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Metformin, the aspirin of the 21 st century: its role in gestational diabetes,

prevention of preeclampsia and cancer, and the promotion of longevity

Article  in  American Journal of Obstetrics and Gynecology · June 2017

DOI: 10.1016/j.ajog.2017.06.003

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1 56
2 Metformin, the aspirin of the 21st century: 57
3 58
4 its role in gestational diabetes mellitus, 59
5 60
6 prevention of preeclampsia and cancer, 61
7 62
8 and the promotion of longevity 63
9 Q47 Roberto Romero, MD; Offer Erez,



; Maik Hüttemann,



; Eli Maymon,



; 64
10 Bogdan Panaitescu,



; Agustin Conde-Agudelo,



; Percy Pacora,



; 65
11 Q1 Bo Hyun Yoon,



; Lawrence I. Grossman,



66
12 67
13 68
14
15
S uddenly, it’s metformin time. Want
to live longer and be healthier?
3,4
Take metformin. Don’t want to get
1-6
Metformin is everywhere. Originally introduced in clinical practice as an antidiabetic
agent, its role as a therapeutic agent is expanding to include treatment of prediabetes
69
70
16 7-10 71
cancer? Take metformin. Do you mellitus, gestational diabetes mellitus, and polycystic ovarian disease and, more
17 11-14 72
have polycystic ovary syndrome, recently, experimental studies and observations in randomized clinical trials suggest that
18 15 73
congestive heart failure, chronic liver metformin could have a place in the treatment or prevention of preeclampsia. This article
19 15 15 74
disease, chronic kidney disease, provides a brief overview of the history of metformin in the treatment of diabetes mellitus,
20 75
reviews the results of metaanalyses of metformin in gestational diabetes mellitus, and the
21 76
treatment of obese non-diabetic pregnant women to prevent macrosomia. We highlight
22 From the Perinatology Research Branch, 77
the results of a randomized clinical trial in which metformin administration in early
23 Program for Perinatal Research and Obstetrics, 78
pregnancy did not reduce the frequency of large-for-gestational-age infants (primary
24 Division of Intramural Research, Eunice Kennedy 79
Shriver National Institute of Child Health and endpoint) but did decrease the frequency of preeclampsia (a secondary endpoint). The
25 80
Human Development, National Institutes of mechanisms by which metformin may prevent preeclampsia include a reduction in the
26 81
Health, U.S. Department of Health and Human production of antiangiogenic factors (soluble vascular endothelial growth factor receptor-
27 Services (NICHD/NIH/DHHS), Bethesda, MD, 82
1 and soluble endoglin), and improvement of endothelial dysfunction, probably through
28 and Detroit, MI (Drs Romero, Erez, Maymon, 83
an effect on the mitochondria. Another potential mechanism whereby metformin may
29 Panaitescu, Conde-Agudelo, and Pacora); the 84
Department of Obstetrics and Gynecology, play a role in the prevention of preeclampsia is its ability to modify cellular homeostasis
30 85
University of Michigan, Ann Arbor, MI (Drs and energy disposition, mediated by mechanistic target of rapamycin. Metformin has a
31 86
Romero, Erez, Maymon, Panaitescu, and molecular weight of 129 Dalton and therefore readily crosses the placenta. There is
32 Pacora); the Department of Epidemiology and 87
considerable evidence to suggest that this agent is safe during pregnancy. New literature
33 Biostatistics, Michigan State University, East 88
on the role of metformin in the prevention of cancer, a chemotherapeutic adjuvant, and in
34 Lansing, MI (Dr Romero); the Center for 89
Molecular Medicine and Genetics, Wayne State prolonging life and protecting against aging is reviewed briefly. Herein we discuss the
35 90
University, Detroit, MI (Drs Romero, Hüttemann, mechanisms of action and potential benefits of metformin.
36 91
and Grossman); the Department of Obstetrics
37 and Gynecology, Seoul National University Key words: diabetes mellitus, metformin Q2 92
38 College of Medicine, Seoul, Republic of Korea 93
39 (Dr Yoon). 94
40 Received Jan. 27, 2017; revised May 30, 2017; 95
41 accepted June 5, 2017. multiple sclerosis,16,17 renal tubu- pregnancy disorders, other than dia- 96
42 This work was supported, in part, by the lointerstitial fibrosis,18 or nonalcoholic betes mellitus and obesity, now and 97
43 Perinatology Research Branch, Program for fatty liver disease19—metformin into the future. 98
44
Perinatal Research and Obstetrics, Division of (Figure 1). ½F1 99
Intramural Research, Eunice Kennedy Shriver The good news for obstetricians is Metformin: from the pharaohs to the
45 National Institute of Child Health and Human 100
46 Development, National Institutes of Health, U.S.
that preeclampsia has the potential to present 101
47 Department of Health and Human Services be added to this list.20 This could be Metformin (dimethylbiguanide) is a 102
48 (NICHD/NIH/DHHS); and, in part, with Federal quite important because preeclampsia constituent of many herbal remedies, 103
funds from NICHD/NIH/DHHS under Contract affects approximately 5e7% of preg- and the Ebers Papyrus, written in
49 104
No. HHSN275201300006C. nancies worldwide, is a leading cause 1500 BCE,21 records its use in Egypt
50 105
The authors report no conflict of interest. of maternal and perinatal morbidity since the time of the Pharaohs
51 106
52
Corresponding author: Roberto Romero, MD. rr. and death, and imposes substantial (Figure 2). In Europe, herbal remedies ½F2 107
ajoged@gmail.com costs on the healthcare system,20 We derived from the plant Galega offici-
53 108
0002-9378/$36.00 believed it was time to review how nalis (Figure 3) that contained met- ½F3 109
54 Published by Elsevier Inc.
55 http://dx.doi.org/10.1016/j.ajog.2017.06.003 metformin works and what it can formin have been prescribed to treat 110
offer obstetricians for the treatment of polyuria and other symptoms of

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111 167
112 FIGURE 1 168
113 Different effects of metformin and its signaling pathways 169
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114 170
115 171
116 172
117 173
118 174
119 175
120 176
121 177
122 178
123 179
124 180
125 181
126 182
127 183
128 184
129 185
130 186
131 187
132 188
133 189
134 190
135 191
136 192
137 193
138 194
139 195
140 196
141 197
142 198
143 199
144 200
145 201
146 202
Metformin reduces insulin resistance, secretion, glucose blood levels, inflammation, and angiogenesis and reduces cell growth and metabolism that
147 203
mediates its anti-tumor activity. These effects are regulated by both 5’ adenosine monophosphate-activated protein kinaseedependent or e
148 204
independent mechanisms that lead to the inhibition of mechanistic target of rapamycin signaling.
149 205
ACC, acetyl-CoA carboxylase; AMPK, 5’ adenosine monophosphate-activated protein kinase; EGF, Epidermal growth factor; FAS, fatty acid synthase; IGF, insulin-like growth factor; mTOR, mechanistic target
150 of rapamycin; PAI-1, plasminogen-activator inhibitor-1; PI3K, Phosphatidylinositol-4,5-bisphosphate 3-kinase; TSC2, tuberous sclerosis 2; VEGF, vascular endothelial growth factor 206
151 (Reproduced with permission from Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) 2012;122:253-70; and 207
Q18 http://diabetesmanager.pbworks.com/f/1255202482/metformin.JPG.)
152 208
Romero. Metformin, the aspirin of the 21st century. Am J Obstet Gynecol 2017.
153 209
154 210
155 211
156 diabetes mellitus since the Middle clinical use because it caused lactic effective in the treatment of malaria; 212
157 Ages,21-24 but it was not until the early acidosis,29 and, although metformin the hypoglycemic effects of the 213
158 1900s that guanidine was identified as did not have this side-effect, its use, as antimalarial agent chloroguanidine 214
159 responsible for the hypoglycemic ef- well as the use of other biguanide hydrochloride eventually paved the 215
160 fects of G officinalis extracts.25,26 derivatives to treat diabetes mellitus, way for the development of metfor- 216
161 Guanidine was too toxic for clinical was displaced by insulin, which was min for the treatment of diabetes 217
162 use, and isoamylene guanidine (gale- purified and synthesized in 1921 and mellitus by Professor Jean Sterne at 218
163 gine) was used as an antidiabetic agent used clinically to treat diabetes melli- the Hopital Laennec in Paris, who 219
164 in the 1920s until the development of tus in humans the next year.30,31 coined the name “glucophage” 220
165 metformin and phenformin.27,28 Nevertheless, research with bigua- (“glucose eater”) for metformin 221
166 Phenformin was withdrawn from nides continued, because they were (Figure 4).32 Two unexpected ½F4
222

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223 279
224 side-effects of some biguanides (lactic 280
FIGURE 2
225 acidosis and increased cardiac death) 281
Ebers papyrus

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226 then caused the biguanides to be 282
227 withdrawn from clinical use in the 283
228 United States22,33-38; however, met- 284
229 formin was relatively safe and, after 20 285
230 years of clinical use in Europe, was 286
231 approved by the Food and Drug 287
232 Administration in 1995 for the treat- 288
233 ment of diabetes mellitus in the 289
234 United States. A joint consensus 290
235 statement by the American Diabetes 291
236 Association and the European Asso- 292
237 ciation for the Study of Diabetes now 293
238 recommends metformin as initial oral 294
239 therapy for patients with type 2 dia- 295
240 betes mellitus.39,40 Recently, the Pro- 296
241 fessional Practice Committee of the 297
242 American Diabetes Association has 298
243 recommended the use of metformin 299
This document, 20 m long, contains a collection of medical texts that are considered to be the most
244 for patients with prediabetes mellitus 300
comprehensive account of practice in Egyptian medicine. Its encyclopedic content addresses
245 (fasting glucose 100e125 mg/dL, 2- 301
multiple illnesses (eg, treatment for diabetes mellitus, but also crocodile bites, mental illness, and
246 hour post-load glucose 140e199 mg/ 302
treatment for death [half an onion and froth of a beer.]. The papyrus was purchased by the Chief of
247 dL, or A1C 5.7e6.4%), especially in 303
Egyptology (Georg Ebers) at the University of Leipzig in Germany where it currently resides. The story
248 those who are <60 years old, have a 304
goes that the papyrus was discovered between the legs of a mummy.
249 body mass index >35 kg/m2 or have a 305
(Adapted from http://spheresoflight.com.au/axismundi/content/images/ebers-papyrus-colonnes1-2.jpg.) Q19

250 history of gestational diabetes melli- 306

Romero. Metformin, the aspirin of the 21st century. Am J Obstet Gynecol 2017.
251 tus.41-43 307
252 Several mechanisms of action that 308
253 are considered responsible for this 309
effect include (1) a decrease in hepatic Important results from the FIGURE 3
254 310
Galega officinalis

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255 glucose production by suppression of metaanalyses: metformin reduces the 311
256 gluconeogenesis,44,45 (2) an increased frequency of gestational hypertension 312
257 insulin suppression of endogenous in gestational diabetes mellitus 313
258 glucose production by the liver,44,45 In 2013, the efficacy and safety of 314
259 (3) reduction of glucose absorption metformin in the management of 315
260 by the gastrointestinal tract.44,45 By far gestational diabetes mellitus had been 316
261 the most important mechanism is the compared with that of insulin in 5 317
262 reduction in hepatic glucose produc- randomized clinical trials.56,71-74 Gui 318
263 tion that is considered mediated by et al75 published a systematic review 319
264 the activation of the global energy and metaanalysis in which metformin 320
265 sensor in cells, adenosine was shown to be superior to insulin in 321
266 monophosphate-activated protein ki- the reduction of maternal weight gain 322
267 nase (Figure 1).46 during pregnancy and in the fre- 323
268 Metformin was mostly used in quency of gestational hypertension 324
nonpregnant diabetic patients until (Figure 5, A); however, metformin did ½F5
269 325
270 Coetzee and Jackson47-50 reported not change the frequency of large-for- This plant (also known as goat’s rue, French lilac, 326
271 its use in the late 1970s with gestational-age (LGA) or small-for- or Italian fitch) was used for many years to treat 327
272 pregnant diabetic women from gestational-age (SGA) fetuses or of the symptoms of diabetes mellitus. In 1920, the 328
273 South Africa, after which metformin hypoglycemia and preeclampsia.75 antidiabetic class of drugs called biguanides, 329
274 became the treatment of choice for Two subsequent metaanalyses originating from this plant, was introduced for 330
275 gestational diabetes mellitus51-68 and, confirmed metformin’s effect on the treatment of diabetes mellitus. 331
276 in the 1990s, for type 2 diabetes maternal weight gain during preg- (Adapted from http://www.naturalmedicinefacts.info/plant/ 332
galega-officinalis.html.)
mellitus69,70 because of its ease of
Q20

277 nancy and on gestational hyperten- 333

Romero. Metformin, the aspirin of the 21st century. Am J
278 administration and high compliance sion76,77; furthermore, Butalia et al77 Obstet Gynecol 2017. 334
rate. reported that, compared with insulin,

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335 391
336 was to reduce the rate of LGA in- 392
FIGURE 4
337 fants96: the primary outcome was a 393
Professor Jean Sterne at the Hospital Laennec, Paris, France reduction of median neonatal birth-
338 394
339 weight by 0.3 standard deviations, 395
340 which would represent a 50% reduc- 396
341 tion in the incidence of LGA neonates. 397
342 Although metformin did not reduce 398
343 the frequency of LGA neonates, it 399
344 significantly reduced the frequency of 400
345 preeclampsia and maternal weight 401
346 gain, although not the rate of gesta- 402
347 tional diabetes mellitus.96 The finding 403
348 that metformin decreased the fre- 404
349 quency of preeclampsia was consistent 405
350 with the findings reported in a meta- 406
351 analysis by Gui et al75 and Feng and 407
352 Yang.76 408
353 409
354 Trial design and execution may explain 410
355 the contradictory results of the 2 411
356 United Kingdom trials 412
357 Differences in trial design, execution, 413
358 and compliance are the most likely 414
359 explanations for the contradictory 415
360 results obtained in these 2 randomized 416
361 Introduction of metformin (“glucophage”) into clinical medicine. clinical trials from the United 417
362Q21 (Reproduced with permission from Bailey CJ, Day C. Metformin: its botanical background. Practical Diabetes International 2004;21:115-7.) Kingdom. In the Fetal Medicine 418
363 Romero. Metformin, the aspirin of the 21st century. Am J Obstet Gynecol 2017. Foundation trial, women had a higher 419
364 body mass index (>35 vs >30 kg/m2), 420
365 were treated with a higher starting and 421
366 metformin significantly decreased to receiving metformin began treat- maximum dose of metformin, and 422
367 the frequency of neonatal hypoglyce- ment at 12e16 weeks of gestation were more compliant than women in 423
368 mia, LGA neonates, and admissions with a starting dose of 500 mg that the EMPOWaR trial.95,96 In the Fetal 424
369 to a neonatal intensive care unit was increased, as necessary, to a Medicine Foundation trial, almost 425
370 (Figure 5, B).56,72-74,77-83 Gui et al75 maximum tolerable dose not 80% of women took at least 50% of 426
371 suggested that metformin reduced exceeding 2500 mg. In this trial, the total number of tablets prescribed, 427
372 the rate of gestational hypertension metformin had no significant effect on and 91% of those who were prescribed 428
373 because of its effects on endothelial birthweight, maternal weight gain >2.5 g/day did so.96 By contrast, in 429
374 function and its decrease in the pro- during gestation, preeclampsia, or the EMPOWaR trial, compliance was 430
375 duction of reactive oxygen species, combined adverse pregnancy out- defined as ingestion of at least 1 tablet 431
376 which are the 2 mechanisms impli- comes, which included miscarriage, for at least 29% of the days between 432
377 cated in the pathophysiologic condi- termination of pregnancy, or fetal or randomization and delivery; only 67% 433
378 tion of preeclampsia.84-94 neonatal death.95 of women fulfilled this criterion.95 434
379 The treatment of obese (defined Suboptimal compliance in random- 435
380 Two trials from the United Kingdom here as a body mass index >35 kg/ ized trials is well known to cause 436
381 report conflicting results of the m2), nondiabetic, pregnant women negative results.97-101 It is also note- Q3 437
382 treatment of obese, nondiabetic, with metformin was compared with worthy that only 13% of the eligible 438
383 pregnant women with metformin placebo in another randomized clin- patients (443/3329) consented to 439
384 In a randomized controlled clinical ical trial in the United Kingdom, the participate in the EMPOWaR study, 440
385 trial, “Efficacy of Metformin in Preg- Fetal Medicine Foundation trial.96 In whereas 47% of eligible women (400/ 441
386 nant Obese Women” (EMPOWaR), this trial, women who were assigned 844) were recruited to the Fetal 442
387 the effect of metformin was compared randomly to receive metformin star- Medicine Foundation study, which 443
388 with placebo in nondiabetic, obese ted treatment at 12e18 weeks of made the latter group more repre- 444
389 (defined here as a body mass index gestation at a dose of 1 g/day that was sentative of women who meet the 445
390 >30 kg/m2), pregnant women.95 increased by 0.5 g/week to a study’s eligibility criteria and to whom 446
Women who were assigned randomly maximum dose of 3g/day. The goal the study’s results apply.

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447 503
448 Mechanisms by which metformin 504
FIGURE 5
449 may prevent preeclampsia 505
Results of the metaanalyses that compared the efficacy of treatment with

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450 The role of angiogenic and 506
antiangiogenic factors in the genesis of
metformin vs insulin in women with gestational diabetes mellitus
451 507
452 preeclampsia 508
453 For >100 years, preeclampsia was 509
454 thought to be caused by the release 510
455 of “toxic factors” from an 511
456 ischemic placenta, hence, the name 512
457 “toxemia.”102-117 The most widely 513
458 known “toxins” at this time are soluble 514
459 fms-like tyrosine kinase-1 (sFlt-1 or 515
460 soluble vascular endothelial growth fac- 516
461 tor receptor 1 [sVEGFR-1]) and soluble 517
462 endoglin.118-142 518
463 It has been hypothesized that 519
464 sVEGFR-1 is produced in preeclamp- 520
465 sia because the placenta is ischemic 521
466 or hypoxic, and sVEGFR-1 antago- 522
467 nizes angiogenic molecules, such 523
468 as vascular endothelial growth factor 524
469 and placental growth factor.119,143-150 525
470 Soluble endoglin transforming 526
471 growth factor is a cell surface co- 527
472 receptor for transforming growth 528
473 factor-b1, which blocks TGF-b1e 529
474 mediated activation of endothelial 530
475 nitric oxide synthase and promotes 531
476 vasorelaxation.124 There is excessive Romero. Metformin, the aspirin of the 21st century. Am J Obstet Gynecol 2017. (continued) 532
477 production of sVEGFR-1 and soluble 533
478 endoglin in the uterus of patients with 534
479 preeclamptic121 that is proportional 535
480 to the severity of the disease151-153 thrombocytopenia, and intrauterine membranes, fetal growth restriction, 536
481 that causes maternal plasma concen- growth restriction124; similar results fetal death, and other complications of 537
482 trations of sVEGFR-1 and soluble have been obtained in mice.141 This pregnancy.186-189 538
483 endoglin to increase before pre- condition is indistinguishable from Brownfoot et al,20 from the Trans- 539
484 eclampsia is diagnosed, which makes the hemolysis, elevated liver enzymes, lational Obstetrics Group of the 540
485 them potential biomarkers for the and low platelet count (HELLP) Department of Obstetrics and Gyne- 541
486 disease.111,120,128,129,132,133,137,138,154-179 syndrome that is observed in cology, Mercy Hospital for Women, at 542
487 The increase of sVEGFR-1 causes humans.181-184 the University of Melbourne, Heidel- 543
488 a parallel decrease of maternal Although the emphasis on the toxic berg, Victoria, Australia, reported that 544
489 plasma concentrations of PIGF in factors produced by an ischemic metformin reduced the production of 545
490 preeclampsia.119,143-150 placenta has been on the balance be- sFlt-1 (also known as sVEGFR-1) and 546
491 The administration of sFlt-1 (or tween angiogenic and antiangiogenic soluble endoglin in a dose-dependent 547
492 sVEGFR-1) and/or soluble endoglin to factors, evidence now suggests that manner by endothelial cells, villous 548
493 animals produces changes character- cytokines (such as tumor necrosis trophoblast, and villous explants 549
494 istic of preeclampsia. For example, if factor-a and interleukin-10) are (Figure 6); the report also suggested ½F6 550
495 sVEGFR-1 is administered to rats us- altered in early and late preeclampsia that metformin regulates these anti- 551
496 ing an adenovirus vector, the animals and that the changes correlate with angiogenic factors at the level of the 552
497 develop hypertension, proteinuria, the type of histopathologic changes in mitochondria. Metformin also 553
498 and glomerular endotheliosis.180 the placenta.185 The importance of decreased the expression of vascular 554
499 Additionally, if sVEGFR1 and soluble ischemic placental disease, not limited cell adhesion molecule 1, which is 555
500 endoglin are given to pregnant rats, to preeclampsia, has been the subject expressed by endothelial cells that are 556
501 the animals not only develop pre- of several recent studies (ie, preterm dysfunctional or have been stimulated 557
502 eclampsia but also liver dysfunction, labor, preterm premature rupture of by incubation with tumor necrosis 558

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559 615
560 factor alpha, a cytokine increased in 616
FIGURE 5
561 the circulation of patients with pre- 617
(Continued ) eclampsia. 190-195
562 618
563 However, the most persuasive evi- 619
564 dence that metformin has a vascular 620
565 effect is the finding that it reverses the 621
566 impairment of vascular relaxation that 622
567 is induced by incubating the maternal 623
568 blood vessels that were obtained from 624
569 the omentum at the time of cesarean 625
570 delivery with placental-conditioned 626
571 media of patients with preeclamp- 627
572 sia.20 Metformin also abrogated the 628
573 reduction of angiogenic sprouting that 629
574 is induced in human omental vessel 630
575 explants by incubation with VEGFR-1 631
576 (Figure 7).20 Overall, the findings of ½F7 632
577 Brownfoot et al20 suggest that met- 633
578 formin may have a role in the pre- 634
579 vention of preeclampsia through its 635
580 effect on cell metabolism, on the 636
581 antiangiogenic state, and, most likely, 637
582 on other processes associated with this 638
583 obstetric syndrome.20 639
584 640
585 Preeclampsia as a mitochondrial 641
586 disorder and the effect of metformin 642
587 on mitochondrial function 643
588 Torbergsen et al196 first suggested that 644
589 mitochondria might be involved in 645
590 the pathogenesis of preeclampsia 646
591 based on the high frequency of pre- 647
592 eclampsia in a family that experiences 648
593 mitochondrial dysfunction. Six of 10 649
594 women with a mitochondrial disease 650
595 had at least 1 pregnancy complicated 651
596 by preeclampsia or eclampsia, whereas 652
597 none had been hypertensive in the 653
598 nonpregnant state. Torbergsen et al 654
599 suggested that these women experi- 655
600 enced preeclampsia because their 656
601 dysfunctional mitochondria could not 657
602 meet the increased energy demands of 658
603 pregnancy and because the failure of 659
A, The panels present the beneficial effects of metformin vs insulin in women with gestational adequate cellular energy production
604 diabetes mellitus that indicate a reduction in (1) maternal weight gain during pregnancy and (2) 660
605 led to an accumulation of adenosine 661
gestational hypertension. (Reproduced with permission from Gui J, Liu Q, Feng L. Metformin vs pyrophosphate, which is able to
606 insulin in the management of gestational diabetes mellitus: a meta-analysis. PLoS One 662
607Q22 mediate most of the changes seen in 663
2013;8:e64585.) B, The panels present the beneficial effects of metformin vs insulin in women with preeclampsia.89,197 Adenosine pyro-
608 gestational diabetes mellitus that indicate a reduction in (1) neonatal hypoglycemia, (2) large-for- 664
609 phosphate is a vasoconstrictor, causes 665
gestational-age neonates, and (3) admissions to the neonatal intensive care unit. platelet aggregation, and breaks down
610 CI, confidence interval; IV, inverse variance; M-H, Mantel-Haenszel. 666
611 to uric acid. 667
(Reproduced with permission from Butalia S, Gutierrez L, Lodha A, Aitken E, Zakariasen A, Donovan L. Short- and long-term outcomes of
612Q23 metformin compared with insulin alone in pregnancy: a systematic review and meta-analysis. Diabet Med 2017;34:27-36.) In 1990, Shanklin and Sibai198 re- 668
613 Romero. Metformin, the aspirin of the 21st century. Am J Obstet Gynecol 2017. ported that mitochondria from 669
614 small vessels, myometrial smooth 670
muscle, myometrial interstitial cells,

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671 727
672 FIGURE 6 728
673 Effect of metformin on soluble fms-like tyrosine kinase-1/soluble vascular endothelial growth factor receptor-1 729
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674 secretion, soluble endoglin, and isoforms e15a and i13 expression in endothelial cells and placental tissue 730
675 731
676 732
677 733
678 734
679 735
680 736
681 737
682 738
683 739
684 740
685 741
686 742
687 743
688 744
689 745
690 746
691 747
692 748
693 749
694 750
695 751
696 752
697 753
698 754
699 755
700 756
701 757
702 758
703 759
704 760
705 761
706 762
707 Metformin reduced, in a dose-dependent manner, soluble fms-like tyrosine kinase-1 from A, endothelial cells, B, villous cytotrophoblast cells, and C, 763
708 preterm preeclamptic placental villous explants. Metformin also reduced endothelial cell expression of D, the soluble fms-like tyrosine kinase-1 i13 764
709 isoform, E, villous cytotrophoblast cells, and F, preterm preeclamptic placental villous explant messenger RNA expression of soluble fms-like tyrosine 765
710 kinase-1 e15a. Metformin reduced soluble endoglin secretion from G, endothelial cells and H, villous cytotrophoblast cells, but it did not change soluble 766
711 endoglin secretion from I, preterm preeclamptic placental villous explants. The single asterisk indicates P<.05; the double asterisk indicates P<.01; the 767
712 triple asterisk indicates P<.0001; and the quadruple asterisk indicates P<.00001. 768
mM, millimolar; sENG, soluble endoglin; sFlt-1, soluble fms-like tyrosine kinase-1).
713 769
(Modified with permission from Brownfoot FC, Hastie R, Hannan NJ, et al. Metformin as a prevention and treatment for preeclampsia: effects on soluble fms-like tyrosine kinase 1 and soluble endoglin
714 Q24 secretion and endothelial dysfunction. Am J Obstet Gynecol 2016;214:356.e1-15.) 770
715 Romero. Metformin, the aspirin of the 21st century. Am J Obstet Gynecol 2017. 771
716 772
717 773
718 774
719 circulating leukocytes, epidermal and apparatus, endoplasmic reticulum, endomyocardial biopsy obtained from 775
720 dermal cells, and hepatocytes in and small, unidentified microvesicles; a 20-year-old nulliparous woman, 776
721 women with preeclampsia all had these mitochondrial changes were not known to have mitochondrial myop- 777
722 morphologic changes that were quite limited to uterine tissues, thus athy, who had severe preeclampsia.199 778
723 different from those seen in normal implying that mitochondrial dysfunc- Since that time, the following findings 779
724 pregnancies.198 The tissues of women tion was a systemic disorder. That have further implicated mitochondria in 780
725 with preeclampsia showed central same year, Berkowitz et al199 reported the pathogenesis of preeclampsia: (1) 781
726 disruption in mitochondrial a case of abnormal mitochondrial Comparative proteomics analysis of 782
morphology and changes in the Golgi morphology that was observed in an placental mitochondria in normal

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783 839
784 FIGURE 7 840
785 Effect of soluble fms-like tyrosine kinase-1/soluble vascular endothelial growth factor receptor-1 and metformin 841
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786 on angiogenesis 842

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Q25 Omental vessel rings cultured with soluble fms-like tyrosine kinase-1/soluble vascular endothelial growth factor receptor-1 reduced the vessel
814 870
outgrowth (white arrow, middle panel). This effect was resolved when metformin (1 mmol/L) was added to the culture media (right panel).
815 871
sFlt-1, soluble fms-like tyrosine kinase-1.
816 872
(Reproduced with permission from Brownfoot FC, Hastie R, Hannan NJ, et al. Metformin as a prevention and treatment for preeclampsia: effects on soluble fms-like tyrosine kinase 1 and soluble endoglin
817Q26 secretion and endothelial dysfunction. Am J Obstet Gynecol 2016;214:356.e1-15.) 873
818 Romero. Metformin, the aspirin of the 21st century. Am J Obstet Gynecol 2017. 874
819 875
820 876
821 877
822 patients and those with preeclampsia has signal/alarmin that is responsible for the effects on sterile inflammation and iron 878
823 shown up-regulation of 4 proteins and sterile (absence of infection) intravas- metabolism, miR-210 also modulates 879
824 down-regulation of 22 proteins. Using cular inflammatory processes of this mitochondrial function. The laboratory 880
825 bioinformatic tools, differentially condition202,203; (3) the placentas of of Professor Leslie Myatt provided evi- 881
826 expressed proteins in this study were patients with preeclampsia,204 as well as dence that placental mitochondrial 882
827 identified as participating in many crit- those from pregnancies with pre- dysfunction is mediated, at least in part, 883
828 ical processes of preeclampsia, such as eclampsia and SGA,205 overexpress the by miR-210 by demonstrating that 884
829 reactive oxygen species generation, microRNA (miR)-210, which has, as mitochondrial complexes I, III, and IV 885
830 apoptosis, fatty acid oxidation, respira- potential targets, the regulation of tran- decreased in preeclampsia, along with a 886
831 tory chain function, and the tricarbox- scription of the innate immune decrease in the iron-sulfur cluster scaf- 887
832 ylic acid cycle200; (2) the median response. Additionally, it was demon- fold homologue.207 Importantly, trans- 888
833 maternal whole blood mitochondrial strated that miR-210 was induced by fection of cells with miR-210 resulted in 889
834 DNA copy number was higher in women hypoxia, and RNA interference knock- a significant reduction in oxygen con- 890
835 with preeclampsia than in those who down resulted in autophagosomal and sumption by mitochondria, mitochon- 891
836 experienced a normal pregnancy siderosomal iron accumulation, which drial respiratory deficiency, and 892
837 (P<.001201), which suggests that an implicated siderosis or interstitial tro- production of ROS(207). Q4
893
838 influx of mitochondrial DNA into the phoblasts as mechanisms in preeclamp- Recently, Professor Gennady 894
maternal circulation may act as a danger sia and SGA206; and (4) aside from its Sukhikh’s Research Institute in

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895 951
896 FIGURE 8 952
897 Effect of metformin on the mitochondrial respiratory transport chain complex 1 953
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898 954
899 955
900 956
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902 958
903 959
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922 978
923 979
924 980
925 981
926 982
927 Metformin crosses the plasma membrane of the cell by passive diffusion; the mitochondria is its main intracellular target. Metformin inhibits mito- 983
928 chondrial respiratory transport chain complex 1 and induces a decrease in the reduced form of nicotinamide adenosine dinucleotide oxidation, proton 984
929 pumping across the inner mitochondrial membrane, and the oxygen consumption rate, which leads to a reduction of adenosine triphosphate synthesis. 985
ADP, adenosine pyrophosphate; ATP, adenosine triphosphate; Cyt c, cytochrome complex; eþ,



; FAD, flavin adenine dinucleotide; Hþ, hydrogen ion; H2O, water; NAD, nicotinamide adenine dinucleotide;
930 Q28 NADH, nicotinamide adenosine dinucleotide; OCT, organic cation transporter; Q,



. 986
931 Q27 (Reproduced with permission from Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) 2012;122:253-70.) 987
932 Romero. Metformin, the aspirin of the 21st century. Am J Obstet Gynecol 2017. 988
933 989
934 990
935 991
936 Moscow has reported the following mitochondrial membrane, which is a preeclampsia. Thus, early-onset pre- 992
937 findings that indicate that mitochon- fine-tuned process crucial for mito- eclampsia is associated with mito- 993
938 drial functional changes in the chondrial quality control; (2) a 5-fold chondrial activation, up-regulation of 994
939 placenta occur in both early- and late- decrease in the mitochondrial tran- OPA-1, active DNA replication 995
940 onset preeclampsia when compared scription factor-A; (3) a 1.5-fold (resulting from a high respiration 996
941 with normal pregnancy208: Women increase of the relative placental rate), and mitochondrial transcription 997
942 with early-onset preeclampsia had (1) mitochondrial DNA copy number; factor down-regulation, although both 998
943 a 2-fold increase in the mRNA and (4) increased mitochondrial early and late preeclampsia are asso- 999
944 expression of OPA (optic atrophy)-1 respiration in the presence of Com- ciated with an elevated phosphate/ 1000
945 and a 3-fold increase in OPA-1 pro- plex I substrates.208 oxygen ratio.208 1001
946 tein expression (cleaved and An increase in the phosphate/oxy- Collectively, this evidence, coupled 1002
947 uncleaved forms) in patients with gen ratio (a measure for how much with the conduction of workshop Q5 1003
948 early-onset preeclampsia. This gene is adenosine triphosphate is synthesized recently held by the International 1004
949 involved in mitochondrial fusion and per 2 electrons transferred to oxygen) Federation of Placental Associations 1005
950 in the cristae structure of the inner was observed in both early and late on the role of mitochondria in 1006

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1007 1063
1008 FIGURE 9 1064
1009 Nutrient-sensing pathways in the evolution of species from unicellular to multicellular organisms 1065
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1010 1066
1011 1067
1012 1068
1013 1069
1014 1070
1015 1071
1016 1072
1017 1073
1018 1074
1019 1075
1020 1076
1021 1077
1022 1078
1023 1079
1024 1080
1025 1081
1026 1082
1027 1083
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1029 1085
1030 1086
1031 1087
1032 1088
1033 1089
1034 1090
1035 Unicellular organisms have 2 distinct nutrient pathways (PII and chemoreceptors), although fungi evolved 3 distinct nutrient-sensing pathways (Ssy1-Ptr3- 1091
1036 Q30 Ssy5, Snf3/Rgt2, and 2-C-methyl-D-erythritol 4-phosphate).



are denoted, followed by the sensing pathways that are conserved from yeast to man. 1092
1037 Q29
Blue bars indicate the presence of the nutrient-sensing pathways used by different organisms. 1093
1038 AMPK, 5’ adenosine monophosphate-activated protein kinase; GCN2, general control nonderepressible 2; MEP, 2-C-methyl-D-erythritol 4-phosphate; PII,



; Snf3/Rgt2,



; SPS, Ssy1-Ptr3-Ssy5; 1094
TOR, target of rapamycin.
1039 Q32 1095
(Reproduced with permission from Chantranupong L, Wolfson RL, Sabatini DM. Nutrient-sensing mechanisms across evolution. Cell 2015;161:67-83.)
1040 1096
Q31 Romero. Metformin, the aspirin of the 21st century. Am J Obstet Gynecol 2017.
1041 1097
1042 1098
1043 1099
1044 placental function,209 suggests that mitochondrial electron transport inhibitors (antimycin and rotenone) 1100
1045 mitochondrial dysfunction plays a chain (Figure 8). blocked secretion of sFlt-1 and ½F8 1101
1046 major role in the pathogenesis of The reduction in the secretion of soluble endoglin, which suggests that 1102
1047 preeclampsia. antiangiogenic factors by metformin the electron transport chain is the 1103
1048 Brownfoot et al20 found that met- was reversed when succinate (whose major effector of the benefits of met- 1104
1049 formin can improve endothelial metabolism via complex II bypasses formin. Indeed, succinate in the 1105
1050 dysfunction, reduce the expression of complex I) was used as an electron absence of metformin appears to 1106
1051 vascular adhesion molecule 1 mRNA source.20 However, succinate is also an have no effect.20 The role that ROS 1107
1052 induced by tumor necrosis factor-a, inhibitor of HIF-1a,213 which has and the electron transport chain Q7 1108
1053 and improve whole-blood vessel been implicated in the exaggerated play in the genesis of preeclampsia Q6 1109
1054 angiogenesis impaired by sFlt-1 or production of sFlt-1 and in the path- could be parsed both pharmacologi- 1110
1055 sVEGFR-1. Given the evidence that ophysiologic condition of preeclamp- cally and genetically.216-219 The 1111
1056 metformin acts through the mito- sia214,215; therefore, succinate could changes in the mitochondrial function 1112
1057 chondrial electron transport chain by also be acting by inhibiting HIF-1a, in preeclampsia suggest that there 1113
1058 inhibiting complex I,46,210-212 Brown- rather than the mitochondrial elec- are perturbations in the cellular en- 1114
1059 foot et al20 investigated whether the tron transport chain. However, ergy balance of patients with this 1115
1060 effects on sFlt-1 and soluble endoglin Brownfoot et al20 demonstrated that syndrome that affect cell growth and 1116
1061 production are regulated through the other electron transport chain division (especially in the placenta 1117
1062 1118

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1119 1175
1120 FIGURE 10 1176
1121 Mechanisms of nutrient-sensing within unicellular and multicellular organisms 1177
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1122 1178
1123 1179
1124 1180
1125 1181
1126 1182
1127 1183
1128 1184
1129 1185
1130 1186
1131 1187
1132 1188
1133 1189
1134 1190
1135 1191
1136 1192
1137 1193
1138 1194
1139 A, Prokaryotes can sense amino acids through a variety of sensors present in the cytosol and extracellular compartments. B, Similarly, yeast cells sense 1195
1140 extracellular amino acids via plasma membrane transporters and cytosolic sensors. Eukaryote cells have another potential compartment, such as a 1196
1141 vacuole, where sensing may occur. C, In mammalian cells, sensing may occur via cell membrane transporters in the cytosol and within the lysosome. 1197
1142 GCN2, general control nonderepressible 2; mTORC1, mechanistic target of rapamycin complex 1; PII,



; SPS, Ssy1-Ptr3-Ssy5.) 1198
1143 Q34 (Reproduced with permission from Chantranupong L, Wolfson RL, Sabatini DM. Nutrient-sensing mechanisms across evolution. Cell 2015;161:67-83. 1199
1144 Q33 Romero. Metformin, the aspirin of the 21st century. Am J Obstet Gynecol 2017. 1200
1145 1201
1146 1202
1147 1203
1148 and the fetus); all are modified by for storage: eukaryotes have a third the intervillous space. In this strategic 1204
1149 metformin. compartment that allows intracellular location, the nutrient-sensing mecha- 1205
1150 storage; here, nutrient sensing can also nisms of the syncytiotrophoblast can 1206
1151 The biologic basis for the effects of occur (Figure 10).221 Nutrient sensing detect changes in maternal blood 1207
1152 metformin on fetal growth became more complex in metazoans, composition, which enables the placenta 1208
1153 Nutrient sensing: key for the survival because they were required to maintain to monitor it constantly, not only 1209
1154 of all living forms homeostasis of different tissues and or- regarding the nutritional status of 1210
1155 “Cell growth and division are the 220
two gans. Indeed, over the course of millions maternal circulation but also for any 1211
1156 most fundamental features of life.” All of years, specific pathways have evolved threat it contains to the fetus (ie, mi- 1212
1157 organisms must be able to for glucose, amino-acids, and energy, croorganisms). Thus, it is easy to envi- 1213
1158 detect nutrient levels in their environ- and metazoans eventually evolved the sion that the syncytiotrophoblast and 1214
1159 ment to coordinate growth and devel- endocrine and paracrine systems to meet other components of the placenta 1215
1160 opment. This is true of bacteria that must their requirements for nutrient sensing. contain the nutrient-sensing systems 1216
1161 choose whether to grow, remain sta- The coordinated actions of hormones that allow the fetus to regulate its own 1217
1162 tionary, and, in the case of motile bac- (such as insulin, leptin, and ghrelin) growth by extracting nutrition from the 1218
1163 teria, determine in which direction to regulate the organism’s response to the maternal blood. 1219
1164 move, depending on the availability of presence or absence of nutrients, Disorders in nutrient-sensing path- 1220
1165 nutrients. Bacteria evolved specific che- modulate anabolic and catabolic pro- ways may lead to fetal growth disorders, 1221
1166 moreceptors for this purpose that coor- cesses, and control 222-224 feeding behavior by and studies by Powell and Jansson.225 1222
1167 dinate information received from the signaling the brain. Roos et al,226 and Rosario et al227 have 1223
1168 environment with specialized structures, provided unique insights into nutrient 1224
1169 such as flagella, to move toward nutri- Fetal-placental nutrient sensing sensing by the human placenta. For 1225
1170 ents. The evolutionary history of Nutrient sensing is a crucial requirement example, down-regulation of mecha- 1226
1171 nutrient-sensing pathways from bacteria 221
for fetal development. The key structure nistic target of rapamycin (mTOR) in the 1227
1172 ½F9to humans is displayed in Figure 9. in the placenta responsible for nutrient placenta has been reported in SGA/ 1228
1173 The evolution from prokaryotes (a 2- sensing is the syncytiotrophoblast, growth-restricted fetuses (Figure 11).226½F111229
1174 compartment system) to eukaryotes which covers the villous tree and is in Whether this represents a primary 1230
(Figure 10) created unique opportunities direct contact with the maternal blood in defect in the sensing mechanisms or an
½F10
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1231 1287
1232 FIGURE 11 1288
1233 Effect of maternal nutrition on the placental nutritional sensing system and fetal growth 1289
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1234 1290
1235 1291
1236 1292
1237 1293
1238 1294
1239 1295
1240 1296
1241 1297
1242 1298
1243 1299
1244 1300
1245 1301
1246 1302
1247 1303
1248 1304
1249 1305
1250 1306
1251 1307
1252 1308
1253 1309
1254 1310
1255 1311
1256 1312
1257 1313
1258 The placenta plays a critical role in modulating maternal-fetal resource allocation, thereby affecting fetal growth and the long-term health of the offspring. 1314
1259 Maternal under-nutrition decreases circulating levels of insulin growth factor-1, leptin, and insulin and increases maternal serum adiponectin con- 1315
1260 centrations, which leads to low fetal nutrient availability. Maternal over-nutrition is associated with increased insulin, insulin-like growth factor-1, and 1316
1261 leptin concentrations in the maternal circulation and decreased levels of circulating levels of adiponectin, which leads to fetal overgrowth. The placenta 1317
1262 integrates maternal and fetal nutritional signals with information from intrinsic nutrient sensors such as mammalian target of rapamycin signaling. 1318
IGF-1, insulin-like growth factor-1; mTOR, mechanistic target of rapamycin.
1263 1319
Q36 (Modified with permission from Jansson T, Powell TL. Role of placental nutrient sensing in developmental programming. Clin Obstet Gynecol 2013;56:591-601; and Jansson T, Aye IL, Goberdhan DC. The
1264 emerging role of mTORC1 signaling in placental nutrient-sensing. Placenta 2012;33(suppl2):e23-9; and https://clipartfest.com/download/2ccb316331956e87398d72be2d6d14e49c1a9be8.html.) 1320
1265 Q35 Romero. Metformin, the aspirin of the 21st century. Am J Obstet Gynecol 2017. 1321
1266 1322
1267 1323
1268 1324
1269 adaptive response by the fetoplacental activated under conditions that are higroscopicus228 that inhibits the 1325
1270 unit remains to be determined. Similarly, essential amino-acids deficiency or growth of Candida albicans and that 1326
1271 when the placenta senses an excess of imbalance; and (5) the mTOR complex 1 was first discovered in soil on Easter 1327
1272 nutrients (as in obesity, diabetes melli- (mTORC1) pathway, which integrates Island (Rapa Nui). The story of its 1328
1273 tus, or other metabolic disorders) mTOR nutrient and growth factor signaling. discovery is similar to that of peni- 1329
1274 activation and fetal growth acceleration Each of these nutrient-sensing pathways cillin: its isolation from Aspergillus 1330
1275 may be expected to occur. is present in the human placenta.225-227 penicillinum and its capacity to inhibit 1331
1276 Nutrient sensing occurs through There are also changes in these path- bacterial growth. However, rapamy- 1332
1277 several pathways,225 the most important ways in cases of fetal growth restriction cin’s popularity is due to its powerful 1333
1278 of which are (1) the adenosine caused by maternal starvation or immunosuppressive properties, which 1334
1279 monophosphate-activated protein ki- impaired placentation where there is made it a drug of choice for patients 1335
1280 nase pathway, which is a global energy down-regulation of placental nutrient with renal transplants229 and not its 1336
1281 sensor in cells; (2) glycogen synthase 3, transport.225,226 antimicrobial properties. 1337
1282 which acts as a glucose sensor; (3) the Rapamycin can also prolong the life 1338
1283 hexose-amino signaling pathway, which The mTOR translates maternal cycle of many species as diverse as 1339
1284 depends on the availability of nutrients nutritional status via the placenta to worms and mice, and its signaling 1340
1285 such as glucose, glutamine, and acetyl- the fetus system has been implicated as the 1341
1286 CoA; (4) the amino-acid response Rapamycin is an antifungal master regulator of cellular growth 1342
signal transduction pathway, which is agent produced by Streptomyces and metabolism. A family of

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1343 1399
1344 molecules that are the mTOR complex 1400
FIGURE 12
1345 has been attributed a major role in 1401
Metformin suppresses cell growth and promotes longevity

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1346 the biology of cell metabolism, 1402
1347 growth, longevity, and even preterm 1403
1348 birth.230-236 1404
1349 Rapamycin acts by interacting with a 1405
1350 family of TOR molecules that is highly 1406
1351 conserved functionally and evolution- 1407
1352 arily from yeast to humans, and it con- 1408
1353 tains 2 multiprotein complexes that are 1409
1354 functionally and structurally different: 1410
1355 the first, mTORC1, is rapamycin- 1411
1356 sensitive; the second, mTORC2, is 1412
1357 rapamycin-resistant.237 Both complexes 1413
1358 control cell growth and metabolism in 1414
1359 response to the availability of nutrients, 1415
1360 energy, and growth factors. On activa- 1416
1361 tion, the serine/threonine kinases acti- 1417
1362 vate a cascade of intracellular processes 1418
1363 that involve the mitochondria and the 1419
1364 nucleus of the cell to promote cellular 1420
growth and, to a certain extent, aging. Metformin slows Caenorhabditis elegans (roundworm) growth by inhibiting the mitochondrial electron
1365 1421
Rapamycin prolongs lifespan by inhib- transport chain, which limits the transit of the Ras-related GTP binding C protein through the nuclear
1366 1422
1367 iting the effects of mTOR.238,239 pore complex that results in a reduced activity of the mechanistic target of rapamycin complex 1. The
1423
MTOR is a major human nutrient- metformin-induced inhibition of mechanistic target of rapamycin complex 1 leads to the up-regulation
1368 1424
1369 sensing receptor in the placenta.225 of the transcription factor protein skinhead-1/nuclear-factor-erythroid-related factor-1 (a regulator of Q37
1425
This signaling system is highly antioxidant genes) and the expression of acyl-CoA dehydrogenase family member-10 gene.
1370 1426
1371 expressed in the syncytiotrophoblast, ACAD10, acyl-CoA dehydrogenase family member-10; mTORC1, mechanistic target of rapamycin complex 1; NPC, nuclear pore complex;
1427
RagC, Ras-related GTP binding C; RNAi, RNA interference; SKN-1/Nrf1, protein skinhead-1/nuclear-factor-erythroid-related factor-1. Q39
1372 and its activity is regulated 1428
(Reproduced with permission from Wu L, Zhou B, Oshiro-Rapley N, et al. An ancient, unified mechanism for metformin growth inhibition
1373 by glucose and amino-acid in C elegans and cancer. Cell 2016;167:1705-18.e13.) Q38
1429
1374 concentrations.226,227,240 Romero. Metformin, the aspirin of the 21st century. Am J Obstet Gynecol 2017.
1430
1375 MTOR has key properties in the 1431
1376 placenta225,226 that include its activa- 1432
1377 tion by insulin, insulin-like growth 1433
1378 factor-1, and leptin and its inhibition direct diffusion without affecting the embryonic development found that 1434
1379 by cortisol. MTOR regulates 2 key facilitated transfer of glucose.242 this drug carries no increased risk for 1435
1380 amino-acid transport systems (A and Indeed, an ex vivo dually perfused congenital malformations245,246 and 1436
1381 L). The activation of mTOR is corre- human placental lobule demonstrated currently is classified as category B in 1437
1382 lated positively with the first-trimester the rapid transfer of metformin from the United States and as category C in 1438
1383 maternal body mass index, which maternal to fetal circulation with a lag Australia.247,248 Similarly, no excess of 1439
1384 links maternal over-nutrition and time of 1.70.28 minutes that simi- fetal or neonatal complications could 1440
1385 nutrient-sensing by the placenta, larly was observed in women with be demonstrated when the adminis- 1441
1386 although its expression is down- normal pregnancies and those diag- tration of metformin was compared 1442
1387 regulated when fetal growth is nosed with gestational diabetes melli- with glyburide and insulin.249 In 1443
1388 restricted (in both animal models and tus.242 In vivo studies reported the addition, a study that investigated 1444
1389 humans). The mTOR Akt-mTOR- detection of metformin in the umbil- the neurodevelopmental effect at 1445
1390 HIF-1a signaling pathway also affects ical cord blood of neonates from 2 years of age could not identify 1446
1391 placental angiogenesis by its ability to women with polycystic ovarian syn- a significant difference between 1447
1392 increase VEGF and endoglin expres- drome who were treated with met- children exposed in utero to metfor- 1448
1393 sion in response to hypoxia in a formin throughout gestation.243,244 min and those exposed to insulin.250 1449
1394 trophoblast cell line.241 Similar concentrations of metformin Moreover, there were no differences 1450
1395 in the umbilical artery and umbilical in fat measurements, total fat mass, 1451
1396 Safety of metformin during vein suggest negligible metformin and percentage of body fat.251 1452
1397 pregnancy metabolism by the fetus.244 Several Those who were exposed to metfor- 1453
1398 Metformin has a molecular weight of metaanalyses that studied the terato- min during fetal life had a larger 1454
129 Dalton and crosses the placenta in genic effect of metformin on upper arm circumference and bigger

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1455 1511
1456 TABLE 1 1512
1457 Association between prepregnancy body mass index and the risk of mild and severe preeclampsia and 1513
1458 Q40 gestational hypertensiona 1514
1459 1515
Odds ratiob (95% confidence interval)
1460 1516
1461 Body mass Preeclampsia Gestational hypertension 1517
1462 Ethnicity index (kg/m2) Mild Severe Mild Severe 1518
1463 White 17 0.7 (0.6e0.8) 0.8 (0.5e1.1) 0.7 (0.6e0.8) 0.4 (0.2e0.7) 1519
1464 1520
20 Reference Reference Reference Reference
1465 1521
1466 25 1.8 (1.5e2.1) 1.7 (1.1e2.5) 1.8 (1.6e2.0) 3.6 (2.0e6.5) 1522
1467 30 3.0 (2.3e3.8) 3.4 (2.1e5.6) 3.0 (2.6e3.5) 8.8 (4.4e17.6) 1523
1468 35 4.9 (3.5e 7.6 (4.2e13.7) 4.9 (4.0e 6.1) 17.4 (8.5e35.9) 1524
1469 1525
African American 17 1.0 (0.7e1.3) 1.4 (0.8e2.3) 1.0 (0.8e1.2) 1.4 (0.6e3.6)
1470 1526
1471 20 1.4 (1.1e1.6) 1.6 (1.1e2.3) 1.2 (1.0e 1.3) 1.9 (1.0e 3.7) 1527
1472 25 2.2 (1.8e2.7) 2.1 (1.4e3.2) 1.5 (1.4e1.7) 3.0 (1.6e 5.8) 1528
1473 1529
30 3.1 (2.5e3.9) 3.2 (2.1e5.0) 2.2 (1.9e2.5) 4.9 (2.5e9.6)
1474 1530
1475 35 4.2 (3.1e5.7) 5.3 (2.9e9.7) 3.3 (2.7e4.0) 8.0 (3.7e17.5) 1531
a b
1476 According to ethnicity in a multinomial regression model (n¼35,422 for preeclampsia in white women and n¼36,936 for gestational hypertension); Adjusted for maternal age, smoking status, 1532
marital status, socioeconomic status, parity, and maternal height.
1477 1533
Q42 (Modified from Bodnar LM, Catov JM, Klebanoff MA, Ness RB, Roberts JM.



. Epidemiology 2007;18:234-9.)
1478 1534
Q41 Romero. Metformin, the aspirin of the 21st century. Am J Obstet Gynecol 2017.
1479 1535
1480 1536
1481 subscapular skin folds and biceps, effects such as mild erythema and anticancer agent (Figure 1).7-10 The first 1537
1482 which suggests a better fat distribu- decreased vitamin B12 absorption have observation that metformin might 1538
1483 tion than children who are exposed to been associated with long-term reduce the risk of cancer was made in a 1539
1484 insulin.251 administration.252 population-based case-control study of 1540
1485 Maternal side-effects that have been patients with type 2 diabetic who were 1541
1486 reported with the use of metformin A role for metformin in cancer and treated with metformin.253 A cohort 1542
1487 are mainly gastrointestinal (ie, nausea aging study of patients with type 2 diabetic 1543
1488 and diarrhea).248 The rate of hypo- Originally introduced for the treatment newly treated with metformin later fol- 1544
1489 glycemia is lower than that reported of diabetes mellitus, metformin is now lowed, in which the frequency of cancer 1545
1490 with insulin.79 In addition, rare side- gaining attention as a potential was significantly lower in patients who 1546
1491 1547
1492 1548
1493 1549
1494 TABLE 2 1550
1495 Summary of metabolic changes in pregnancy and preeclampsia 1551
Q43
1496 Normal pregnancy Preeclampsia 1552
1497 Variable Early Late Early Late 1553
1498 Maternal metabolism Anabolic Catabolic Anabolic Catabolic
1554
1499 1555
1500 Glucose intolerance w Y wY YY 1556
1501 Insulin sensitivity w Y wY YY 1557
1502 Free fatty acids [ [[ [[ [[[ 1558
1503 1559
Triglycerides [ [[ [[[ [[[
1504 1560
1505 Cholesterol w [ w[ [ 1561
1506 w: Similar compared with nonpregnant control subjects; [, [[, [[[: elevated (relative degree increasing by number of arrows) compared with nonpregnant control subjects; Y, YY: lower 1562
compared with nonpregnant control subjects.
1507 1563
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1583 1639
1584 these epidemiologic findings (ie, that the nuclear pore complex and Strippoli GF, Pellegrini F, Nicolucci A. Metformin
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1585 suppression of cancer stem cells264; in- acyl-CoA dehydrogenase family diabetes: systematic review. PloS One 2013;8: 1641
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1592 may also have an adjunctive effect in sulin sensitivity is unknown at this macologic therapy of diabetes and overall can-
1648
1593 patients who receive chemotherapy270; time. cer risk and mortality: a meta-analysis of 265
1649
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1595 registered in clinicaltrials.gov that are Conclusion Metformin modulates human leukocyte/endo- 1651
1596 studying the role of metformin in cancer Metformin, long known to be an thelial cell interactions and proinflammatory cy- 1652
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1653
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1654
that extend lifespan has identified a mellitus into a drug with a signifi- 12. Tan X, Li S, Chang Y, et al. Effect of met-
1599 formin treatment during pregnancy on women 1655
1600 disproportionate number of genes that cantly wider array of beneficial effects with PCOS: a systematic review and meta- 1656
1601 function in mitochondrial meta- that range from cancer treatment to analysis. Clin Invest Med 2016;39:E120-31. 1657
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