Skip to main content

Advertisement

SpringerLink
Log in

Anatomical and physiological alterations of pregnancy

  • Review Paper
  • Published:
Journal of Pharmacokinetics and Pharmacodynamics Aims and scope Submit manuscript

Abstract

The extensive metabolic demands of pregnancy require specific physiological and anatomical changes. These changes affect almost all organ systems, including the cardiovascular, respiratory, renal, gastrointestinal, and hematologic system. The placenta adds another layer of complexity. These changes make it challenging for clinicians to understand presenting signs and symptoms, or to interpret laboratory and radiological tests. Furthermore, these physiological alterations can affect the pharmacokinetics and pharmacodynamics of drugs. Drug safety in lactation is only supported by limited evidence. In addition, the teratogenic effects of medications are often extrapolated from animals, which further adds uncertainties. Unfortunately, pregnant women are only rarely included in clinical drug trials, while doses, regimens, and side effects are often extrapolated from studies conducted in non-pregnant populations. In this comprehensive review, we present the changes occurring in each system with its effects on the pharmacokinetic variables. Understanding these physiological changes throughout normal pregnancy helps clinicians to optimize the health of pregnant women and their fetuses. Furthermore, the information on pregnancy-related physiology is also critical to guide study design in this vulnerable ‘orphan’ population, and provides a framework to explore pregnancy-related pathophysiology such as pre-eclampsia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Mitchell AA, Gilboa SM, Werler MM et al (2011) Medication use during pregnancy, with particular focus on prescription drugs: 1976–2008. Am J Obstet Gynecol 205:51. https://doi.org/10.1016/j.ajog.2011.02.029

    Article  PubMed  PubMed Central  Google Scholar 

  2. Broussard CS, Louik C, Honein MA, Mitchell AA (2010) Herbal use before and during pregnancy. Am J Obstet Gynecol 202:443. https://doi.org/10.1016/j.ajog.2009.10.865

    Article  PubMed  Google Scholar 

  3. Lupattelli A, Spigset O, Twigg MJ et al (2014) Medication use in pregnancy: a cross-sectional, multinational web-based study. BMJ Open 4:e004365. https://doi.org/10.1136/bmjopen-2013-004365

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Adam MP, Polifka JE, Friedman JM (2011) Evolving knowledge of the teratogenicity of medications in human pregnancy. Am J Med Genet Part C 157:175–182. https://doi.org/10.1002/ajmg.c.30313

    Article  Google Scholar 

  5. Sheffield JS, Siegel D, Mirochnick M et al (2014) Designing drug trials: considerations for pregnant women. Clin Infect Dis 59:S437–S444. https://doi.org/10.1093/cid/ciu709

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Zhao Y, Hebert MF, Venkataramanan R (2014) Basic obstetric pharmacology. Semin Perinatol 38:475–486. https://doi.org/10.1053/j.semperi.2014.08.011

    Article  PubMed  PubMed Central  Google Scholar 

  7. Jeong H (2010) Altered drug metabolism during pregnancy: hormonal regulation of drug-metabolizing enzymes. Expert Opin Drug Metab Toxicol 6:689–699. https://doi.org/10.1517/17425251003677755

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Fisk NM, Atun R (2009) Systematic analysis of research underfunding in maternal and perinatal health. BJOG 116:347–355. https://doi.org/10.1111/j.1471-0528.2008.02027.x

    Article  PubMed  CAS  Google Scholar 

  9. Van der Graaf R, Van der Zande ISE, Den Ruijter HM et al (2018) Fair inclusion of pregnant women in clinical trials: an integrated scientific and ethical approach. Trials 19:78. https://doi.org/10.1186/s13063-017-2402-9

    Article  PubMed  PubMed Central  Google Scholar 

  10. Ayad M, Costantine MM (2015) Epidemiology of medications use in pregnancy. Semin Perinatol 39:508–511. https://doi.org/10.1053/j.semperi.2015.08.002

    Article  PubMed  PubMed Central  Google Scholar 

  11. Cook MJ, Fairweather FA (1968) Methods used in teratogenic testing. Lab Anim 2:219–228. https://doi.org/10.1258/002367768781082834

    Article  Google Scholar 

  12. Scaffidi J, Mol BW, Keelan JA (2017) The pregnant women as a drug orphan: a global survey of registered clinical trials of pharmacological interventions in pregnancy. BJOG 124:132–140. https://doi.org/10.1111/1471-0528.14151

    Article  PubMed  CAS  Google Scholar 

  13. Dallmann A, Liu XI, Burckart GJ, van den Anker J (2019) Drug transporters expressed in the human placenta and models for studying maternal-fetal drug transfer. J Clin Pharmacol 59(1):S70–S81. https://doi.org/10.1002/jcph.1491

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Dallmann A, Mian P, Van den Anker J, Allegaert K (2019) Clinical pharmacokinetic studies in pregnant women and the relevance of pharmacometric tools. Curr Pharm Des 25:483–495. https://doi.org/10.2174/1381612825666190320135137

    Article  PubMed  CAS  Google Scholar 

  15. Kametas NA, McAuliffe F, Hancock J et al (2001) Maternal left ventricular mass and diastolic function during pregnancy. Ultrasound Obstet Gynecol 18:460–466. https://doi.org/10.1046/j.0960-7692.2001.00573.x

    Article  PubMed  CAS  Google Scholar 

  16. Davies GAL, Herbert WNP (2007) Assessment and management of cardiac disease in pregnancy. J Obstet Gynaecol Canada 29:331–336. https://doi.org/10.1016/S1701-2163(16)32432-X

    Article  Google Scholar 

  17. Northcote RJ, Knight PV, Ballantyne D (1985) Systolic murmurs in pregnancy: value of echocardiographic assessment. Clin Cardiol 8:327–328. https://doi.org/10.1002/clc.4960080604

    Article  PubMed  CAS  Google Scholar 

  18. Desai DK, Moodley J, Naidoo DP (2004) Echocardiographic assessment of cardiovascular hemodynamics in normal pregnancy. Obstet Gynecol 104:20–29. https://doi.org/10.1097/01.AOG.0000128170.15161.1d

    Article  PubMed  Google Scholar 

  19. van Oppen AC, Stigter RH, Bruinse HW (1996) Cardiac output in normal pregnancy: a critical review. Obstet Gynecol 87:310–318. https://doi.org/10.1016/0029-7844(95)00348-7

    Article  PubMed  Google Scholar 

  20. Meah VL, Cockcroft JR, Backx K et al (2016) Cardiac output and related haemodynamics during pregnancy: a series of meta-analyses. Heart 102:518–526. https://doi.org/10.1136/heartjnl-2015-308476

    Article  PubMed  CAS  Google Scholar 

  21. Hunter S, Robson SC (1992) Adaptation of the maternal heart in pregnancy. Heart 68:540–543. https://doi.org/10.1136/hrt.68.12.540

    Article  CAS  Google Scholar 

  22. Ghi T, Degli Esposti D, Montaguti E et al (2015) Maternal cardiac evaluation during uncomplicated twin pregnancy with emphasis on the diastolic function. Am J Obstet Gynecol 213:376. https://doi.org/10.1016/j.ajog.2015.05.003

    Article  PubMed  Google Scholar 

  23. Mahendru AA, Everett TR, Wilkinson IB et al (2014) A longitudinal study of maternal cardiovascular function from preconception to the postpartum period. J Hypertens 32:849–856. https://doi.org/10.1097/HJH.0000000000000090

    Article  PubMed  CAS  Google Scholar 

  24. Clapp JF, Capeless E (1997) Cardiovascular function before, during, and after the first and subsequent pregnancies. Am J Cardiol 80:1469–1473. https://doi.org/10.1016/S0002-9149(97)00738-8

    Article  PubMed  Google Scholar 

  25. Thaler I, Manor D, Itskovitz J et al (1990) Changes in uterine blood flow during human pregnancy. Am J Obstet Gynecol 162:121–125. https://doi.org/10.1016/0002-9378(90)90834-T

    Article  PubMed  CAS  Google Scholar 

  26. Nelson DB, Stewart RD, Matulevicius SA et al (2015) The effects of maternal position and habitus on maternal cardiovascular parameters as measured by cardiac magnetic resonance. Am J Perinatol 32:1318–1323. https://doi.org/10.1055/s-0035-1563719

    Article  PubMed  Google Scholar 

  27. Sanghavi M, Rutherford JD (2014) Cardiovascular physiology of pregnancy. Circulation 130:1003–1008. https://doi.org/10.1161/CIRCULATIONAHA.114.009029

    Article  PubMed  Google Scholar 

  28. Frederiksen MC (2001) Physiologic changes in pregnancy and their effect on drug disposition. Semin Perinatol 25:120–123. https://doi.org/10.1053/sper.2001.24565

    Article  PubMed  CAS  Google Scholar 

  29. Flo K, Wilsgaard T, Vårtun A, Acharya G (2011) A longitudinal study of the relationship between maternal cardiac output measured by impedance cardiography and uterine artery blood flow in the second half of pregnancy. Obstet Anesth Dig 31:178–179. https://doi.org/10.1097/01.aoa.0000400323.42088.c2

    Article  Google Scholar 

  30. Pacheco LD, Costantine MM, Hankins GDV, Cohen MS (2013) Physiologic changes during pregnancy. In: Mattison DR (ed) Clinical pharmacology during pregnancy. Academic Press, New York, pp 5–16

    Chapter  Google Scholar 

  31. Carbillon L, Uzan M, Uzan S (2000) Pregnancy, vascular tone, and maternal hemodynamics: a crucial adaptation. Obstet Gynecol Surv 55:574–581. https://doi.org/10.1097/00006254-200009000-00023

    Article  PubMed  CAS  Google Scholar 

  32. Melchiorre K, Sharma R, Thilaganathan B (2012) Cardiac structure and function in normal pregnancy. Curr Opin Obstet Gynecol 24:413–421. https://doi.org/10.1097/GCO.0b013e328359826f

    Article  PubMed  Google Scholar 

  33. Pieper PG, Hoendermis ES (2011) Pregnancy in women with pulmonary hypertension. Netherlands Hear J 19:504–508. https://doi.org/10.1007/s12471-011-0219-9

    Article  CAS  Google Scholar 

  34. Kinsella SM, Lohmann G (1994) Supine hypotensive syndrome. Obstet Gynecol 83:774–788

    PubMed  CAS  Google Scholar 

  35. Chesley LC (1972) Plasma and red cell volumes during pregnancy. Am J Obstet Gynecol 112:440–450. https://doi.org/10.1016/0002-9378(72)90493-0

    Article  PubMed  CAS  Google Scholar 

  36. Pritchard JA (1965) Changes in the blood volume during pregnancy and delivery. Anesthesiology 26:393–399. https://doi.org/10.1097/00000542-196507000-00004

    Article  PubMed  CAS  Google Scholar 

  37. Hytten FE, Paintin DB (1963) Increase in plasma volume during normal pregnancy. BJOG 70:402–407. https://doi.org/10.1111/j.1471-0528.1963.tb04922.x

    Article  CAS  Google Scholar 

  38. Feghali M, Venkataramanan R, Caritis S (2015) Pharmacokinetics of drugs in pregnancy. Semin Perinatol 39:512–519. https://doi.org/10.1053/j.semperi.2015.08.003

    Article  PubMed  PubMed Central  Google Scholar 

  39. Murphy MM, Scott JM, McPartlin JM, Fernandez-Ballart JD (2002) The pregnancy-related decrease in fasting plasma homocysteine is not explained by folic acid supplementation, hemodilution, or a decrease in albumin in a longitudinal study 1–3. Am J Clin Nutr 76:614–619

    Article  CAS  PubMed  Google Scholar 

  40. Masatoshi H, Yoshihiko U, Kazunori H et al (2002) Changes in urinary excretion of six biochemical parameters in normotensive pregnancy and preeclampsia. Am J Kidney Dis 39:392–400

    Article  Google Scholar 

  41. Richter JE (2005) Review article: the management of heartburn in pregnancy. Aliment Pharmacol Ther 22:749–757. https://doi.org/10.1111/j.1365-2036.2005.02654.x

    Article  PubMed  CAS  Google Scholar 

  42. Law R, Maltepe C, Bozzo P, Einarson A (2010) Treatment of heartburn and acid reflux associated with nausea and vomiting during pregnancy. Can Fam Physician 56:143–144

    PubMed  PubMed Central  Google Scholar 

  43. O’Brien B, Zhou Q (1995) Variables related to nausea and vomiting during pregnancy. Birth 22:93–100. https://doi.org/10.1111/j.1523-536X.1995.tb00566.x

    Article  PubMed  Google Scholar 

  44. Pepper GV, Roberts SC (2006) Rates of nausea and vomiting in pregnancy and dietary characteristics across populations. Proc R Soc B 273:2675–2679. https://doi.org/10.1098/rspb.2006.3633

    Article  PubMed  PubMed Central  Google Scholar 

  45. Brandes JM (1967) First-trimester nausea and vomiting as related to outcome of pregnancy. Obstet Gynecol 30:427–431

    PubMed  CAS  Google Scholar 

  46. Quinlan JD, Hill D (2003) Nausea and vomiting of pregnancy. Am Fam Physician 68:121–128

    Google Scholar 

  47. Klebanoff MA, Koslow PA, Kaslow R, Rhoads GG (1985) Epidemiology of vomiting in early pregnancy. Obs Gynecol 66:612–616

    CAS  Google Scholar 

  48. Ali RAR, Egan LJ (2007) Gastroesophageal reflux disease in pregnancy. Best Pract Res Clin Gastroenterol 21:793–806. https://doi.org/10.1016/j.bpg.2007.05.006

    Article  PubMed  Google Scholar 

  49. Parry E, Shields R, Turnbull AC (1970) Transit time in the small intestine in pregnancy. BJOG 77:900–901. https://doi.org/10.1111/j.1471-0528.1970.tb03423.x

    Article  CAS  Google Scholar 

  50. Macfie AG, Magides AD, Richmond MN, Reilly CS (1991) Gastric emptying in pregnancy. Br J Anaesth 67:54–57. https://doi.org/10.1093/bja/67.1.54

    Article  PubMed  CAS  Google Scholar 

  51. Levy DM, Williams OA, Magides AD, Reilly CS (1994) Gastric emptying is delayed at 8–12 weeks’ gestation. Br J Anaesth 73:237–238. https://doi.org/10.1093/bja/73.2.237

    Article  PubMed  CAS  Google Scholar 

  52. Sandhar BK, Elliott RH, Windram I, Rowbotham DJ (1992) Peripartum changes in gastric emptying. Anaesthesia 47:196–198. https://doi.org/10.1111/j.1365-2044.1992.tb02116.x

    Article  PubMed  CAS  Google Scholar 

  53. Galinksy RE, Levy G (1984) Absorption and metabolism of acetaminophen shortly before parturition. Drug Intell Clin Pharm 18:977–979. https://doi.org/10.1177/106002808401801205

    Article  Google Scholar 

  54. Skelin M, Lucijanić T, Amidžić Klarić D et al (2017) Factors affecting gastrointestinal absorption of levothyroxine: a review. Clin Ther 39:378–403. https://doi.org/10.1016/j.clinthera.2017.01.005

    Article  PubMed  CAS  Google Scholar 

  55. Anderson GD, Carr DB (2009) Effect of pregnancy on the pharmacokinetics of antihypertensive drugs. Clin Pharmacokinet 48:159–168. https://doi.org/10.2165/00003088-200948030-00002

    Article  PubMed  CAS  Google Scholar 

  56. Tracy TS, Venkataramanan R, Glover DD, Caritis SN (2005) Temporal changes in drug metabolism (CYP1A2, CYP2D6 and CYP3A Activity) during pregnancy. Am J Obstet Gynecol 192:633–639. https://doi.org/10.1016/j.ajog.2004.08.030

    Article  PubMed  CAS  Google Scholar 

  57. Hodge LS, Tracy TS (2007) Alterations in drug disposition during pregnancy: implications for drug therapy. Expert Opin Drug Metab Toxicol 3:557–571. https://doi.org/10.1517/17425225.3.4.557

    Article  PubMed  CAS  Google Scholar 

  58. Dempsey D, Jacob P III, Benowitz NL (2002) Accelerated metabolism of nicotine and cotinine in pregnant smokers. J Pharmacol Exp Ther 301:594–598. https://doi.org/10.1124/jpet.301.2.594

    Article  PubMed  CAS  Google Scholar 

  59. Tomson T, Lindbom U, Ekqvist B, Sundqvist A (1994) Disposition of carbamazepine and phenytoin in pregnancy. Epilepsia 35:131–135. https://doi.org/10.1111/j.1528-1157.1994.tb02922.x

    Article  PubMed  CAS  Google Scholar 

  60. Hebert MF, Easterling TR, Kirby B et al (2008) Effects of pregnancy on CYP3A and P-glycoprotein activities as measured by disposition of midazolam and digoxin: a University of Washington specialized center of research study. Clin Pharmacol Ther 84:248–253. https://doi.org/10.1038/clpt.2008.1

    Article  PubMed  CAS  Google Scholar 

  61. Tukey RH, Strassburg CP (2002) Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annu Rev Pharmacol Toxicol 40:581–616. https://doi.org/10.1146/annurev.pharmtox.40.1.581

    Article  Google Scholar 

  62. Jeong H, Choi S, Song JW et al (2008) Regulation of UDP-glucuronosyltransferase (UGT) 1A1 by progesterone and its impact on labetalol elimination. Xenobiotica 38:62–75. https://doi.org/10.1080/00498250701744633

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Sibai BM, Mabie WC, Shamsa F et al (1990) A comparison of no medication versus methyldopa or labetalol in chronic hypertension during pregnancy. Am J Obstet Gynecol 162:960–967. https://doi.org/10.1016/0002-9378(90)91297-P

    Article  PubMed  CAS  Google Scholar 

  64. Allegaert K, Peeters MY, Beleyn B et al (2015) Paracetamol pharmacokinetics and metabolism in young women. BMC Anesthesiol 15:163. https://doi.org/10.1186/s12871-015-0144-3

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Conrad KP, Davison JM (2014) The renal circulation in normal pregnancy and preeclampsia: is there a place for relaxin? Am J Physiol Ren Physiol 306:F1121–F1135. https://doi.org/10.1152/ajprenal.00042.2014

    Article  CAS  Google Scholar 

  66. Danielson LA, Conrad KP (1995) Acute blockade of nitric oxide synthase inhibits renal vasodilation and hyperfiltration during pregnancy in chronically instrumented conscious rats. J Clin Invest 96:482–490. https://doi.org/10.1172/JCI118059

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Dunlop W (1981) Serial changes in renal haemodynamics during normal human pregnancy. BJOG 88:1–9. https://doi.org/10.1111/j.1471-0528.1981.tb00929.x

    Article  CAS  Google Scholar 

  68. Davison JM, Dunlop W (1984) Changes in renal hemodynamics and tubular function induced by normal human pregnancy. Semin Nephrol 4:198–207

    Google Scholar 

  69. Frederice CP, Amaral E, De Oliveira FN (2013) Urinary symptoms and pelvic floor muscle function during the third trimester of pregnancy in nulliparous women. J Obstet Gynaecol Res 39:188–194

    Article  PubMed  Google Scholar 

  70. Nguyen MT, Maynard SE, Kimmel PL (2009) Misapplications of commonly used kidney equations: renal physiology in practice. Clin J Am Soc Nephrol 4:528–534. https://doi.org/10.2215/CJN.05731108

    Article  PubMed  PubMed Central  Google Scholar 

  71. Anderson GD (2005) Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach. Clin Pharmacokinet 44:989–1008. https://doi.org/10.2165/00003088-200544100-00001

    Article  PubMed  CAS  Google Scholar 

  72. Wesseloo R, Wierdsma AI, Van Kamp IL et al (2017) Lithium dosing strategies during pregnancy and the postpartum period. Br J Psychiatry 211:31–36. https://doi.org/10.1192/bjp.bp.116.192799

    Article  PubMed  PubMed Central  Google Scholar 

  73. Allegaert K, van Mieghem T, Verbesselt R et al (2009) Cefazolin pharmacokinetics in maternal plasma and amniotic fluid during pregnancy. Am J Obstet Gynecol 200:170. https://doi.org/10.1016/j.ajog.2008.08.067

    Article  PubMed  CAS  Google Scholar 

  74. Davison JM, Hytten FE (1975) The effect of pregnancy on the renal handling of glucose. BJOG 82:374–381. https://doi.org/10.1111/j.1471-0528.1975.tb00652.x

    Article  CAS  Google Scholar 

  75. Roberts J, August P, Bakris G et al (2013) Hypertension in pregnancy. Obstet Gynecol 122:1122–1131. https://doi.org/10.1097/01.AOG.0000437382.03963.88

    Article  Google Scholar 

  76. Kattah A, Milic N, White W, Garovic V (2017) Spot urine protein measurements in normotensive pregnancies, pregnancies with isolated proteinuria and preeclampsia. Am J Physiol-Regul Integr Comp Physiol 313:R418–R424. https://doi.org/10.1152/ajpregu.00508.2016

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Barron WM, Lindheimer MD (1985) Renal function and volume homeostasis during pregnancy. In: Gleicher N, Buttino L, Elkayam U (eds) Principles of medical therapy in pregnancy, 3rd edn. Appleton and Lange, Stanford, pp 779–790

    Chapter  Google Scholar 

  78. Davison JM, Vallotton MB, Lindheimer MD (1981) Plasma osmolality and urinary concentration and dilution during and after pregnancy: evidence that lateral recumbency inhibits maximal urinary concentrating ability. BJOG 88:472–479. https://doi.org/10.1111/j.1471-0528.1981.tb01019.x

    Article  CAS  Google Scholar 

  79. Bailey RR, Rolleston GL (1971) Kidney length and ureteric dilatation in the puerperium. J Obstet Gynaecol Br Commonw 78:55–61

    Article  CAS  PubMed  Google Scholar 

  80. Hertzberg BS, Carroll BA, Bowie JD et al (1993) Doppler US assessment of maternal kidneys: analysis of intrarenal resistivity indexes in normal pregnancy and physiologic pelvicaliectasis. Radiology 186:689–692. https://doi.org/10.1148/radiology.186.3.8430175

    Article  PubMed  CAS  Google Scholar 

  81. Brown MA (1991) Urinary tract dilatation in pregnancy. Am J Obstet Gynecol 164:642–643. https://doi.org/10.1016/S0002-9378(11)80039-6

    Article  PubMed  CAS  Google Scholar 

  82. Rasmussen PE, Nielsen FR (1988) Hydronephrosis during pregnancy: a literature survey. Eur J Obstet Gynecol Reprod Biol 27:249–259. https://doi.org/10.1016/0028-2243(88)90130-X

    Article  PubMed  CAS  Google Scholar 

  83. Berggren EK, Presley L, Amini SB et al (2015) Are the metabolic changes of pregnancy reversible in the first year postpartum? Diabetologia 58:1561–1568. https://doi.org/10.1007/s00125-015-3604-x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Brelje TC, Scharp DW, Lacy PE et al (1993) Effect of homologous placental lactogens, prolactins, and growth hormones on islet b-cell division and insulin secretion in rat, mouse, and human islets: implication for placental lactogen regulation of islet function during pregnancy. Endocrinology 132:879–887. https://doi.org/10.1210/endo.132.2.8425500

    Article  PubMed  CAS  Google Scholar 

  85. Ryan EA, Enns L (1988) Role of gestational hormones in the induction of insulin resistance. J Clin Endocrinol Metab 67:341–347. https://doi.org/10.1210/jcem-67-2-341

    Article  PubMed  CAS  Google Scholar 

  86. Butte NF (2000) Carbohydrate and lipid metabolism in pregnancy: normal compared with gestational diabetes mellitus. Am J Clin Nutr 71:1256–1261

    Article  Google Scholar 

  87. Butler AE, Cao-Minh L, Galasso R et al (2010) Adaptive changes in pancreatic beta cell fractional area and beta cell turnover in human pregnancy. Diabetologia 53:2167–2176. https://doi.org/10.1007/s00125-010-1809-6

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Angueira AR, Ludvik AE, Reddy TE et al (2015) New insights into gestational glucose metabolism: lessons learned from 21st century approaches. Diabetes 64:327–334. https://doi.org/10.2337/db14-0877

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Callesen NF, Ringholm L, Stage E et al (2012) Insulin requirements in type 1 diabetic pregnancy: do twin pregnant women require twice as much insulin as singleton pregnant women? Diabetes Care 35:1246–1248. https://doi.org/10.2337/dc11-2467

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Herrera E, Ortega-Senovilla H (2014) Lipid metabolism during pregnancy and its implications for fetal growth. Curr Pharm Biotechnol 15:24–31. https://doi.org/10.2174/1389201015666140330192345

    Article  PubMed  CAS  Google Scholar 

  91. Herrera E (2002) Lipid metabolism in pregnancy and its consequences in the fetus and newborn. Endocrine 19:43–55. https://doi.org/10.1385/ENDO:19:1:43

    Article  PubMed  CAS  Google Scholar 

  92. Tyson JE, Hwang P, Guyda H, Friesen HG (1972) Studies of prolactin secretion in human pregnancy. Am J Obstet Gynecol 113:14–20. https://doi.org/10.1016/0002-9378(72)90446-2

    Article  PubMed  CAS  Google Scholar 

  93. Molitch ME (2011) Prolactinoma in pregnancy. Best Pract Res Clin Endocrinol Metab 25:885–896. https://doi.org/10.1016/j.beem.2011.05.011

    Article  PubMed  CAS  Google Scholar 

  94. Scheithauer BW, Sano T, Kovacs KT et al (1990) The pituitary gland in pregnancy: a clinicopathologic and immunohistochemical study of 69 cases. Mayo Clin Proc 65:461–474. https://doi.org/10.1016/S0025-6196(12)60946-X

    Article  PubMed  CAS  Google Scholar 

  95. Feldt-Rasmussen U, Mathiesen ER (2011) Endocrine disorders in pregnancy: physiological and hormonal aspects of pregnancy. Best Pract Res Clin Endocrinol Metab 25:875–884. https://doi.org/10.1016/j.beem.2011.07.004

    Article  PubMed  CAS  Google Scholar 

  96. Stalla GK, Bost H, Stalk J et al (1989) Human corticotropin-releasing hormone during pregnancy. Gynecol Endocrinol 3:1–10. https://doi.org/10.3109/09513598909152447

    Article  PubMed  CAS  Google Scholar 

  97. Sasaki A, Shinkawa O, Yoshinaga K (1989) Placental corticotropin-releasing hormone may be a stimulator of maternal pituitary adrenocorticotropic hormone secretion in humans. J Clin Invest 84:1997–2001. https://doi.org/10.1172/JCI114390

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Rees LH, Burke CW, Chard T et al (1975) Possible placental origin of ACTH in normal human pregnancy. Nature 254:620–622. https://doi.org/10.1038/254620b0

    Article  PubMed  CAS  Google Scholar 

  99. Demey-Ponsart E, Foidart JM, Sulon J, Sodoyez JC (1982) Serum CBG, free and total cortisol and circadian patterns of adrenal function in normal pregnancy. J Steroid Biochem 16:165–169

    Article  CAS  PubMed  Google Scholar 

  100. Carr BR, Parker CR, Madden JD et al (1981) Maternal plasma adrenocorticotropin and cortisol relationships throughout human pregnancy. Am J Obstet Gynecol 139:416–422. https://doi.org/10.1016/0002-9378(81)90318-5

    Article  PubMed  CAS  Google Scholar 

  101. Glinoer D, Gershengorn MC, Dubois A, Robbins J (1977) Stimulation of thyroxine-binding globulin synthesis by isolated rhesus monkey hepatocytes after in vivo β-estradiol administration. Endocrinology 100:807–813. https://doi.org/10.1210/endo-100-3-807

    Article  PubMed  CAS  Google Scholar 

  102. Ain KB, Mori Y, Refetoff S (1987) Reduced clearance rate of thyroxine-binding globulin (TBG) with increased sialylation: a mechanism for estrogen-induced elevation of serum TBG concentration. J Clin Endocrinol Metab 65:689–696. https://doi.org/10.1210/jcem-65-4-689

    Article  PubMed  CAS  Google Scholar 

  103. Henrichs J, Ghassabian A, Peeters RP, Tiemeier H (2013) Maternal hypothyroxinemia and effects on cognitive functioning in childhood: how and why? Clin Endocrinol 79:152–162. https://doi.org/10.1111/cen.12227

    Article  Google Scholar 

  104. Casey BM, Thom EA, Peaceman AM et al (2017) Treatment of subclinical hypothyroidism or hypothyroxinemia in pregnancy. N Engl J Med 376:815–825. https://doi.org/10.1056/NEJMoa1606205

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. American College of Obstetricians and Gynecologists (2015) Practice bulletin No. 148: thyroid disease in pregnancy. Obstet Gynecol 125:996–1005. https://doi.org/10.1097/01.AOG.0000462945.27539.93

    Article  Google Scholar 

  106. Alexander EK, Pearce EN, Brent GA et al (2017) 2017 guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid 27:315–389

    Article  PubMed  Google Scholar 

  107. Moleti M, Trimarchi F, Vermiglio F (2014) Thyroid physiology in pregnancy. Endocr Pract 20:589–596. https://doi.org/10.4158/EP13341.RA

    Article  PubMed  Google Scholar 

  108. Glinoer D (1999) What happens to the normal thyroid during pregnancy? Thyroid 9:631–635. https://doi.org/10.1089/thy.1999.9.631

    Article  PubMed  CAS  Google Scholar 

  109. Alexander EK, Marqusee E, Lawrence J et al (2004) Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med 351:241–249. https://doi.org/10.1056/NEJMoa040079

    Article  PubMed  CAS  Google Scholar 

  110. Bernstein IM, Ziegler W, Badger GJ (2001) Plasma volume expansion in early pregnancy. Obstet Gynecol 97:669–672

    PubMed  CAS  Google Scholar 

  111. Lund CJ, Donovan JC (1967) Blood volume during pregnancy. Significance of plasma and red cell volumes. Am J Obstet Gynecol 98:393–403. https://doi.org/10.1016/0002-9378(67)90160-3

    Article  Google Scholar 

  112. de Haas S, Ghossein-Doha C, van Kuijk SMJ et al (2017) Physiological adaptation of maternal plasma volume during pregnancy: a systematic review and meta-analysis. Ultrasound Obstet Gynecol 49:177–187. https://doi.org/10.1002/uog.17360

    Article  PubMed  Google Scholar 

  113. Goonewardene M, Shehata M, Hamad A (2012) Anaemia in pregnancy. Best Pract Res Clin Obstet Gynaecol 26:3–24. https://doi.org/10.1016/j.bpobgyn.2011.10.010

    Article  PubMed  Google Scholar 

  114. Huisman A, Aarnoudse JG, Huisjes HJ et al (1987) Whole blood viscosity during normal pregnancy. BJOG 94:1143–1149. https://doi.org/10.1111/j.1471-0528.1987.tb02313.x

    Article  CAS  Google Scholar 

  115. American College of Obstetricians and Gynecologists (2008) ACOG practice bulletin no. 95: Anemia in pregnancy. Obstet Gynecol 112:201–207. https://doi.org/10.1097/AOG.0b013e3181809c0d

    Article  Google Scholar 

  116. Haider BA, Olofin I, Wang M et al (2013) Anaemia, prenatal iron use, and risk of adverse pregnancy outcomes: systematic review and meta-analysis. BMJ 347:f3443. https://doi.org/10.1136/bmj.f3443

    Article  Google Scholar 

  117. Peña-Rosas J, De-Regil L, Dowswell T, Viteri F (2015) Daily oral iron supplementation during pregnancy. Cochrane Database Syst Rev 2015:CD004736. https://doi.org/10.1002/14651858.CD004736.pub2

    Article  PubMed Central  Google Scholar 

  118. Ahmadzia HK, Phillips JM, James AH et al (2018) Predicting peripartum blood transfusion in women undergoing cesarean delivery: a risk prediction model. PLoS ONE 13:e0208417. https://doi.org/10.1371/journal.pone.0208417

    Article  PubMed  PubMed Central  Google Scholar 

  119. Kühnert M, Strohmeier R, Stegmüller M, Halberstadt E (1998) Changes in lymphocyte subsets during normal pregnancy. Eur J Obstet Gynecol Reprod Biol 76:147–151. https://doi.org/10.1016/S0301-2115(97)00180-2

    Article  PubMed  Google Scholar 

  120. Boehlen F, Hohlfeld P, Extermann P et al (2000) Platelet count at term pregnancy: a reappraisal of the threshold. Obstet Gynecol 95:29–33. https://doi.org/10.1016/S0029-7844(99)00537-2

    Article  PubMed  CAS  Google Scholar 

  121. Han L, Liu X, Li H et al (2014) Blood coagulation parameters and platelet indices: changes in normal and preeclamptic pregnancies and predictive values for preeclampsia. PLoS ONE 9:e114488. https://doi.org/10.1371/journal.pone.0114488

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Maymon R, Zimerman AL, Strauss S, Gayer G (2007) Maternal spleen size throughout normal pregnancy. Semin Ultrasound CT MRI 28:64–66. https://doi.org/10.1053/j.sult.2006.10.005

    Article  Google Scholar 

  123. Kenny LC, McCrae KR, Gary Cunningham F (2014) Platelets, coagulation, and the liver. In: Taylor RN, Roberts JM, Cunningham FG, Lindheimer MDBT-CHD in P (Fourth E (eds) Chesley’s Hypertensive Disorders in Pregnancy, 4th edn. Academic Press, San Diego, pp 379–396

  124. Uchikova EH, Ledjev II (2005) Changes in haemostasis during normal pregnancy. Eur J Obstet Gynecol Reprod Biol 119:185–188. https://doi.org/10.1016/j.ejogrb.2004.06.038

    Article  PubMed  CAS  Google Scholar 

  125. McLean KC, Bernstein IM, Brummel-Ziedins KE (2012) Tissue factor-dependent thrombin generation across pregnancy. Am J Obstet Gynecol 207:135. https://doi.org/10.1016/j.ajog.2012.05.027

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Sharief LT, Lawrie AS, Mackie IJ et al (2014) Changes in factor XIII level during pregnancy. Haemophilia 20:e144. https://doi.org/10.1111/hae.12345

    Article  PubMed  CAS  Google Scholar 

  127. Gary Cunningham F, Nelson DB (2015) Disseminated intravascular coagulation syndromes in obstetrics. Obstet Gynecol 126:999–1011

    Article  CAS  PubMed  Google Scholar 

  128. Hellgren M (1996) Hemostasis during pregnancy and puerperium. Pathophysiol Haemost Thromb 26:244–247. https://doi.org/10.1159/000217305

    Article  CAS  Google Scholar 

  129. Hayes M, Bourjeily G, Rosene-Montella K (2009) Venous thromboembolic disease and pregnancy [10]. N Engl J Med 360:639

    PubMed  CAS  Google Scholar 

  130. Cantwell R, Clutton-Brock T, Cooper G et al (2011) Saving mothers’ lives: reviewing maternal deaths to make motherhood safer: 2006–2008. The eighth report of the confidential enquiries into maternal deaths in the United Kingdom. BJOG 118:1–203. https://doi.org/10.1111/j.1471-0528.2010.02847.x

    Article  PubMed  Google Scholar 

  131. James AH, Jamison MG, Brancazio LR, Myers ER (2006) Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am J Obstet Gynecol 194:1311–1315. https://doi.org/10.1016/j.ajog.2005.11.008

    Article  PubMed  Google Scholar 

  132. James AH (2012) The natural history of pelvic vein thrombosis: the natural history of involution? Am J Obstet Gynecol 206:276–277. https://doi.org/10.1016/j.ajog.2012.01.013

    Article  PubMed  Google Scholar 

  133. James AH, Rhee E, Thames B, Philipp CS (2014) Characterization of antithrombin levels in pregnancy. Thromb Res 134:648–651. https://doi.org/10.1016/j.thromres.2014.07.025

    Article  PubMed  CAS  Google Scholar 

  134. Patel JP, Green B, Patel RK et al (2013) Population pharmacokinetics of enoxaparin during the antenatal period. Circulation 128:1462–1469. https://doi.org/10.1161/CIRCULATIONAHA.113.003198

    Article  PubMed  CAS  Google Scholar 

  135. Jensen D, Duffin J, Lam YM et al (2008) Physiological mechanisms of hyperventilation during human pregnancy. Respir Physiol Neurobiol 161:76–86. https://doi.org/10.1016/j.resp.2008.01.001

    Article  PubMed  CAS  Google Scholar 

  136. Lyons H, Antonio R (1959) The sensitivity of the respiratory center in pregnancy and after administration of progesterone. Trans Assoc Am Physicians 72:173–180

    CAS  Google Scholar 

  137. LoMauro A, Aliverti A (2015) Respiratory physiology of pregnancy. Breathe 11:297–301. https://doi.org/10.1183/20734735.008615

    Article  PubMed  PubMed Central  Google Scholar 

  138. Ellegrad E (2006) Pregnancy rhinitis. Immunol Allergy Clin N Am 26:119–135

    Article  Google Scholar 

  139. Toppozada H, Michaels L, Toppozada M et al (1982) The human respiratory nasal mucosa in pregnancy. An electron microscopic and histochemical study. J Laryngol Otol 96:613–626

    Article  CAS  PubMed  Google Scholar 

  140. Weinberger SE, Weiss ST, Cohen WR et al (1980) Pregnancy and the lung. Am Rev Respir Dis 121:559–581. https://doi.org/10.1164/arrd.1980.121.3.559

    Article  PubMed  CAS  Google Scholar 

  141. Gilroy RJ, Mangura BT, Lavietes MH (1988) Rib cage and abdominal volume displacements during breathing in pregnancy. Am Rev Respir Dis 137:668–672. https://doi.org/10.1164/ajrccm/137.3.668

    Article  PubMed  CAS  Google Scholar 

  142. Goldsmith LT, Weiss G, Steinetz BG (1995) Relaxin and its role in pregnancy. Endocrinol Metab Clin North Am 24:171–186

    Article  CAS  PubMed  Google Scholar 

  143. Marx GF, Murthy PK, Orkin LR (1970) Static compliance before and after vaginal delivery. Br J Anaesth 42:1100–1104. https://doi.org/10.1093/bja/42.12.1100

    Article  PubMed  CAS  Google Scholar 

  144. Gee JB, Packer BS, Millen JE, Robin ED (1967) Pulmonary mechanics during pregnancy. J Clin Invest 46:945–952. https://doi.org/10.1172/JCI105600

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Tenholder MF, South-Paul JE (1989) Dyspnea in pregnancy. Chest 96:381–388. https://doi.org/10.1378/chest.96.2.381

    Article  PubMed  CAS  Google Scholar 

  146. Prowse CM, Gaensler EA (1965) Respiratory and acid-base changes during pregnancy. Anesthesiology 26:381–392. https://doi.org/10.1097/00000542-196507000-00003

    Article  PubMed  CAS  Google Scholar 

  147. Crapo RO (1996) Normal cardiopulmonary physiology during pregnancy. Clin Obstet Gynecol 39:3–16

    Article  CAS  PubMed  Google Scholar 

  148. Costantine MM (2014) Physiologic and pharmacokinetic changes in pregnancy. Front Pharmacol 5:65. https://doi.org/10.3389/fphar.2014.00065

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  149. Cugell DW, Frank NR, Gaensler EA, Badger TL (1953) Pulmonary function in pregnancy. I. Serial observations in normal women. Obstet Gynecol Surv 8:658–662

    Google Scholar 

  150. Siddiqui AH, Tauheed N, Ahmad A, Mohsin Z (2014) Pulmonary function in advanced uncomplicated singleton and twin pregnancy. J Bras Pneumol 40:244–249. https://doi.org/10.1590/s1806-37132014000300007

    Article  PubMed  PubMed Central  Google Scholar 

  151. Templeton A, Kelman GR (1976) Maternal blood-gases, (PAO2-PaO2), physiological shunt and VD/VT in normal pregnancy. Br J Anaesth 48:1001–1004. https://doi.org/10.1093/bja/48.10.1001

    Article  PubMed  CAS  Google Scholar 

  152. Liberatore SM, Pistelli R, Patalano F et al (1984) Respiratory function during pregnancy. Respiration 46:145–150. https://doi.org/10.1159/000194683

    Article  PubMed  CAS  Google Scholar 

  153. Awe RJ, Brooke Nicotra M, Newsom TD, Viles R (1979) Arterial oxygenation and alveolar-arterial gradients in term pregnancy. Obstet Gynecol 53:182–186

    PubMed  CAS  Google Scholar 

  154. Ueki R, Tatara T, Kariya N et al (2009) Comparison of placental transfer of local anesthetics in perfusates with different pH values in a human cotyledon model. J Anesth 23:526–529. https://doi.org/10.1007/s00540-009-0815-7

    Article  PubMed  Google Scholar 

  155. Johnson RF, Herman NL, Johnson HV et al (1996) Effects of fetal pH on local anesthetic transfer across the human placenta. Anesthesiology 85:608–615. https://doi.org/10.1097/00000542-199609000-00021

    Article  PubMed  CAS  Google Scholar 

  156. Lucius H, Gahlenbeck H, Kleine HO et al (1970) Respiratory functions, buffer system, and electrolyte concentrations of blood during human pregnancy. Respir Physiol 9:311–317. https://doi.org/10.1016/0034-5687(70)90088-5

    Article  PubMed  CAS  Google Scholar 

  157. Tsai CH, de Leeuw NKM (1982) Changes in 2, 3-diphosphoglyeerate during pregnancy and puerperium in normal women and in β-thalassemia heterozygous women. Am J Obstet Gynecol 142:520–523. https://doi.org/10.1016/0002-9378(82)90754-2

    Article  PubMed  CAS  Google Scholar 

  158. Gin T, Mainland P, Chan MTV, Short TG (1997) Decreased thiopental requirements in early pregnancy. Anesthesiology 86:73–78. https://doi.org/10.1097/00000542-199701000-00011

    Article  PubMed  CAS  Google Scholar 

  159. Nejdlova M, Johnson T (2012) Anaesthesia for non-obstetric procedures during pregnancy. Contin Educ Anaesth Crit Care Pain 12:203–206. https://doi.org/10.1093/bjaceaccp/mks022

    Article  Google Scholar 

  160. Koren G, Ornoy A (2018) The role of the placenta in drug transport and fetal drug exposure. Expert Rev Clin Pharmacol 11:373–385. https://doi.org/10.1080/17512433.2018.1425615

    Article  PubMed  CAS  Google Scholar 

  161. Vargesson N (2015) Thalidomide-induced teratogenesis: history and mechanisms. Birth Defects Res Part C 105:140–156. https://doi.org/10.1002/bdrc.21096

    Article  CAS  Google Scholar 

  162. Joshi AA, Vaidya SS, St-Pierre MV et al (2016) Placental ABC transporters: biological impact and pharmaceutical significance. Pharm Res 33:2847–2878. https://doi.org/10.1007/s11095-016-2028-8

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  163. Desforges M, Sibley CP (2010) Placental nutrient supply and fetal growth. Int J Dev Biol 54:377–390. https://doi.org/10.1387/ijdb.082765md

    Article  PubMed  CAS  Google Scholar 

  164. Pacifici GM, Nottoli R (1995) Placental transfer of drugs administered to the mother. Clin Pharmacokinet 28:235–269. https://doi.org/10.2165/00003088-199528030-00005

    Article  PubMed  CAS  Google Scholar 

  165. Cardonick E, Iacobucci A (2004) Use of chemotherapy during human pregnancy. Lancet Oncol 5:283–291. https://doi.org/10.1016/S1470-2045(04)01466-4

    Article  PubMed  CAS  Google Scholar 

  166. Andrew M, Boneu B, Cade J et al (1985) Placental transport of low molecular weight heparin in the pregnant sheep. Br J Haematol 59:103–108. https://doi.org/10.1111/j.1365-2141.1985.tb02969.x

    Article  PubMed  CAS  Google Scholar 

  167. Jovanovic L, Pettitt DJ (2007) Treatment with insulin and its analogs in pregnancies complicated by diabetes. Diabetes Care 30:S220–S224. https://doi.org/10.2337/dc07-s220

    Article  PubMed  CAS  Google Scholar 

  168. Pentsuk N, Van Der Laan JW (2009) An interspecies comparison of placental antibody transfer: New insights into developmental toxicity testing of monoclonal antibodies. Birth Defects Res Part B 86:1–17

    Article  CAS  Google Scholar 

  169. Tun GSZ, Lobo AJ (2015) Evaluation of pharmacokinetics and pharmacodynamics and clinical efficacy of certolizumab pegol for Crohn’s disease. Expert Opin Drug Metab Toxicol 11:317–327. https://doi.org/10.1517/17425255.2015.995166

    Article  PubMed  CAS  Google Scholar 

  170. Clowse MEB, Wolf DC, Förger F et al (2015) Pregnancy outcomes in subjects exposed to certolizumab pegol. J Rheumatol 42:2270–2278. https://doi.org/10.3899/jrheum.140189

    Article  PubMed  CAS  Google Scholar 

  171. Staelens AS, Vonck S, Molenberghs G et al (2016) Maternal body fluid composition in uncomplicated pregnancies and preeclampsia: a bioelectrical impedance analysis. Eur J Obstet Gynecol Reprod Biol 204:69–73. https://doi.org/10.1016/j.ejogrb.2016.07.502

    Article  PubMed  Google Scholar 

  172. Kreepala C, Kitporntheranunt M, Sangwipasnapaporn W et al (2018) Assessment of preeclampsia risk by use of serum ionized magnesium-based equation. Ren Fail 40:99–106. https://doi.org/10.1080/0886022X.2017.1422518

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  173. Lopes van Balen VA, Gansewinkel TAG, Haas S et al (2019) Maternal kidney function during pregnancy: systematic review and meta-analysis. Ultrasound Obstet Gynecol 54:297–307. https://doi.org/10.1002/uog.20137

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  174. Datta S, Kodali BS, Segal S (2010) Maternal physiological changes during pregnancy, labor, and the postpartum period. Obstetric anesthesia handbook, 5th edn. Springer, New York, New York, NY, pp 1–14

    Chapter  Google Scholar 

  175. Robson SC, Dunlop W, Moore M, Hunter S (1987) Haemodynamic changes during the puerperium: a Doppler and M-mode echocardiographic study. BJOG 94:1028–1039. https://doi.org/10.1111/j.1471-0528.1987.tb02286.x

    Article  CAS  Google Scholar 

  176. Rachael JP, Nelson-Piercy C (2004) Management of hypertension before, during, and after pregnancy. Heart 90:1499–1504

    Article  Google Scholar 

  177. Schalkwijk S, Buaben AO, Freriksen JJM et al (2018) Prediction of fetal darunavir exposure by integrating human ex-vivo placental transfer and physiologically based pharmacokinetic modeling. Clin Pharmacokinet 57:705–716. https://doi.org/10.1007/s40262-017-0583-8

    Article  PubMed  CAS  Google Scholar 

  178. Liu XI, Momper JD, Rakhmanina N et al (2019) Physiologically based pharmacokinetic models to predict maternal pharmacokinetics and fetal exposure to emtricitabine and acyclovir. J Clin Pharmacol 60:240–255. https://doi.org/10.1002/jcph.1515

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  179. Horton S, Tuerk A, Cook D et al (2012) Maximum recommended dosage of lithium for pregnant women based on a PBPK model for lithium absorption. Adv Bioinform 2012:9. https://doi.org/10.1155/2012/352729

    Article  CAS  Google Scholar 

  180. Mian P, van den Anker JN, van Calsteren K et al (2019) Physiologically based pharmacokinetic modeling to characterize acetaminophen pharmacokinetics and N-Acetyl-p-benzoquinone imine (NAPQI) formation in non-pregnant and pregnant women. Clin Pharmacokinet. https://doi.org/10.1007/s40262-019-00799-5

    Article  PubMed Central  Google Scholar 

  181. Darakjian LI, Kaddoumi A (2019) Physiologically based pharmacokinetic/pharmacodynamic model for caffeine disposition in pregnancy. Mol Pharm 16:1340–1349. https://doi.org/10.1021/acs.molpharmaceut.8b01276

    Article  PubMed  CAS  Google Scholar 

  182. Lumen A, McNally K, George N et al (2015) Quantitative global sensitivity analysis of a biologically based dose-response pregnancy model for the thyroid endocrine system. Front Pharmacol 6:107. https://doi.org/10.3389/fphar.2015.00107

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  183. Jarvis S, Nelson-Piercy C (2014) Common symptoms and signs during pregnancy. Obstet Gynaecol Reprod Med 24:245–249. https://doi.org/10.1016/j.ogrm.2014.05.006

    Article  Google Scholar 

  184. Tan EK, Tan EL (2013) Alterations in physiology and anatomy during pregnancy. Best Pract Res Clin Obstet Gynaecol 27:791–802. https://doi.org/10.1016/j.bpobgyn.2013.08.001

    Article  PubMed  Google Scholar 

  185. Philipson A (1977) Pharmacokinetics of ampicillin during pregnancy. J Infect Dis 136:370–376. https://doi.org/10.1093/infdis/136.3.370

    Article  PubMed  CAS  Google Scholar 

  186. Philipson A, Stiernstedt G, Ehrnebo M (1987) Comparison of the pharmacokinetics of cephradine and cefazolin in pregnant and non-pregnant women. Clin Pharmacokinet 12:136–144. https://doi.org/10.2165/00003088-198712020-00004

    Article  PubMed  CAS  Google Scholar 

  187. Dungan JS (2009) Changes in enoxaparin pharmacokinetics during pregnancy and implications for antithrombotic therapeutic strategy. Yearb Obstet Gynecol Women’s Heal 2009:88–89. https://doi.org/10.1016/s1090-798x(09)79028-9

    Article  Google Scholar 

  188. Heikkinen T, Ekblad U, Palo P, Laine K (2003) Pharmacokinetics of fluoxetine and norfluoxetine in pregnancy and lactation. Clin Pharmacol Ther 73:330–337. https://doi.org/10.1016/S0009-9236(02)17634-X

    Article  PubMed  CAS  Google Scholar 

  189. Pennell PB (2010) Erratum: The impact of pregnancy and childbirth on the metabolism of lamotrigine (Neurology (2004) 62 (292–295)). Neurology 74:2028. https://doi.org/10.1212/WNL.0b013e3181e78c1d

    Article  Google Scholar 

  190. Chopra IJ, Baber K (2003) Treatment of primary hypothyroidism during pregnancy: is there an increase in thyroxine dose requirement in pregnancy? Metabolism 52:122–128. https://doi.org/10.1053/meta.2003.50019

    Article  PubMed  CAS  Google Scholar 

  191. Fischer JH, Sarto GE, Hardman J et al (2014) Influence of gestational age and body weight on the pharmacokinetics of labetalol in pregnancy. Clin Pharmacokinet 53:373–383. https://doi.org/10.1007/s40262-013-0123-0

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  192. Ter Laak MA, Roos C, Ouw DJ et al (2015) Pharmacokinetics of nifedipine slow-release tablets during sustained tocolysis. Int J Clin Pharmacol Ther 53:84–91. https://doi.org/10.5414/CP202215

    Article  PubMed  CAS  Google Scholar 

  193. Dallmann A, Ince I, Meyer M et al (2017) Gestation-specific changes in the anatomy and physiology of healthy pregnant women: an extended repository of model parameters for physiologically based pharmacokinetic modeling in pregnancy. Clin Pharmacokinet 56:1303–1330. https://doi.org/10.1007/s40262-017-0539-z

    Article  PubMed  CAS  Google Scholar 

Download references

Funding

The project was funded by NHLBI Grant (K23HL141640).

Author information

Authors and Affiliations

  1. Division of Maternal-Fetal Medicine, Department of Obstetrics & Gynecology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA

    Jamil M. Kazma & Homa K. Ahmadzia

  2. Division of Clinical Pharmacology, Children’s National Hospital, Washington, DC, USA

    John van den Anker

  3. Pediatric Pharmacology and Pharmacometrics, University of Basel Children’s Hospital, Basel, Switzerland

    John van den Anker

  4. Department of Development and Regeneration, and Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium

    Karel Allegaert

  5. Department of Clinical Pharmacy, Erasmus MC, Rotterdam, The Netherlands

    Karel Allegaert

  6. Clinical Pharmacometrics, Research & Development, Pharmaceuticals, Bayer AG, Leverkusen, Germany

    André Dallmann

Authors
  1. Jamil M. Kazma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John van den Anker
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Karel Allegaert
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. André Dallmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Homa K. Ahmadzia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Homa K. Ahmadzia.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kazma, J.M., van den Anker, J., Allegaert, K. et al. Anatomical and physiological alterations of pregnancy. J Pharmacokinet Pharmacodyn 47, 271–285 (2020). https://doi.org/10.1007/s10928-020-09677-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10928-020-09677-1

Keywords

Search

Navigation