circulating plasma concentrations (solid lines) of analytes and the 25th and 75th percentiles (dotted lines). None of 1114
1059 the comparisons between esomeprazole (blue) and placebo (red) were significant. Numbers that were still undelivered at each 5-day time point and could 1115
1060 have contributed to the data are shown below each graph. 1116
PlGF, placental growth factor.
1061 1117
Cluver et al. Esomeprazole to treat preterm preeclampsia. Am J Obstet Gynecol 2018.
1062 1118

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 ajog.org OBSTETRICS Original Research
1119 1175
1120 FIGURE 6 1176
1121 Circulating plasma levels of endothelin1 and soluble vascular cell adhesion molecule-1 in women who were treated 1177
1122 with either placebo or esomeprazole 1178
web 4C=FPO

1123 1179
1124 1180
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1164 1220
1165 1221
1166 1222
1167 The graphs show analyte concentrations among A and B, the entire cohort or the entire cohort split according to whether women were C and D, under or E 1223
1168 and F, over 29 weeks gestation at recruitment. All graphs depict median circulating plasma concentrations (solid lines) of analytes, and the 25th and 75th 1224
1169 centiles (dotted lines). None of the comparisons between esomeprazole (blue) and placebo (red) were significant. Numbers that were still undelivered at 1225
1170 each 5-day time point and that could have contributed to the data for A and B are shown below graph A; numbers that were still undelivered at each 5-day 1226
1171 time point and that could have contributed to the data for C and D are shown below graph C; numbers that were still undelivered at each 5-day time point 1227
1172 and that could have contributed to the data for E and F are shown below graph E. 1228
ET-1, endothelin -1; sVCAM1, soluble vascular cell adhesion molecule-1.
1173 1229
Cluver et al. Esomeprazole to treat preterm preeclampsia. Am J Obstet Gynecol 2018.
1174 1230

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1231 1287
1232 FIGURE 7 1288
1233 Placental messenger RNA expression 1289
1234 1290
web 4C=FPO

1235 1291
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1275 1331
1276 A, Soluble fms-like tyrosine kinase 1, B, placental growth factor, C, vascular endothelial growth factor, and D, heme oxygenase -1 in placental tissues 1332
1277 that were collected from women who received placebo (n¼32) or esomeprazole (n¼33). None of the comparisons were significant. Data are mean fold 1333
1278 changestandard error of the mean. 1334
1279 HO-1, heme oxygenase-1; mRNA, messenger RNA; PlGF, placental growth factor; sFlt1, soluble fms-like tyrosine kinase 1; VEGF, vascular endothelial growth factor. 1335
1280 Cluver et al. Esomeprazole to treat preterm preeclampsia. Am J Obstet Gynecol 2018. 1336
1281 1337
1282 1338
1283 significantly in the circulation of preg- endoglin concentrations were extremely were obtained from those who were still 1339
1284 nant women with preeclampsia and may high among trial participants, and there undelivered at each time point) between 1340
1285 have a role in the pathophysiology of the were no significant differences in con- the groups (Figure 3; Figure 4 shows ½F31341
1286 disease. Circulating sFlt1 and soluble centrations on serial samples (which analyte concentrations split into the 2 ½F41342

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 ajog.org OBSTETRICS Original Research
1343 1399
1344 FIGURE 8 1400
1345 Pharmacokinetic analysis 1401
1346 1402
web 4C=FPO

1347 1403
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1373 1429
1374 1430
1375 1431
1376 Pharmacokinetic analysis showed that esomeprazole was detectable in the maternal circulation, with levels peaking soon after administration and a 1432
1377 decline in concentration by 500 minutes after administration. Metabolites of esomeprazole (5-hydroxy, 5-O-desmethyl and omeprazole sulphone) were 1433
1378 also detectable at lower levels soon after administration with overall higher levels of the metabolite omeprazole sulphone and a steady decrease across 1434
the first 1400 minutes.
1379 1435
Cluver et al. Esomeprazole to treat preterm preeclampsia. Am J Obstet Gynecol 2018.
1380 1436
1381 1437
1382 gestational age strata). Concentrations of between the esomeprazole and placebo extremely low in the umbilical cord 1438
1383 both rapidly declined after delivery, as arms (Figure 7). blood taken at birth. ½F7
1439
1384 expected. There were also no differences 1440
1385 in circulating levels of PlGF (a proan- Esomeprazole pharmacokinetics Adverse events and adherence 1441
1386 giogenic factor that is decreased in pre- Esomeprazole and its metabolites were Adherence was excellent. Only 1 partic- 1442
1387½F5 eclampsia; Figure 5), endothelin 1 measured in 10 participants who were ipant in the placebo group stopped tak- 1443
1388 (endogenous vasoconstriction factor assigned randomly to esomeprazole; ing the trial medication. There were no 1444
1389 that is increased in preeclampsia), or exposure was similar to that of healthy significant differences in the incidences 1445
1390 vascular cell adhesion molecule-1 nonpregnant volunteers with area under of serious adverse events between the 2 1446
1391 (associated with endothelial dysfunc- the curve geometric means of 5.88 groups (Table 3). Q5 1447
1392½F6 ½T31448
tion; Figure 6). Analysis of placental mmol
h/L (95% CI, 2.96e11.68
1393 messenger RNA expression of sFlt1, mmol
h/L; Figure 8). In contrast, eso- Comment 16
½F8
1449
1394 PlGF, vascular endothelial growth factor meprazole and these metabolites were all In our trial, a daily dose of 40 mg of oral 1450
1395 (proangiogenic factor) and heme undetectable in 9 participants who were esomeprazole did not prolong gestation 1451
1396 oxygenaes-1 (endogenous antioxidant administered placebo. Concentrations of statistically further than expectant 1452
1397 molecule) showed no differences esomeprazole and the metabolites were management alone. Additionally, there 1453
1398 1454

MONTH 2018 American Journal of Obstetrics & Gynecology 1.e13

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1455 1511
1456 of the disease.5,19 We and others have 1512
TABLE 3
1457 pegged decreasing sFlt1 secretion as a 1513
Severe adverse events
1458 strategy to treat preeclampsia.6,20-24 We 1514
1459 Esomeprazole Placebo did not find changes in any of these 1515
Adverse event (n¼59), n (%) (n¼60), n (%) P value markers, which provides biologic evi-
1460 1516
1461 Maternal dence to support our clinical findings 1517
1462 that 40 mg of oral esomeprazole does not 1518
Eclampsia 0 3 (5) .24
1463 seem to arrest the disease course of 1519
Pulmonary edema 1 (1.7) 1 (1.7) .99 preeclampsia once it is diagnosed.
1464 1520
Blood loss of >1000 mL 0 3 (5) .24 We note that rescuing a pregnancy
1465 1521
1466 Fetal/neonatal with advanced preterm disease with se- 1522
1467 vere placental involvement may be a 1523
Intrauterine death 1 (1.7) 1 (1.7) .99
1468 difficult proposition. It has been re- 1524
Neonatal death 8 (13.6) 8 (13.3) .99 ported recently that proton inhibitor
1469 1525
1470
Necrotizing enterocolitis 4 (6.8) 3 (5) .68 use, to combat reflux, was associated 1526
1471 Neonatal sepsis 9 (15.3) 5 (8.3) .24 with decreased sFlt1, soluble endoglin, 1527
1472 and endothelin-1 levels.7 We believe it 1528
Intracranial hemorrhage 2 (3.4) 0 .15
1473 remains possible that a 40-mg dose may 1529
NOTE: No participant had any of the following serious adverse events: maternal death, severe renal impairment, cerebral
1474 vascular event, liver or rupture, posterior reversible encephalopathy syndrome, left ventricular failure, disseminated intra- still have merit as a preventative treat- 1530
1475
vascular coagulation, fetal or neonatal congenital anomaly. ment for preeclampsia and may be more 1531
Cluver et al. Esomeprazole to treat preterm preeclampsia. Am J Obstet Gynecol 2018. realistic. Whether this is the case will also
1476 1532
1477 require clinical trials. 1533
1478 was no difference in any of the prolongation or the instantaneous haz- Esomeprazole is prescribed widely 1534
1479 biomarker outcomes or secondary ard of delivery to support this. There was during pregnancy, and levels in the 1535
1480 maternal, fetal, and neonatal outcomes, a decrease in the incidence of placental umbilical cord have not been reported 1536
1481 except for placental abruption. However, abruption, but this difference was no previously. It was reassuring therefore 1537
1482 this is a secondary outcome and did not longer significant after we adjusted for that there was very little, or no, esome- 1538
1483 remain significant on an adjusted the fact that we performed multiple prazole detected in umbilical cord blood 1539
1484 analysis. comparisons for all the different sec- that was sampled at birth among those 1540
1485 Ours is only one of very few ondary outcomes. Therefore, the signif- who received the drug. It provides 1541
1486 completed randomized trials to explore icance of this finding, if any, is uncertain. further reassurance that there is likely to 1542
1487 treatments for preterm preeclampsia. Esomeprazole is 97% bound to pro- be minimal fetal exposure and is 1543
1488 We have completed perhaps the fastest tein and 80% renally excreted. We were consistent with epidemiologic data that 1544
1489 recruitment for a randomized trial of a concerned that the significant protein- show no adverse effects of PPIs on fetal 1545
1490 drug treatment for preterm preeclamp- uria that often is associated with preterm development.9-11 1546
1491 sia, and we achieved this at 1 site by preeclampsia may alter esomeprazole There have not been many competed Q6 1547
1492 undertaking our study in an area with a pharmacokinetics. Those who received phase II clinical trials that have tested 1548
1493 very high incidence of disease. It is also esomeprazole had exposure levels candidate treatments for preterm pre- 1549
1494 the first completed randomized treat- similar to healthy nonpregnant volun- eclampsia. Previous trials have met 1550
1495 ment trial of preterm preeclampsia in teers that had been reported previ- problems with recruitment. One of the 1551
1496 which blood biomarkers of preeclampsia ously.17 The esomeprazole main difficulties is that the incidence of 1552
1497 or endothelial dysfunction were concentrations that were observed in our disease is low in the developing world. 1553
1498 measured, as well as placental messenger participants were around the lower Sildenafil was assessed in a single-site, 1554
1499 RNA expression of genes that are rele- range of concentrations that were used in double-blind randomized controlled 1555
1500 vant to the pathophysiology of our preclinical in vitro studies.6 Thus, trial in Brazil.25 Over a 28-month period, 1556
1501 preeclampsia. although 40 mg may be an optimal dose 100 women were recruited. There was a 1557
1502 There was a nonsignificant trend in that is effective in decreasing gastric significant prolongation of gestation in 1558
1503 median prolongation in the esomepra- pH,18 it is possible that a higher dose or the sildenafil group of 4 days; however, 1559
1504 zole group of 3 days; however, to show an intravenous dose, which has a higher given that sildenafil is a vasodilator, it is 1560
1505 that such a difference is significant, we exposure over time and peak concen- possible that this prolongation in gesta- 1561
1506 would have needed 402 participants in tration,16 may be effective in treating tion may have occurred because the drug 1562
1507 each arm (alpha error, 5% for 90% po- preeclampsia. decreased blood pressure and mitigated 1563
1508 wer; a post hoc analysis that was calcu- There is now strong (though circum- a clinical reason to deliver, rather than 1564
1509 lated from the actual length of gestation stantial) evidence that placental secre- temporize disease progression. Anti- 1565
1510 observed in the current trial). Despite tion of sFlt1 (which causes endothelial thrombin was assessed to treat preterm 1566
this, there were no trends in the mean dysfunction) may be a significant driver preeclampsia in the PRESERVE-1 trial

1.e14 American Journal of Obstetrics & Gynecology MONTH 2018

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 ajog.org OBSTETRICS Original Research
1567 1623
1568 that enrolled 120 women from 23 ter- studies. This raises the possibility that endothelin-1 levels in women with confirmed or
1624
tiary hospitals in the United States over higher doses may be effective. Reassur- suspected preeclampsia using proton pump
1569 inhibitors. Hypertension 2017;70:594–600. 1625
1570 28 months (ISRCTN23410175).26 There ingly, levels of esomeprazole in the um- 8. Andersson T, Röhss K, Bredberg E, Hassan- 1626
1571 was no difference in prolongation of bilical cord blood were very low, or not Alin M. Pharmacokinetics and pharmacody- 1627
1572 pregnancy or composite neonatal out- detectable, which provides further reas- namics of esomeprazole, the S-isomer of
1628
1573 comes.27 Trials that have assessed ser- surance that very little reaches the fetal omeprazole. Aliment Pharmacol Ther 2001;15:
1629
elaxin (NCT01566630), pravastatin, compartment. 1563–9.
1574 9. Matok I, Levy A, Wiznitzer A, Uziel E, Koren G, 1630
1575 high doses of antithrombin,28 and cele- Furthermore, we have developed and Gorodischer R. The safety of fetal exposure to 1631
1576 coxib (NCT00442676) have been successfully completed a new protocol proton-pump inhibitors during pregnancy. Dig 1632
1577 attempted, but all were terminated, to evaluate drugs to treat preterm pre- Dis Sci 2012;57:699–705.
1633
1578 perhaps because of poor recruitment. eclampsia that embeds mechanistic in- 10. Gill SK, O’Brien L, Einarson TR, Koren G.
1634
A potential limitation of our trial is sights and pharmacokinetics with The safety of proton pump inhibitors (PPIs) in
1579 pregnancy: a meta-analysis. Am J Gastroenterol 1635
1580 that we were powered to detect a 5-day clinical endpoints. We also completed 2009;104:1541–5. 1636
1581 prolongation of pregnancy and there- recruitment in a reasonable timeframe 11. Pasternak B, Hviid A. Use of proton-pump 1637
1582 fore cannot exclude the possibility that by performing this trial in an area inhibitors in early pregnancy and the risk of
1638
1583 40 mg of esomeprazole may be effective where the incidence of preterm pre- birth defects. N Engl J Med 2010;363:2114–23.
1639
in prolonging pregnancy by 3 days (there eclampsia is very high. We propose this 12. Cluver CA, Walker SP, Mol BW, et al. Double
1584 blind, randomised, placebo-controlled trial to 1640
1585 was a nonsignificant median difference may be an optimal approach when evaluate the efficacy of esomeprazole to treat 1641
1586 of 3 days). However, given the findings of designing clinical trials for preterm early onset pre-eclampsia (PIE Trial): a study 1642
1587 pharmacokinetic and biomarker studies, preeclampsia. n protocol. BMJ Open 2015;5:e008211.
1643
1588 we are inclined to pursue further trials 13. Hall DR. Understanding expectant man-
1644
with higher doses rather than to repeat Acknowledgments agement of pre-eclampsia. Obstet Gynaecol
1589 Forum 2016;26:22–7. 1645
1590 this same trial with a larger number of We thank the members of the Data Monitoring
14. Harris PA, Taylor R, Thielke R, Payne J, 1646
participants. and Safety Committee (Drs Jim Holberton,
1591 Gonzalez N, Conde JG. Research electronic 1647
Jonathan Morris, and Lisa Yelland) and the staff
1592 Our trial has several strengths. As data capture (REDCap): a metadata-driven
1648
at Tygerberg Hospital, Stellenbosch University,
1593 noted, we performed an integrated trial who identified participants and assisted with
methodology and workflow process for
1649
in which we not only obtained data on providing translational research informatics
1594 sample collection; Juanita Ottaway and Liddy 1650
support. J Biomed Inform 2009;42:377–81.
1595 clinical outcomes but also derived Griffith at the South Australian Health & Medical
15. Hall DR, Odendaal HJ, Steyn DW, Grove D. 1651
important insights by undertaking Research for setting up and managing the off-
1596 Expectant management of early onset, severe 1652
site, online randomization sequencing; and the
1597 biomarker studies and pharmacokinetics pre-eclampsia: maternal outcome. BJOG
1653
participants who consented to participate in this
1598 that will inform our next trial. Further- clinical trial.
2000;107:1252–7.
1654
more, it was run at 1 center, which 16. Hassan-Alin M, Andersson T, Bredberg E,
1599 Röhss K. Pharmacokinetics of esomeprazole 1655
1600 allowed us to obtain a high recruitment References after oral and intravenous administration of sin- 1656
1601 rate, to closely monitor compliance, and 1. Abalos E, Cuesta C, Grosso AL, Chou D, gle and repeated doses to healthy subjects. Eur 1657
1602 to collect uniform high-quality data. Say L. Global and regional estimates of pre- J Clin Pharmacol 2000;56:665–70.
1658
1603 Importantly, by basing this trial at an eclampsia and eclampsia: a systematic review. 17. Chunduri RHB, Dannana GS. Develop-
1659
academic center that is embedded within Eur J Obstet Gynecol Reprod Biol 2013;170: ment and validation of a high throughput
1604 1–7. UPLCeMS/MS method for simultaneous 1660
1605 a population with a high incidence of quantification of esomeprazole, rabeprazole 1661
2. Duley LM. The global impact of pre-eclampsia
1606 preterm preeclampsia, we overcame the and eclampsia. Semin Perinatol 2009;33:130–7. and levosulpiride in human plasma. J Pharm 1662
1607 problem faced by previous trials of low 3. Baschat AA, Cosmi E, Bilardo CM, et al. Anal 2016;6:190–8.
1663
1608 recruitment. Predictors of neonatal outcome in early- onset 18. Röhss K, Hasselgren G, Hedenström H.
1664
In conclusion, in women with a placental dysfunction. Obstet Gynecol Effect of esomeprazole 40 mg vs omeprazole
1609 2007;109:253–61. 40 mg on 24-hour intragastric ph in patients with 1665
1610 diagnosis of preterm preeclampsia at symptoms of gastroesophageal reflux disease. 1666
4. Levine RJ, Maynard SE, Qian C, et al. Circu-
1611 26e32 weeks gestation, a daily oral dose lating angiogenic factors and the risk of pre- Dig Dis Sci 2002;47:954–8. 1667
1612 of 40 mg of esomeprazole did not pro- eclampsia. N Engl J Med 2004;350:672–83. 19. Maynard SE, Min JY, Merchan J, et al.
1668
1613 long pregnancies. Circulating levels of 5. Powe CE, Levine RJ, Karumanchi SA. Pre- Excess placental soluble fms-like tyrosine
1669
sFlt1 and other antiangiogenic markers eclampsia, a disease of the maternal endothe- kinase 1 (sFlt1) may contribute to endothelial
1614 lium the role of antiangiogenic factors and dysfunction, hypertension, and proteinuria in 1670
1615 were extremely high among the cohort preeclampsia. J Clin Invest 2003;111: 1671
implications for later cardiovascular disease.
1616 and were not lowered by esomeprazole. Circulation 2011;123:2856–69. 649–58. 1672
1617 The drug appears safe and is well toler- 6. Onda K, Tong S, Beard S, et al. Proton pump 20. Brownfoot FC, Tong S, Hannan NJ, 1673
1618 ated. In pharmacokinetic studies, we inhibitors decrease soluble fms-like tyrosine Hastie R, Cannon P, Kaitu’u-Lino TJ. Effects of
1674
found that esomeprazole was present in kinase-1 and soluble endoglin secretion, simvastatin, rosuvastatin and pravastatin on
1619 decrease hypertension, and rescue endothelial soluble fms-like tyrosine kinase 1 (sFlt-1) and 1675
1620 the maternal circulation, but concen- 1676
dysfunction. Hypertension 2017;69:457–68. soluble endoglin (sENG) secretion from human
1621 trations were relatively low compared 7. Saleh L, Samantar R, Garrelds IM, van den umbilical vein endothelial cells, primary tropho- 1677
1622 with those required to elicit tissue/cell Meiracker AH, Visser W, Danser AHJ. Low sol- blast cells and placenta. BMC Pregnancy 1678
responses in our previous laboratory uble fms-like tyrosine kinase-1, endoglin, and Childbirth 2016;16:117.

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1679 1735
21. Brownfoot FC, Hastie R, Hannan NJ, et al. recombinant antithrombin in very preterm pre- Victoria, Australia; the Department of Obstetrics and
1680 Metformin as a prevention and treatment for eclampsia (PRESERVE-1). Am J Reprod Gynaecology, Monash School of Medicine, Monash Uni- 1736
1681 preeclampsia: effects on soluble fms-like tyro- Immunol 2013;69:539–44. versity, Melbourne, Victoria, Australia (Dr Mol); LCMS 1737
1682 sine kinase 1 and soluble endoglin secretion and 27. Sibai B, Paidas MJ. LB02: randomized Central Analytical Facility and Department of Biochem- 1738
1683 endothelial dysfunction. Am J Obstet Gynecol double-blind placebo controlled evaluation of istry, Stellenbosch University, Stellenbosch, South Africa 1739
2016;214:356.e1–15. the safety and efficacy of recombinant anti- (Dr Stander and Ms Adams).
1684 1740
22. Brownfoot FC, Tong S, Hannan NJ, et al. thrombin vs placebo in preterm preeclampsia. Received May 7, 2018; revised July 17, 2018;
1685 Effects of pravastatin on human placenta, Am J Obstet Gynecol 2017;216(suppl): accepted July 20, 2018. 1741
1686 endothelium, and women with severe pre- S559–60. Supported by The Geoff and Helen Handbury Foun- 1742
1687 eclampsia. Hypertension 2015;66:687–97;dis- 28. D’Angelo A, Valsecchi L. High dose dation, The Beischer Medical Foundation for Mothers and 1743
1688 cussion 445. antithrombin supplementation in early pre- Babies, The Mercy Foundation and The Kilvington Trust; 1744
23. Hannan NJ, Brownfoot FC, Cannon P, et al. eclampsia: a randomized, double blind, placebo- the National Health and Medical Research Foundation of
1689 1745
Resveratrol inhibits release of soluble fms-like controlled study. Thromb Res 2016;140:7–13. Australia provided salary support to S.T. and B.W.M.; the
1690 tyrosine kinase (sFlt-1) and soluble endoglin and University of Melbourne provided a CR Roper Fellowship 1746
1691 improves vascular dysfunction - implications as a (salary support) to N.J.H.; C.A.C. received the Discovery 1747
1692 preeclampsia treatment. Sci Rep 2017;7:1819. Author and article information Academic Fellowship and the South African Medical 1748
1693 24. Thadhani R, Kisner T, Hagmann H, et al. Pilot From the Department of Obstetrics and Gynaecology, Association PhD Bursary. Q17
1749
study of extracorporeal removal of soluble fms- Stellenbosch University and Tygerberg Hospital, (Drs The funders had no role in the study design, the
1694 1750
like tyrosine kinase 1 in preeclampsia. Circula- Cluver, van Papendorp, Theron, and Hall); the Division of collection, analysis, and interpretation of the data, in the
1695 tion 2011;124:940–50. Clinical Pharmacology, Department of Medicine, Stel- writing of the report, or in the decision to submit this 1751
1696 25. Vigil-De Gracia P, Ludmir J. Perinatal and lenbosch University and Tygerberg Hospital (Dr Decloed); article for publication. 1752
1697 hemodynamic evaluation of sildenafil citrate for the Division of Chemical Pathology, Stellenbosch Uni- This trial is registered with the Pan African Clinical 1753
1698 preeclampsia treatment. Obstet Gynecol versity and National Health Laboratory Service (Dr Trials Registry, PACTR201 504000771349. 1754
2016;128:1181–2. Rensburg and Mr Schubert), Cape Town, South Africa; The authors report no conflict of interest.
1699 1755
26. Paidas MJ, Sibai BM, Triche EW, Frieling J, the Translational Obstetrics Group (Drs Cluver, Hannan, Presented at the Society for Maternal-Fetal Medicine
1700 Lowry S; PRESERVE-1 Study Group. Exploring Walker, and Tong and Ms Beard), Mercy Perinatal (Drs 28th Annual Pregnancy Meeting, January 29eFebruary 1756
1701 the role of antithrombin replacement for the Hannan, Walker, and Tong and Ms Beard), and the 3, 2018, Dallas, Texas. 1757
1702 treatment of preeclampsia: a prospective ran- Department of Anaesthetics (Mr Hiscock), University of Corresponding author: Catherine Anne Cluver, MMed. 1758
1703 domized evaluation of the safety and efficacy of Melbourne, Mercy Hospital for Women, Melbourne, cathycluver@hotmail.com 1759
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1.e16 American Journal of Obstetrics & Gynecology MONTH 2018

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 ajog.org
1791
1792 Supplemental Material
1793 Measuring plasma concentrations
1794 of esomeprazole and its
1795 metabolites
1796 Plasma concentrations of esomeprazole
1797 and its metabolites (5-hydroxy omepra-
1798 zole, omeprazole sulphone, and 5-
1799 O-desmethyl omeprazole) were
1800 determined with the use of a validated ultra-
1801 performance liquid chromatographye
1802 tandem mass spectrometry method. A
1803 Waters Acquity ultra-performance liquid
1804 chromatograph (Waters Corporation,
1805 Milford, MA) with a Waters HSS T3
1806 column was linked to a Xevo TQ-S mass
1807 spectrometer (Waters Corporation). A
1808 gradient of 0.1% formic acid to aceto-
1809 nitrile was used, with d3-esomeprazole
1810 as the internal standard. In brief, the
1811 drugs were extracted with a buffered (2
1812 mmol/L ammonium formate; pH 5.5)
1813 acetonitrile 60% solution, and the
1814 precipitated plasma proteins were sepa-
1815 rated by centrifugation (12 000g). The
1816 intra- and interday accuracy of the
1817 quality control samples was >90% and
1818 85%, respectively; the intra- and interday
1819 precision was <11% and <15%, except
1820 for 5-O-desmethyl omeprazole that was
1821 20% at the lower limit of quantification.
1822 The limit of quantitation was 1 ng/mL
1823 for all analytes. Phoenix WinNonlin
1824 software (version



; Certara,
Q8Q7
1825 Princeton, NJ) was used to characterize
1826 the pharmacokinetic parameters of eso-
1827 meprazole with the use of non-
1828 compartmental analyses. The area under
1829 the plasma concentration-time curve
1830 was calculated for the 24-hr dosing in-
1831 terval with the log-linear trapezoidal
1832
1833
1834
1835
1836
1837
1838
1839
1840
1841
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1844
1845
1846
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OBSTETRICS Original Research
1847
method. Pharmacokinetic data were Laboratories, Inc, Hercules, CA). Pro- 1848
summarized as geometric mean values tein levels were determined with BioRad 1849
with 95% confidence intervals. Microplate Manager software (version 6; 1850
BioRad Laboratories, Inc). 1851
Preparation of placental tissue for 1852
analysis Measuring expression of genes in 1853
Placental tissue was dissected from the placental tissue 1854
whole placenta. Four pieces were Total RNA was extracted from placental 1855
dissected from distant sites; the tissue tissue (from placebo [n¼32] and eso- 1856
pieces were then washed in sterile meprazole [n¼33] treated women) with 1857
phosphate-buffered saline solution, and the use of the RNeasy mini kit (Qiagen, 1858
smaller pieces were then dissected (to Valencia, CA) and was quantified with a 1859
allow appropriate penetration of RNA Nanodrop ND 1000 spectrophotometer 1860
preservation buffer [RNAlater]). Each (NanoDrop Technologies Inc, Wil- 1861
piece was immersed in RNAlater ac- mington, DE). RNA (0.2 mg) was con- 1862
cording to manufacturer’s instruction. verted to complementary DNA with the 1863
Tissue samples were then blotted dry, use of a high-capacity complementary 1864
snap frozen, and stored at e80oC until DNA reverse transcriptase kit (Applied 1865
subsequent analysis. Biosystems Life Technologies,



), 1866
according to manufacturer guidelines. Q9 1867
Measuring analytes in the plasma Quantitative polymerase chain reac- 1868
by enzyme-linked immunosorbent tion was performed with the use of 1869
assay Taqman gene expression assays for the 1870
Patient plasma was assessed with the use following genes: sFlt1, HO-1, PlGF and 1871
of enzyme-linked immunosorbent assay VEGFA. Polymerase chain reaction was 1872
for the presence of the following soluble performed on the CFX 384 (BioRad 1873
factors: soluble Flt-1 (DuoSet VEGF R1/ Laboratories, Inc) using FAM-labeled 1874
Flt-1 kit; R&D Systems by Bioscience, Taqman universal polymerase chain 1875
Waterloo, Australia), soluble endoglin reaction mastermix (Applied Bio- 1876
(DuoSet Human Endoglin CD/105; systems) with the following run condi- 1877
R&D Systems), placental growth factor tions: 50 C for 2 minutes, 95 C for 10 1878
(P DuoSet PlGF; R&D Systems), minutes, 95 C for 15 seconds, 60 C for 1879
endothelin-1 (Quantikine endothelin-1; 1 minute (40 cycles). All data were 1880
R&D Systems), and soluble vascular normalized to the housekeeping genes
1881
cell adhesion molecule-1 (human TOP1 and CYC1 as an internal control 1882
VCAM-1/CD106 DuoSet; R&D Sys- and calibrated against the average cycle 1883
tems). Optical density for enzyme- threshold of the control samples. The Q10 1884
linked immunosorbent assays was results were expressed as fold-change 1885
determined with a BioRad X-Mark relative to control subjects. All samples 1886
microplate spectrophotometer (BioRad were run in triplicate. 1887
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MONTH 2018 American Journal of Obstetrics & Gynecology 1.e17
DTD

YMOB12269_proof
No other uses without permission.
Copyright
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©2018.
10:42
Elsevier pmrights
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ce reserved.