Login Register Cart 0
Generic placeholder image

Current Vascular Pharmacology

Editor-in-Chief

ISSN (Print): 1570-1611
ISSN (Online): 1875-6212

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

The Myometrium in Pregnant Women with Obesity

Author(s): Jorge A. Carvajal* and Joaquín I. Oporto

Volume 19, Issue 2, 2021

Published on: 25 May, 2020

Page: [193 - 200] Pages: 8

DOI: 10.2174/1570161118666200525133530

Price: $65

Abstract

Obesity is a worldwide public health problem, affecting at least one-third of pregnant women. One of the main problems of obesity during pregnancy is the resulting high rate of cesarean section. The leading cause of this higher frequency of cesarean sections in obese women, compared with that in nonobese women, is an altered myometrial function that leads to lower frequency and potency of contractions. In this article, the disruptions of myometrial myocytes were reviewed in obese women during pregnancy that may explain the dysfunctional labor. The myometrium of obese women exhibited lower expression of connexin43, a lower function of the oxytocin receptor, and higher activity of the potassium channels. Adipokines, such as leptin, visfatin, and apelin, whose concentrations are higher in obese women, decreased myometrial contractility, perhaps by inhibiting the myometrial RhoA/ROCK pathway. The characteristically higher cholesterol levels of obese women alter myometrial myocyte cell membranes, especially the caveolae, inhibiting oxytocin receptor function, and increasing the K+ channel activity. All these changes in the myometrial cells or their environment decrease myometrial contractility, at least partially explaining the higher rate of cesarean of sections in obese women.

Keywords: Myometrium, obesity, adipokines, leptin, cholesterol, myometrial contractility.

« Previous Next »
Graphical Abstract

[1]
Carvajal JA, Vidal RJ, Cuello MA, Poblete JA, Weiner CP. Mechanisms of paracrine regulation by fetal membranes of human uterine quiescence. J Soc Gynecol Investig 2006; 13(5): 343-9.
[http://dx.doi.org/10.1016/j.jsgi.2006.04.005] [PMID: 16814163]
[2]
Flegal KM, Kruszon-Moran D, Carroll MD, Fryar CD, Ogden CL. Trends in obesity among adults in the United States, 2005 to 2014. JAMA 2016; 315(21): 2284-91.
[http://dx.doi.org/10.1001/jama.2016.6458] [PMID: 27272580]
[3]
Dutton H, Borengasser SJ, Gaudet LM, Barbour LA, Keely EJ. Obesity in pregnancy: optimizing outcomes for mom and baby. Med Clin North Am 2018; 102(1): 87-106.
[http://dx.doi.org/10.1016/j.mcna.2017.08.008] [PMID: 29156189]
[4]
Bachelet VC, Lanas F. Smoking and obesity in Chile’s Third National Health Survey: light and shade. Rev Panam Salud Publica 2018; 42e132
[http://dx.doi.org/10.26633/RPSP.2018.132] [PMID: 31093160]
[5]
AlSaif S, Mumtaz S, Wray S. A short review of adipokines, smooth muscle and uterine contractility. Life Sci 2015; 125: 2-8.
[http://dx.doi.org/10.1016/j.lfs.2015.02.001] [PMID: 25711427]
[6]
Wispelwey BP, Sheiner E. Cesarean delivery in obese women: a comprehensive review. J Matern Fetal Neonatal Med 2013; 26(6): 547-51.
[http://dx.doi.org/10.3109/14767058.2012.745506] [PMID: 23130683]
[7]
Gam CMBF, Larsen LH, Mortensen OH, et al. Unchanged mitochondrial phenotype, but accumulation of lipids in the myometrium in obese pregnant women. J Physiol 2017; 595(23): 7109-22.
[http://dx.doi.org/10.1113/JP274838] [PMID: 29119568]
[8]
Cedergren MI. Non-elective caesarean delivery due to ineffective uterine contractility or due to obstructed labour in relation to maternal body mass index. Eur J Obstet Gynecol Reprod Biol 2009; 145(2): 163-6.
[http://dx.doi.org/10.1016/j.ejogrb.2009.05.022] [PMID: 19525054]
[9]
Ellis JA, Brown CM, Barger B, Carlson NS. Influence of maternal obesity on labor induction: a systematic review and meta-analysis. J Midwifery Womens Health 2019; 64(1): 55-67.
[http://dx.doi.org/10.1111/jmwh.12935] [PMID: 30648804]
[10]
Ruhstaller K. Induction of labor in the obese patient. Semin Perinatol 2015; 39(6): 437-40.
[http://dx.doi.org/10.1053/j.semperi.2015.07.003] [PMID: 26409443]
[11]
Carlson NS, Hernandez TL, Hurt KJ. Parturition dysfunction in obesity: time to target the pathobiology. Reprod Biol Endocrinol 2015; 13: 135.
[http://dx.doi.org/10.1186/s12958-015-0129-6] [PMID: 26684329]
[12]
Walsh J, Foley M, O’Herlihy C. Dystocia correlates with body mass index in both spontaneous and induced nulliparous labors. J Matern Fetal Neonatal Med 2011; 24(6): 817-21.
[http://dx.doi.org/10.3109/14767058.2010.531313] [PMID: 21158492]
[13]
Zhang J, Bricker L, Wray S, Quenby S. Poor uterine contractility in obese women. BJOG 2007; 114(3): 343-8.
[http://dx.doi.org/10.1111/j.1471-0528.2006.01233.x] [PMID: 17261121]
[14]
Lowe NK, Corwin EJ. Proposed biological linkages between obesity, stress, and inefficient uterine contractility during labor in humans. Med Hypotheses 2011; 76(5): 755-60.
[http://dx.doi.org/10.1016/j.mehy.2011.02.018] [PMID: 21382668]
[15]
Slack E, Best KE, Rankin J, Heslehurst N. Maternal obesity classes, preterm and post-term birth: a retrospective analysis of 479,864 births in England. BMC Pregnancy Childbirth 2019; 19(1): 434.
[http://dx.doi.org/10.1186/s12884-019-2585-z] [PMID: 31752763]
[16]
Poston L, Caleyachetty R, Cnattingius S, et al. Preconceptional and maternal obesity: epidemiology and health consequences. Lancet Diabetes Endocrinol 2016; 4(12): 1025-36.
[http://dx.doi.org/10.1016/S2213-8587(16)30217-0] [PMID: 27743975]
[17]
Gyamf I-Bannerman C. Maternal obesity is an independent risk factor for spontaneous extremely preterm delivery. Evid Based Med 2014; 19(2): 71.
[http://dx.doi.org/10.1136/eb-2013-101477] [PMID: 24037124]
[18]
Cnattingius S, Villamor E, Johansson S, et al. Maternal obesity and risk of preterm delivery. JAMA 2013; 309(22): 2362-70.
[http://dx.doi.org/10.1001/jama.2013.6295] [PMID: 23757084]
[19]
Wuntakal R, Kaler M, Hollingworth T. Women with high BMI: should they be managed differently due to antagonising action of leptin in labour? Med Hypotheses 2013; 80(6): 767-8.
[http://dx.doi.org/10.1016/j.mehy.2013.03.006] [PMID: 23570649]
[20]
Carvajal JA, Weiner CP. Mechanisms underlying myometrial quiescence during pregnancy. Fetal Matern Med Rev 2003; 14(3): 209-37.
[http://dx.doi.org/10.1017/S0965539503001098]
[21]
Carvajal JA. Determinism of labor.Pérez Sánchez A, Donoso E, Editors, Obstetricia Cuarta 4 Edition Santiago: Editorial Mediterráneo Ltda.. 2011; pp. 322-9.
[22]
Muir R, Ballan J, Clifford B, et al. Modelling maternal obesity: the effects of a chronic high-fat, high-cholesterol diet on uterine expression of contractile-associated proteins and ex vivo contractile activity during labour in the rat. Clin Sci (Lond) 2016; 130(3): 183-92.
[http://dx.doi.org/10.1042/CS20150539] [PMID: 26543049]
[23]
Grotegut CA, Gunatilake RP, Feng L, Heine RP, Murtha AP. The influence of maternal body mass index on myometrial oxytocin receptor expression in pregnancy. Reprod Sci 2013; 20(12): 1471-7.
[http://dx.doi.org/10.1177/1933719113488446] [PMID: 23653389]
[24]
Garabedian MJ, Hansen WF, McCord LA, Manning MA, O’Brien JM, Curry TE Jr. Up-regulation of oxytocin receptor expression at term is related to maternal body mass index. Am J Perinatol 2013; 30(6): 491-7.
[http://dx.doi.org/10.1055/s-0032-1329179] [PMID: 23355275]
[25]
Higgins CA, Martin W, Anderson L, et al. Maternal obesity and its relationship with spontaneous and oxytocin-induced contractility of human myometrium in vitro. Reprod Sci 2010; 17(2): 177-85.
[http://dx.doi.org/10.1177/1933719109349780] [PMID: 19828431]
[26]
Carlhäll S, Källén K, Thorsell A, Blomberg M. Maternal plasma leptin levels in relation to the duration of the active phase of labor. Acta Obstet Gynecol Scand 2018; 97(10): 1248-56.
[http://dx.doi.org/10.1111/aogs.13380] [PMID: 29772056]
[27]
Domali E, Messinis IE. Leptin in pregnancy. J Matern Fetal Neonatal Med 2002; 12(4): 222-30.
[http://dx.doi.org/10.1080/jmf.12.4.222.230] [PMID: 12572590]
[28]
Wuntakal R, Hollingworth T. Leptin--a tocolytic agent for the future? Med Hypotheses 2010; 74(1): 81-2.
[http://dx.doi.org/10.1016/j.mehy.2009.07.039] [PMID: 19692183]
[29]
Moynihan AT, Hehir MP, Glavey SV, Smith TJ, Morrison JJ. Inhibitory effect of leptin on human uterine contractility in vitro. Am J Obstet Gynecol 2006; 195(2): 504-9.
[http://dx.doi.org/10.1016/j.ajog.2006.01.106] [PMID: 16647683]
[30]
Bełtowski J. Apelin and visfatin: unique “beneficial” adipokines upregulated in obesity? Med Sci Monit 2006; 12(6): RA112-9.
[PMID: 16733497]
[31]
Hehir MP, Morrison JJ. The adipokine apelin and human uterine contractility. Am J Obstet Gynecol 2012; 206(4): 359.
[http://dx.doi.org/10.1016/j.ajog.2012.01.032]
[32]
Mumtaz S, AlSaif S, Wray S, Noble K. Inhibitory effect of visfatin and leptin on human and rat myometrial contractility. Life Sci 2015; 125: 57-62.
[http://dx.doi.org/10.1016/j.lfs.2015.01.020] [PMID: 25645057]
[33]
Wendremaire M, Mourtialon P, Goirand F, et al. Effects of leptin on lipopolysaccharide-induced remodeling in an in vitro model of human myometrial inflammation. Biol Reprod 2013; 88(2): 45.
[http://dx.doi.org/10.1095/biolreprod.112.104844] [PMID: 23303680]
[34]
Hayward CE, Cowley EJ, Mills TA, Sibley CP, Wareing M. Maternal obesity impairs specific regulatory pathways in human myometrial arteries. Biol Reprod 2014; 90(3): 65.
[http://dx.doi.org/10.1095/biolreprod.113.112623] [PMID: 24478391]
[35]
Hayward CE, Cowley EJ, Sibley CP, Myers JE, Wareing M. Exposure to omentum adipose tissue conditioned medium from obese pregnant women promotes myometrial artery dysfunction. J Obstet Gynaecol Res 2018; 44(1): 124-33.
[http://dx.doi.org/10.1111/jog.13482] [PMID: 29027317]
[36]
Liesa M, Shirihai OS. Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metab 2013; 17(4): 491-506.
[http://dx.doi.org/10.1016/j.cmet.2013.03.002] [PMID: 23562075]
[37]
Youle RJ, van der Bliek AM. Mitochondrial fission, fusion, and stress. Science 2012; 337(6098): 1062-5.
[http://dx.doi.org/10.1126/science.1219855] [PMID: 22936770]
[38]
Hoppins S, Nunnari J. The molecular mechanism of mitochondrial fusion. Biochim Biophys Acta 2009; 1793(1): 20-6.
[http://dx.doi.org/10.1016/j.bbamcr.2008.07.005] [PMID: 18691613]
[39]
Lee JY, Kapur M, Li M, et al. MFN1 deacetylation activates adaptive mitochondrial fusion and protects metabolically challenged mi-tochondria. J Cell Sci 2014; 127(Pt 22): 4954-63.
[http://dx.doi.org/10.1242/jcs.157321] [PMID: 25271058]
[40]
Mishra P, Varuzhanyan G, Pham AH, Chan DC. Mitochondrial dynamics is a distinguishing feature of skeletal muscle fiber types and regulates organellar compartmentalization. Cell Metab 2015; 22(6): 1033-44.
[http://dx.doi.org/10.1016/j.cmet.2015.09.027] [PMID: 26603188]
[41]
Liu MY, Jin J, Li SL, et al. Mitochondrial fission of smooth muscle cells is involved in artery constriction. Hypertension 2016; 68(5): 1245-54.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.116.07974] [PMID: 27572148]
[42]
Gam CMBF, Mortensen OH, Qvortrup K, Damm P, Quistorff B. Effect of high-fat diet on rat myometrium during pregnancy-isolated myometrial mitochondria are not affected. Pflugers Arch 2015; 467(7): 1539-49.
[http://dx.doi.org/10.1007/s00424-014-1599-7] [PMID: 25139192]
[43]
Parton RG, Tillu VA, Collins BM. Caveolae. Curr Biol 2018; 28(8): R402-5.
[http://dx.doi.org/10.1016/j.cub.2017.11.075] [PMID: 29689223]
[44]
Parton RG, McMahon KA, Wu Y. Caveolae: Formation, dynamics, and function. Curr Opin Cell Biol 2020; 65: 8-16.
[http://dx.doi.org/10.1016/j.ceb.2020.02.001] [PMID: 32146331]
[45]
Brainard AM, Miller AJ, Martens JR, England SK. Maxi-K channels localize to caveolae in human myometrium: a role for an actin-channel-caveolin complex in the regulation of myometrial smooth muscle K+ current. Am J Physiol Cell Physiol 2005; 289(1): C49-57.
[http://dx.doi.org/10.1152/ajpcell.00399.2004] [PMID: 15703204]
[46]
Ciray HN, Güner H, Håkansson H, Tekelioglu M, Roomans GM, Ulmsten U. Morphometric analysis of gap junctions in nonpregnant and term pregnant human myometrium. Acta Obstet Gynecol Scand 1995; 74(7): 497-504.
[http://dx.doi.org/10.3109/00016349509024378] [PMID: 7618446]
[47]
Noble K, Zhang J, Wray S. Lipid rafts, the sarcoplasmic reticulum and uterine calcium signalling: an integrated approach. J Physiol 2006; 570(Pt 1): 29-35.
[http://dx.doi.org/10.1113/jphysiol.2005.098475] [PMID: 16239270]
[48]
Darby PJ, Kwan CY, Daniel EE. Caveolae from canine airway smooth muscle contain the necessary components for a role in Ca(2+) handling. Am J Physiol Lung Cell Mol Physiol 2000; 279(6): L1226-35.
[http://dx.doi.org/10.1152/ajplung.2000.279.6.L1226] [PMID: 11076813]
[49]
Dopico AM, Bukiya AN, Singh AK. Large conductance, calcium- and voltage-gated potassium (BK) channels: regulation by cholesterol. Pharmacol Ther 2012; 135(2): 133-50.
[http://dx.doi.org/10.1016/j.pharmthera.2012.05.002] [PMID: 22584144]
[50]
Babiychuk EB, Smith RD, Burdyga T, Babiychuk VS, Wray S, Draeger A. Membrane cholesterol regulates smooth muscle phasic contraction. J Membr Biol 2004; 198(2): 95-101.
[http://dx.doi.org/10.1007/s00232-004-0663-1] [PMID: 15138749]
[51]
Greenwood IA, Tribe RM. Kv7 and Kv11 channels in myometrial regulation. Exp Physiol 2014; 99(3): 503-9.
[http://dx.doi.org/10.1113/expphysiol.2013.075754] [PMID: 24121285]
[52]
Buxton IL, Heyman N, Wu YY, Barnett S, Ulrich C. A role of stretch-activated potassium currents in the regulation of uterine smooth muscle contraction. Acta Pharmacol Sin 2011; 32(6): 758-64.
[http://dx.doi.org/10.1038/aps.2011.62] [PMID: 21642947]
[53]
Brainard AM, Korovkina VP, England SK. Potassium channels and uterine function. Semin Cell Dev Biol 2007; 18(3): 332-9.
[http://dx.doi.org/10.1016/j.semcdb.2007.05.008] [PMID: 17596977]
[54]
Khan RN, Matharoo-Ball B, Arulkumaran S, Ashford ML. Potassium channels in the human myometrium. Exp Physiol 2001; 86(2): 255-64.
[http://dx.doi.org/10.1113/eph8602181] [PMID: 11429642]
[55]
Parkington HC, Stevenson J, Tonta MA, et al. Diminished hERG K+ channel activity facilitates strong human labour contractions but is dysregulated in obese women. Nat Commun 2014; 5: 4108.
[http://dx.doi.org/10.1038/ncomms5108] [PMID: 24937480]
[56]
Carvajal JA, Germain AM, Huidobro-Toro JP, Weiner CP. Molecular mechanism of cGMP-mediated smooth muscle relaxation. J Cell Physiol 2000; 184(3): 409-20.
[http://dx.doi.org/10.1002/1097-4652(200009)184:3<409:AID-JCP16>3.0.CO;2-K] [PMID: 10911373]
[57]
Lartey J, López Bernal A. RHO protein regulation of contraction in the human uterus. Reproduction 2009; 138(3): 407-24.
[http://dx.doi.org/10.1530/REP-09-0160] [PMID: 19589855]
[58]
Word RA. Myosin phosphorylation and the control of myometrial contraction/relaxation. Semin Perinatol 1995; 19(1): 3-14.
[http://dx.doi.org/10.1016/S0146-0005(95)80043-3] [PMID: 7754409]
[59]
Harrod JS, Rada CC, Pierce SL, England SK, Lamping KG. Altered contribution of RhoA/Rho kinase signaling in contractile activity of myometrium in leptin receptor-deficient mice. Am J Physiol Endocrinol Metab 2011; 301(2): E362-9.
[http://dx.doi.org/10.1152/ajpendo.00696.2010] [PMID: 21558549]
[60]
O’Brien M, Carbin S, Morrison JJ, Smith TJ. Decreased myometrial p160 ROCK-1 expression in obese women at term pregnancy. Reprod Biol Endocrinol 2013; 11: 79.
[http://dx.doi.org/10.1186/1477-7827-11-79] [PMID: 23948067]
[61]
Kumari M, Wang X, Lantier L, et al. IRF3 promotes adipose inflammation and insulin resistance and represses browning. J Clin Invest 2016; 126(8): 2839-54.
[http://dx.doi.org/10.1172/JCI86080] [PMID: 27400129]
[62]
Boden G. Obesity and free fatty acids. Endocrinol Metab Clin North Am 2008; 37(3): 635-46.
[http://dx.doi.org/10.1016/j.ecl.2008.06.007] [PMID: 18775356]
[63]
Di Meo S, Iossa S, Venditti P. Skeletal muscle insulin resistance: role of mitochondria and other ROS sources. J Endocrinol 2017; 233(1): R15-42.
[http://dx.doi.org/10.1530/JOE-16-0598] [PMID: 28232636]
[64]
Tumova J, Andel M, Trnka J. Excess of free fatty acids as a cause of metabolic dysfunction in skeletal muscle. Physiol Res 2016; 65(2): 193-207.
[http://dx.doi.org/10.33549/physiolres.932993] [PMID: 26447514]
[65]
Pantham P, Aye IL, Powell TL. Inflammation in maternal obesity and gestational diabetes mellitus. Placenta 2015; 36(7): 709-15.
[http://dx.doi.org/10.1016/j.placenta.2015.04.006] [PMID: 25972077]
[66]
Crankshaw DJ, Walsh JM, Morrison JJ. The effects of methyl palmitate, a putative regulator from perivascular fat, on the contractility of pregnant human myometrium. Life Sci 2014; 116(1): 25-30.
[http://dx.doi.org/10.1016/j.lfs.2014.08.018] [PMID: 25200873]
[67]
Wray S. Insights into the uterus. Exp Physiol 2007; 92(4): 621-31.
[http://dx.doi.org/10.1113/expphysiol.2007.038125] [PMID: 17468199]
[68]
Buxton IL, Vittori JC. Cholesterol depletion enhances both spontaneous and agonist-evoked uterine smooth muscle contractions in a reversible manner. Proc West Pharmacol Soc 2005; 48: 126-8.
[PMID: 16416677]
[69]
Jie Zhang, Kendrick A, Quenby S, Wray S. Contractility and calcium signaling of human myometrium are profoundly affected by cholesterol manipulation: implications for labor? Reprod Sci 2007; 14(5): 456-66.
[http://dx.doi.org/10.1177/1933719107306229] [PMID: 17913965]
[70]
Smith RD, Babiychuk EB, Noble K, Draeger A, Wray S. Increased cholesterol decreases uterine activity: functional effects of cholesterol alteration in pregnant rat myometrium. Am J Physiol Cell Physiol 2005; 288(5): C982-8.
[http://dx.doi.org/10.1152/ajpcell.00120.2004] [PMID: 15613497]
[71]
Shmygol A, Noble K, Wray S. Depletion of membrane cholesterol eliminates the Ca2+-activated component of outward potassium current and decreases membrane capacitance in rat uterine myocytes. J Physiol 2007; 581(Pt 2): 445-56.
[http://dx.doi.org/10.1113/jphysiol.2007.129452] [PMID: 17331986]
[72]
Sandall J, Tribe RM, Avery L, et al. Short-term and long-term effects of caesarean section on the health of women and children. Lancet 2018; 392(10155): 1349-57.
[http://dx.doi.org/10.1016/S0140-6736(18)31930-5] [PMID: 30322585]
[73]
The Lancet. Stemming the global caesarean section epidemic. Lancet 2018; 392(10155): 1279.
[http://dx.doi.org/10.1016/S0140-6736(18)32394-8] [PMID: 30322560]
[74]
Chen I, Opiyo N, Tavender E, et al. Non-clinical interventions for reducing unnecessary caesarean section. Cochrane Database Syst Rev 2018; 9CD005528
[http://dx.doi.org/10.1002/14651858.CD005528.pub3] [PMID: 30264405]
[75]
Visser GHA, Ayres-de-Campos D, Barnea ER, et al. FIGO position paper: how to stop the caesarean section epidemic. Lancet 2018; 392(10155): 1286-7.
[http://dx.doi.org/10.1016/S0140-6736(18)32113-5] [PMID: 30322563]
[76]
Betrán AP, Temmerman M, Kingdon C, et al. Interventions to reduce unnecessary caesarean sections in healthy women and babies. Lancet 2018; 392(10155): 1358-68.
[http://dx.doi.org/10.1016/S0140-6736(18)31927-5] [PMID: 30322586]
[77]
Rogers AJG, Harper LM, Mari G. A conceptual framework for the impact of obesity on risk of cesarean delivery. Am J Obstet Gynecol 2018; 219(4): 356-63.
[http://dx.doi.org/10.1016/j.ajog.2018.06.006] [PMID: 29902446]
[78]
Meldrum DR. Introduction: obesity and reproduction. Fertil Steril 2017; 107(4): 831-2.
[http://dx.doi.org/10.1016/j.fertnstert.2017.02.110] [PMID: 28366410]
[79]
Carreau AM, Nadeau M, Marceau S, Marceau P, Weisnagel SJ. Pregnancy after bariatric surgery: balancing risks and benefits. Can J Diabetes 2017; 41(4): 432-8.
[http://dx.doi.org/10.1016/j.jcjd.2016.09.005] [PMID: 28365201]
[80]
Bozkurt L, Göbl CS, Leutner M, Eppel W, Kautzky-Willer A. bariatric surgery impacts levels of serum lipids during pregnancy. Obes Facts 2020; 13(1): 58-65.
[http://dx.doi.org/10.1159/000504176] [PMID: 31991405]
[81]
Shafat A, Butler P, Jensen RL, Donnelly AE. Effects of dietary supplementation with vitamins C and E on muscle function during and after eccentric contractions in humans. Eur J Appl Physiol 2004; 93(1-2): 196-202.
[http://dx.doi.org/10.1007/s00421-004-1198-y] [PMID: 15309547]
[82]
Hehir MP, Morrison JJ. Metformin and human uterine contractility. Endocrine 2012; 42(3): 761-3.
[http://dx.doi.org/10.1007/s12020-012-9687-y] [PMID: 22573046]
[83]
Hyer S, Balani J, Shehata H. Metformin in pregnancy: mechanisms and clinical applications. Int J Mol Sci 2018; 19(7)E1954
[http://dx.doi.org/10.3390/ijms19071954] [PMID: 29973490]
[84]
Rumbold A, Ota E, Nagata C, Shahrook S, Crowther CA. Vitamin C supplementation in pregnancy. Cochrane Database Syst Rev 2015; 9CD004072
[PMID: 26415762]
[85]
Rumbold A, Ota E, Hori H, Miyazaki C, Crowther CA. Vitamin E supplementation in pregnancy. Cochrane Database Syst Rev 2015; 9CD004069
[PMID: 26343254]
[86]
Karalis DG, Hill AN, Clifton S, Wild RA. The risks of statin use in pregnancy: A systematic review. J Clin Lipidol 2016; 10(5): 1081-90.
[http://dx.doi.org/10.1016/j.jacl.2016.07.002] [PMID: 27678424]

Rights & Permissions Print Cite
Article Metrics
42
© 2024 Bentham Science Publishers | Privacy Policy