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Anatomical, Physiological and Metabolic Changes with Gestational Age during Normal Pregnancy

A Database for Parameters Required in Physiologically Based Pharmacokinetic Modelling

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Abstract

Background: Pregnancy is associated with considerable changes in the physiological, anatomical and biochemical attributes in women. These may alter the exposure to xenobiotics between pregnant and non-pregnant women who receive similar doses, with implications for different susceptibility to environmental pollutants or therapeutic agents. Physiologically based pharmacokinetic (PBPK) models together with in vitro in vivo extrapolation (IVIVE) of absorption, distribution, metabolism and excretion (ADME) characteristics may capture the likely changes. However, such models require comprehensive information on the longitudinal variations of PBPK parameter values; a set of data that are as yet not available from a singular source.

Aim: The aim of this article was to collect, integrate and analyse the available time-variant parameters that are needed for the PBPK modelling of xenobiotic kinetics in a healthy pregnant population.

Methods: A structured literature search was carried out on anatomical, physiological and biochemical parameters likely to change in pregnancy and alter the kinetics of xenobiotics. Collated data were carefully assessed, integrated and analysed for trends with gestational age. Algorithms were generated to describe the changes in parameter values with gestational age. These included changes in maternal weight, the individual organ volumes and blood flows, glomerular filtration rates, and some drug-metabolising enzyme activities.

Results: Articles were identified using relevant keywords, quality appraised and data were extracted by two investigators. Some parameters showed no change with gestational age and for others robust data were not available. However, for many parameters significant changes were reported during the course of pregnancy, e.g. cardiac output, protein binding and expression/activity of metabolizing enzymes. The trend for time-variant parameters was not consistent (with respect to direction and mono-tonicity). Hence, various mathematical algorithms were needed to describe individual parameter values.

Conclusion: Despite the limitations identified in the availability of some values, the collected data presented in this paper provide a potentially useful singular resource for key parameters needed for PBPK modelling in pregnancy. This facilitates the risk assessment of environmental chemicals and therapeutic drug dose adjustments in the pregnant population.

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References

  1. Anger GJ, Piquette-Miller M. Pharmacokinetic studies in pregnant women. Clin Pharmacol Ther 2008 Jan; 83(1): 184–7

    Article  PubMed  CAS  Google Scholar 

  2. Jeong H. Altered drug metabolism during pregnancy: hormonal regulation of drug-metabolizing enzymes. Expert Opin Drug Metab Toxicol 2010 Jun; 6(6): 689–99

    Article  PubMed  CAS  Google Scholar 

  3. Ververs FF, Voorbij HA, Zwarts P, et al. Effect of cytochrome P450 2D6 genotype on maternal paroxetine plasma concentrations during pregnancy. Clin Pharmacokinet 2009; 48(10): 677–83

    Article  PubMed  CAS  Google Scholar 

  4. Hodge LS, Tracy TS. Alterations in drug disposition during pregnancy: implications for drug therapy. Expert Opin Drug Metab Toxicol 2007 Aug; 3(4): 557–71

    Article  PubMed  CAS  Google Scholar 

  5. Clapp JF, Capeless E. Cardiovascular function before, during, and after the first and subsequent pregnancies. Am J Cardiol 1997 Dec 1; 80(11): 1469–73

    Article  PubMed  Google Scholar 

  6. De Swiet M. The cardiovascular system. In: Hytten F, Chamberlain G, editors. Clinical physiology in obstetrics. 2nd ed. Oxford: Blackwell Science Ltd, 1991: 3–38

    Google Scholar 

  7. Pritchard JA. Changes in the blood volume during pregnancy and delivery. Anesthesiology 1965 Jul–Aug; 26: 393–9

    Article  PubMed  CAS  Google Scholar 

  8. Chapman AB, Abraham WT, Zamudio S, et al. Temporal relationships between hormonal and hemodynamic changes in early human pregnancy. Kidney Int 1998 Dec; 54(6): 2056–63

    Article  PubMed  CAS  Google Scholar 

  9. Brown MA, Whitworth JA. The kidney in hypertensive pregnancies: victim and villain. Am J Kidney Dis 1992 Nov; 20(5): 427–42

    PubMed  CAS  Google Scholar 

  10. Lindheimer MD, Katz AI. Sodium and diuretics in pregnancy. N Engl J Med 1973 Apr 26; 288(17): 891–4

    Article  PubMed  CAS  Google Scholar 

  11. Headley J, Northstone K, Simmons H, et al. Medication use during pregnancy: data from the Avon Longitudinal Study of Parents and Children. Eur J Clin Pharmacol 2004 Jul; 60(5): 355–61

    Article  PubMed  CAS  Google Scholar 

  12. Andrade SE, Gurwitz JH, Davis RL, et al. Prescription drug use in pregnancy. Am J Obstet Gynecol 2004 Aug; 191(2): 398–407

    Article  PubMed  Google Scholar 

  13. Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA 2006 Feb 1; 295(5): 499–507

    Article  PubMed  CAS  Google Scholar 

  14. Ramos E, St-Andre M, Rey E, et al. Duration of antidepressant use during pregnancy and risk of major congenital malformations. Br J Psychiatry 2008 May; 192(5): 344–50

    Article  PubMed  Google Scholar 

  15. Andrade SE, Raebel MA, Brown J, et al. Use of antidepressant medications during pregnancy: a multisite study. Am J Obstet Gynecol 2008 Feb; 198(2): 194e1–5

    Article  CAS  Google Scholar 

  16. Davis RL, Rubanowice D, McPhillips H, et al. Risks of congenital malformations and perinatal events among infants exposed to antidepressant medications during pregnancy. Pharmacoepidemiol Drug Saf 2007 Oct; 16(10): 1086–94

    Article  PubMed  Google Scholar 

  17. Anderson GD. Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach. Clin Pharmacokinet 2005; 44(10): 989–1008

    Article  PubMed  CAS  Google Scholar 

  18. Little BB. Pharmacokinetics during pregnancy: evidence-based maternal dose formulation. Obstet Gynecol 1999 May; 93(5 Pt 2): 858–68

    Article  PubMed  CAS  Google Scholar 

  19. FDA, Center for Drug Evaluation and Research. Guidance for industry: pharmacokinetics in pregnancy — study design, data analysis, and impact on dosing and labeling [online]. Available from URL: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072133.pdf [Accessed 2010 Sep 11]

  20. Johnson TN, Rostami-Hodjegan A. Resurgence in the use of physiologically based pharmacokinetic models in pediatric clinical pharmacology: parallel shift in incorporating the knowledge of biological elements and increased applicability to drug development and clinical practice. Paediatr Anaesth 2011 Mar; 21(3): 291–301

    Article  PubMed  Google Scholar 

  21. Beaudouin R, Micallef S, Brochot C. A stochastic whole-body physiologically based pharmacokinetic model to assess the impact of inter-individual variability on tissue dosimetry over the human lifespan. Regul Toxicol Pharmacol 2010 Jun; 57(1): 103–16

    Article  PubMed  CAS  Google Scholar 

  22. Jamei M, Dickinson GL, Rostami-Hodjegan A. A framework for assessing inter-individual variability in pharmacokinetics using virtual human populations and integrating general knowledge of physical chemistry, biology, anatomy, physiology and genetics: a tale of ‘bottom-up’ vs ‘top-down’ recognition of covariates. Drug Metab Pharmacokinet 2009; 24(1): 53–75

    Article  PubMed  CAS  Google Scholar 

  23. Andrew MA, Hebert MF, Vicini P. Physiologically based pharmacokinetic model of midazolam disposition during pregnancy. Conf Proc IEEE Eng Med Biol Soc 2008; 2008: 5454–7

    PubMed  Google Scholar 

  24. Corley RA, Mast TJ, Carney EW, et al. Evaluation of physiologically based models of pregnancy and lactation for their application in children’s health risk assessments. Crit Rev Toxicol 2003; 33(2): 137–211

    Article  PubMed  CAS  Google Scholar 

  25. Young JF, Branham WS, Sheehan DM, et al. Physiological “constants” for PBPK models for pregnancy. J Toxicol Environ Health 1997 Dec 12; 52(5): 385–401

    PubMed  CAS  Google Scholar 

  26. Luecke RH, Wosilait WD, Pearce BA, et al. A physiologically based pharmacokinetic computer model for human pregnancy. Teratology 1994 Feb; 49(2): 90–103

    Article  PubMed  CAS  Google Scholar 

  27. Luecke RH, Wosilait WD, Pearce BA, et al. A computer model and program for xenobiotic disposition during pregnancy. Comput Methods Programs Biomed 1997 Jul; 53(3): 201–24

    Article  PubMed  CAS  Google Scholar 

  28. Gentry PR, Covington TR, Andersen ME, et al. Application of a physiologically based pharmacokinetic model for isopropanol in the derivation of a reference dose and reference concentration. Regul Toxicol Pharmacol 2002 Aug; 36(1): 51–68

    Article  PubMed  CAS  Google Scholar 

  29. Gentry PR, Covington TR, Clewell 3rd HJ. Evaluation of the potential impact of pharmacokinetic differences on tissue dosimetry in offspring during pregnancy and lactation. Regul Toxicol Pharmacol 2003 Aug; 38(1): 1–16

    Article  PubMed  CAS  Google Scholar 

  30. Aitchison J, Brown JAC. The log normal distribution. Cambridge: University Press, 1966

    Google Scholar 

  31. Armitage P, Berry J, Matthews JNS. Statistical methods in medical research. 4th ed. Oxford: Blackwell Science, 2002

    Book  Google Scholar 

  32. Haddad S, Restieri C, Krishnan K. Characterization of age-related changes in body weight and organ weights from birth to adolescence in humans. J Toxicol Environ Health 2001 Nov 23; 64(6): 453–64

    Article  CAS  Google Scholar 

  33. Young JF, Luecke RH, Pearce BA, et al. Human organ/tissue growth algorithms that include obese individuals and black/white population organ weight similarities from autopsy data. J Toxicol Environ Health 2009; 72(8): 527–40

    Article  CAS  Google Scholar 

  34. Thomas D, Das SK, Levine JA, et al. New fat free mass: fat mass model for use in physiological energy balance equations. Nutr Metab (Lond) 2010; 7: 39

    Article  Google Scholar 

  35. Butte NF, Ellis KJ, Wong WW, et al. Composition of gestational weight gain impacts maternal fat retention and infant birth weight. Am J Obstet Gynecol 2003 Nov; 189(5): 1423–32

    Article  PubMed  Google Scholar 

  36. Kopp-Hoolihan LE, van Loan MD, Wong WW, et al. Longitudinal assessment of energy balance in well-nourished, pregnant women. Am J Clin Nutr 1999 Apr; 69(4): 697–704

    PubMed  CAS  Google Scholar 

  37. Lof M, Olausson H, Bostrom K, et al. Changes in basal metabolic rate during pregnancy in relation to changes in body weight and composition, cardiac output, insulin-like growth factor I, and thyroid hormones and in relation to fetal growth. Am J Clin Nutr 2005 Mar; 81(3): 678–85

    PubMed  CAS  Google Scholar 

  38. Hebert MF, Easterling TR, Kirby B, et al. 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 2008 Aug; 84(2): 248–53

    Article  PubMed  CAS  Google Scholar 

  39. Lof M, Hilakivi-Clarke L, Sandin SS, et al. Dietary fat intake and gestational weight gain in relation to estradiol and progesterone plasma levels during pregnancy: a longitudinal study in Swedish women. BMC Womens Health 2009; 9: 10

    Article  PubMed  CAS  Google Scholar 

  40. Abrams B, Selvin S. Maternal weight gain pattern and birth weight. Obstet Gynecol 1995 Aug; 86(2): 163–9

    Article  PubMed  CAS  Google Scholar 

  41. Catalano PM, Roman-Drago NM, Amini SB, et al. Longitudinal changes in body composition and energy balance in lean women with normal and abnormal glucose tolerance during pregnancy. Am J Obstet Gynecol 1998 Jul; 179(1): 156–65

    Article  PubMed  CAS  Google Scholar 

  42. de Groot LC, Boekholt HA, Spaaij CK, et al. Energy balances of healthy Dutch women before and during pregnancy: limited scope for metabolic adaptations in pregnancy. Am J Clin Nutr 1994 Apr; 59(4): 827–32

    PubMed  Google Scholar 

  43. Edouard DA, Pannier BM, London GM, et al. Venous and arterial behavior during normal pregnancy. Am J Physiol 1998 May; 274(5 Pt 2): H1605–12

    PubMed  CAS  Google Scholar 

  44. Ghezzi F, Franchi M, Balestreri D, et al. Bioelectrical impedance analysis during pregnancy and neonatal birth weight. Eur J Obstet Gynecol Re-product Biol 2001 Oct; 98(2): 171–6

    Article  CAS  Google Scholar 

  45. Larciprete G, Valensise H, Vasapollo B, et al. Body composition during normal pregnancy: reference ranges. Acta Diabetol 2003 Oct; 40 Suppl. 1: S225–32

    Article  PubMed  Google Scholar 

  46. Wolfe WS, Sobal J, Olson CM, et al. Parity-associated weight gain and its modification by sociodemographic and behavioral factors: a prospective analysis in US women. Int J Obes Relat Metab Disord 1997 Sep; 21(9): 802–10

    Article  PubMed  CAS  Google Scholar 

  47. Hronek M, Klemera P, Tosner J, et al. Anthropometric measured fat-free mass as essential determinant of resting energy expenditure for pregnant and non-pregnant women. Nutrition 2011 Sep; 27(9): 885–90

    Article  PubMed  Google Scholar 

  48. Kopp-Hoolihan LE, van Loan MD, Wong WW, et al. Fat mass deposition during pregnancy using a four-component model. J Appl Physiol 1999 Jul; 87(1): 196–202

    PubMed  CAS  Google Scholar 

  49. Goldberg GR, Prentice AM, Coward WA, et al. Longitudinal assessment of the components of energy balance in well-nourished lactating women. Am J Clin Nutr 1991 Nov; 54(5): 788–98

    PubMed  CAS  Google Scholar 

  50. Lederman SA, Paxton A, Heymsfield SB, et al. Body fat and water changes during pregnancy in women with different body weight and weight gain. Obstet Gynecol 1997 Oct; 90(4 Pt 1): 483–8

    Article  PubMed  CAS  Google Scholar 

  51. Van Loan MD, Kopp LE, King JC, et al. Fluid changes during pregnancy: use of bioimpedance spectroscopy. J Appl Physiol 1995 Mar; 78(3): 1037–42

    PubMed  Google Scholar 

  52. Lof M, Forsum E. Evaluation of bioimpedance spectroscopy for measurements of body water distribution in healthy women before, during, and after pregnancy. J Appl Physiol 2004 Mar; 96(3): 967–73

    Article  PubMed  Google Scholar 

  53. Deurenberg P. Body composition techniques in health and disease. Cambridge: Cambridge University Press, 1995: 45–56

    Book  Google Scholar 

  54. Frederiksen MC, Ruo TI, Chow MJ, et al. Theophylline pharmacokinetics in pregnancy. Clin Pharmacol Ther 1986 Sep; 40(3): 321–8

    Article  PubMed  CAS  Google Scholar 

  55. Lukaski HC, Siders WA, Nielsen EJ, et al. Total body water in pregnancy: assessment by using bioelectrical impedance. Am J Clin Nutr 1994 Mar; 59(3): 578–85

    PubMed  CAS  Google Scholar 

  56. Pipe NG, Smith T, Halliday D, et al. Changes in fat, fat-free mass and body water in human normal pregnancy. Br J Obstet Gynaecol 1979 Dec; 86(12): 929–40

    Article  PubMed  CAS  Google Scholar 

  57. Seitchik J. Total body water and total body density of pregnant women. Obstet Gynecol 1967 Feb; 29(2): 155–66

    PubMed  CAS  Google Scholar 

  58. Valensise H, Andreoli A, Lello S, et al. Multifrequency bioelectrical impedance analysis in women with a normal and hypertensive pregnancy. Am J Clin Nutr 2000 Sep; 72(3): 780–3

    PubMed  CAS  Google Scholar 

  59. Forsum E, Sadurskis A, Wager J. Resting metabolic rate and body composition of healthy Swedish women during pregnancy. Am J Clin Nutr 1988 Jun; 47(6): 942–7

    PubMed  CAS  Google Scholar 

  60. van Marken Lichtenbelt WD, Snel YE, Brummer RJ, et al. Deuterium and bromide dilution, and bioimpedance spectrometry independently show that growth hormone-deficient adults have an enlarged extracellular water compartment related to intracellular water. J Clin Endocrinol Metab 1997 Mar; 82(3): 907–11

    Article  PubMed  Google Scholar 

  61. Clark SL, Cotton DB, Lee W, et al. Central hemodynamic assessment of normal term pregnancy. Am J Obstet Gynecol 1989 Dec; 161(6 Pt 1): 1439–42

    Article  PubMed  CAS  Google Scholar 

  62. Robson SC, Hunter S, Boys RJ, et al. Serial study of factors influencing changes in cardiac output during human pregnancy. Am J Physiol 1989 Apr; 256(4 Pt 2): 1060–5

    Google Scholar 

  63. Easterling TR, Benedetti TJ, Schmucker BC, et al. Maternal hemodynamics in normal and preeclamptic pregnancies: a longitudinal study. Obstet Gynecol 1990 Dec; 76(6): 1061–9

    PubMed  CAS  Google Scholar 

  64. Del Bene R, Barletta G, Mello G, et al. Cardiovascular function in pregnancy: effects of posture. BJOG 2001 Apr; 108(4): 344–52

    Article  PubMed  Google Scholar 

  65. Hale SA, Schonberg A, Badger GJ, et al. Relationship between prepregnancy and early pregnancy uterine blood flow and resistance index. Reprod Sci 2009 Nov; 16(11): 1091–6

    Article  PubMed  Google Scholar 

  66. Hennessy TG, MacDonald D, Hennessy MS, et al. Serial changes in cardiac output during normal pregnancy: a Doppler ultrasound study. Eur J Obstet Gynecol Reproduct Biol 1996 Dec 27; 70(2): 117–22

    Article  CAS  Google Scholar 

  67. Mesa A, Jessurun C, Hernandez A, et al. Left ventricular diastolic function in normal human pregnancy. Circulation 1999 Feb 2; 99(4): 511–7

    Article  PubMed  CAS  Google Scholar 

  68. Salas SP, Marshall G, Gutierrez BL, et al. Time course of maternal plasma volume and hormonal changes in women with preeclampsia or fetal growth restriction. Hypertension 2006 Feb; 47(2): 203–8

    Article  PubMed  CAS  Google Scholar 

  69. Bernstein IM, Ziegler W, Badger GJ. Plasma volume expansion in early pregnancy. Obstet Gynecol 2001 May; 97(5 Pt 1): 669–72

    Article  PubMed  CAS  Google Scholar 

  70. Lund CJ, Donovan JC. Blood volume during pregnancy. Significance of plasma and red cell volumes. Am J Obstet Gynecol 1967 Jun 1; 98(3): 394–403

    PubMed  CAS  Google Scholar 

  71. Whittaker PG, Lind T. The intravascular mass of albumin during human pregnancy: a serial study in normal and diabetic women. Br J Obstet Gynaecol 1993 Jun; 100(6): 587–92

    Article  PubMed  CAS  Google Scholar 

  72. Campbell DM, MacGillivray I. Comparison of maternal response in first and second pregnancies in relation to baby weight. J Obstet Gynaecol Br Commonw 1972 Aug; 79(8): 684–93

    Article  PubMed  CAS  Google Scholar 

  73. Rovinsky JJ, Jaffin H. Cardiovascular hemodynamics in pregnancy. I. Blood and plasma volumes in multiple pregnancy. Am J Obstet Gynecol 1965 Sep 1; 93: 1–15

    PubMed  CAS  Google Scholar 

  74. Caton WL, Roby CC, Reid DE, et al. The circulating red cell volume and body hematocrit in normal pregnancy and the puerperium by direct measurement using radioactive red cells. Am J Obstet Gynecol 1951 Jun; 61(6): 1207–17

    PubMed  CAS  Google Scholar 

  75. Honger PE. Intravascular mass of albumin in pre-eclampsia and normal pregnancy. Scand J Clin Lab Invest 1967; 19(3): 283–7

    Article  PubMed  CAS  Google Scholar 

  76. Verel D, Bury JD, Hope A. Blood volume changes in pregnancy and the puerperium. Clin Sci (Lond) 1956 Feb; 15(1): 1–7

    CAS  Google Scholar 

  77. Whittaker PG, Macphail S, Lind T. Serial hematologic changes and pregnancy outcome. Obstet Gynecol 1996 Jul; 88(1): 33–9

    Article  PubMed  CAS  Google Scholar 

  78. Bruinse HW, van den Berg H, Haspels AA. Smoking and its effect on maternal plasma volume during and after normal pregnancy. Eur J Obstet Gynecol Reproduct Biol 1985 Oct; 20(4): 215–9

    Article  CAS  Google Scholar 

  79. Cope I. Plasma and blood volume changes in late and prolonged pregnancy. J Obstet Gynaecol Br Empire 1958 Dec; 65(6): 877–94

    Article  CAS  Google Scholar 

  80. Hytten FE, Paintin DB. Increase in plasma volume during normal pregnancy. J Obstet Gynaecol Br Emp 1963 Jun; 70: 402–7

    Article  PubMed  CAS  Google Scholar 

  81. Pirani BB, Campbell DM, MacGillivray I. Plasma volume in normal first pregnancy. J Obstet Gynaecol Br Commonw 1973 Oct; 80(10): 884–7

    Article  PubMed  CAS  Google Scholar 

  82. Silver HM, Seebeck M, Carlson R. Comparison of total blood volume in normal, preeclamptic, and nonproteinuric gestational hypertensive pregnancy by simultaneous measurement of red blood cell and plasma volumes. Am J Obstet Gynecol 1998 Jul; 179(1): 87–93

    Article  PubMed  CAS  Google Scholar 

  83. Robson SC, Mutch E, Boys RJ, et al. Apparent liver blood flow during pregnancy: a serial study using indocyanine green clearance. Br J Obstet Gynaecol 1990 Aug; 97(8): 720–4

    Article  PubMed  CAS  Google Scholar 

  84. Darby WJ, Mc GW, Martin MP, et al. The Vanderbilt cooperative study of maternal and infant nutrition. IV: dietary, laboratory and physical findings in 2,129 delivered pregnancies. J Nutr 1953 Dec 10; 51(4): 565–97

    PubMed  CAS  Google Scholar 

  85. Lundstrom P. Studies on erythroid elements and serum iron in normal pregnancy. Acta Soc Med Ups 1950 Jan; 55(1/2): 1–83

    PubMed  CAS  Google Scholar 

  86. Pond SM, Kreek MJ, Tong TG, et al. Altered methadone pharmacokinetics in methadone-maintained pregnant women. J Pharmacol Exp Ther 1985 Apr; 233(1): 1–6

    PubMed  CAS  Google Scholar 

  87. Sala C, Campise M, Ambroso G, et al. Atrial natriuretic peptide and hemodynamic changes during normal human pregnancy. Hypertension 1995 Apr; 25(4 Pt 1): 631–6

    Article  PubMed  CAS  Google Scholar 

  88. Duvekot JJ, Cheriex EC, Pieters FA, et al. Early pregnancy changes in hemodynamics and volume homeostasis are consecutive adjustments triggered by a primary fall in systemic vascular tone. Am J Obstet Gynecol 1993 Dec; 169(6): 1382–92

    Article  PubMed  CAS  Google Scholar 

  89. Haram K, Augensen K, Elsayed S. Serum protein pattern in normal pregnancy with special reference to acute-phase reactants. Br J Obstet Gynaecol 1983 Feb; 90(2): 139–45

    Article  PubMed  CAS  Google Scholar 

  90. Connelly TJ, Ruo TI, Frederiksen MC, et al. Characterization of theophylline binding to serum proteins in pregnant and nonpregnant women. Clin Pharmacol Ther 1990 Jan; 47(1): 68–72

    Article  PubMed  CAS  Google Scholar 

  91. Mendenhall HW. Serum protein concentrations in pregnancy. I: concentrations in maternal serum. Am J Obstet Gynecol 1970 Feb 1; 106(3): 388–99

    PubMed  CAS  Google Scholar 

  92. Tsen LC, Tarshis J, Denson DD, et al. Measurements of maternal protein binding of bupivacaine throughout pregnancy. Anesth Analg 1999 Oct; 89(4): 965–8

    PubMed  CAS  Google Scholar 

  93. Chu CY, Singla VP, Wang HP, et al. Plasma alpha 1-acid glycoprotein levels in pregnancy. Clinica Chimica Acta 1981 May 5; 112(2): 235–40

    Article  CAS  Google Scholar 

  94. Krauer B, Dayer P, Anner R. Changes in serum albumin and alpha 1-acid glycoprotein concentrations during pregnancy: an analysis of fetal-maternal pairs. Br J Obstet Gynaecol 1984 Sep; 91(9): 875–81

    Article  PubMed  CAS  Google Scholar 

  95. Tsen LC, Arthur GR, Datta S, et al. Estrogen-induced changes in protein binding of bupivacaine during in vitro fertilization. Anesthesiology 1997 Oct; 87(4): 879–83

    Article  PubMed  CAS  Google Scholar 

  96. Wang HP, Chu CY. A solid-phase enzyme-linked immunosorbent assay for the quantitation of human plasma alpha 1-acid glycoprotein. Clin Chem 1979 Apr; 25(4): 546–9

    PubMed  CAS  Google Scholar 

  97. Reboud P, Groulade J, Groslambert P, et al. The influence of normal pregnancy and the postpartum state on plasma proteins and lipids. Am J Obstet Gynecol 1963 Jul 15; 86: 820–8

    PubMed  CAS  Google Scholar 

  98. Desoye G, Schweditsch MO, Pfeiffer KP, et al. Correlation of hormones with lipid and lipoprotein levels during normal pregnancy and postpartum. J Clin Endocrinol Metab 1987 Apr; 64(4): 704–12

    Article  PubMed  CAS  Google Scholar 

  99. Alvarez JJ, Montelongo A, Iglesias A, et al. Longitudinal study on lipoprotein profile, high density lipoprotein subclass, and postheparin lipases during gestation in women. J Lipid Res 1996 Feb; 37(2): 299–308

    PubMed  CAS  Google Scholar 

  100. Butler CL, Williams MA, Sorensen TK, et al. Relation between maternal recreational physical activity and plasma lipids in early pregnancy. Am J Epidemiol 2004 Aug 15; 160(4): 350–9

    Article  PubMed  Google Scholar 

  101. Lippi G, Albiero A, Montagnana M, et al. Lipid and lipoprotein profile in physiological pregnancy. Clin Lab 2007; 53(3–4): 173–7

    PubMed  CAS  Google Scholar 

  102. Tracy TS, Venkataramanan R, Glover DD, et al. Temporal changes in drug metabolism (CYP1A2, CYP2D6 and CYP3A activity) during pregnancy. Am J Obstet Gynecol 2005 Feb; 192(2): 633–9

    Article  PubMed  CAS  Google Scholar 

  103. Dunlop W. Serial changes in renal haemodynamics during normal human pregnancy. Br J Obstet Gynaecol 1981 Jan; 88(1): 1–9

    Article  PubMed  CAS  Google Scholar 

  104. Assali NS, Dignam WJ, Dasgupta K. Renal function in human pregnancy: II. Effects of venous pooling on renal hemodynamics and water, electrolyte, and aldosterone excretion during gestation. J Lab Clin Med 1959 Sep; 54: 394–408

    PubMed  CAS  Google Scholar 

  105. Davison JM, Hytten FE. Glomerular filtration during and after pregnancy. J Obstet Gynaecol Br Commonw 1974 Aug; 81(8): 588–95

    Article  PubMed  CAS  Google Scholar 

  106. Irons DW, Baylis PH, Davison JM. Effect of atrial natriuretic peptide on renal hemodynamics and sodium excretion during human pregnancy. Am J Physiol 1996 Jul; 271(1 Pt 2): F239–42

    PubMed  CAS  Google Scholar 

  107. Lafayette RA, Druzin M, Sibley R, et al. Nature of glomerular dysfunction in pre-eclampsia. Kidney Int 1998 Oct; 54(4): 1240–9

    Article  PubMed  CAS  Google Scholar 

  108. Moran P, Baylis PH, Lindheimer MD, et al. Glomerular ultrafiltration in normal and preeclamptic pregnancy. J Am Soc Nephrol 2003 Mar; 14(3): 648–52

    Article  PubMed  Google Scholar 

  109. Sims EA, Krantz KE. Serial studies of renal function during pregnancy and the puerperium in normal women. J Clin Invest 1958 Dec; 37(12): 1764–74

    Article  PubMed  CAS  Google Scholar 

  110. Spaanderman M, Ekhart T, van Eyck J, et al. Preeclampsia and maladaptation to pregnancy: a role for atrial natriuretic peptide? Kidney Int 2001 Oct; 60(4): 1397–406

    Article  PubMed  CAS  Google Scholar 

  111. Sturgiss SN, Wilkinson R, Davison JM. Renal reserve during human pregnancy. Am J Physiol 1996 Jul; 271(1 Pt 2): F16–20

    PubMed  CAS  Google Scholar 

  112. Andrew MA, Easterling TR, Carr DB, et al. Amoxicillin pharmacokinetics in pregnant women: modeling and simulations of dosage strategies. Clin Pharmacol Ther 2007 Apr; 81(4): 547–56

    Article  PubMed  CAS  Google Scholar 

  113. Davison JM, Dunlop W, Ezimokhai M. 24-Hour creatinine clearance during the third trimester of normal pregnancy. Br J Obstet Gynaecol 1980 Feb; 87(2): 106–9

    Article  PubMed  CAS  Google Scholar 

  114. Davison JM, Noble MC. Serial changes in 24 hour creatinine clearance during normal menstrual cycles and the first trimester of pregnancy. Br J Obstet Gynaecol 1981 Jan; 88(1): 10–7

    Article  PubMed  CAS  Google Scholar 

  115. Vural P, Akgul C, Canbaz M. Urinary PGE2 and PGF2alpha levels and renal functions in preeclampsia. Gynecol Obstet Invest 1998; 45(4): 237–41

    Article  PubMed  CAS  Google Scholar 

  116. De Alvarez RR. Renal glomerulotubular mechanisms during normal pregnancy. I: glomerular filtration rate, renal plasma flow, and creatinine clearance. Am J Obstet Gynecol 1958 May; 75(5): 931–44

    Google Scholar 

  117. Nevo O, Soustiel JF, Thaler I. Maternal cerebral blood flow during normal pregnancy: a cross-sectional study. Am J Obstet Gynecol 2010 Nov; 203(5): 475e1–6

    Article  Google Scholar 

  118. Hytten FE, Cheyne GA. The size and composition of the human pregnant uterus. J Obstet Gynaecol Br Commonw 1969 May; 76(5): 400–3

    Article  PubMed  CAS  Google Scholar 

  119. Woessner JF, Brewer TH. Formation and breakdown of collagen and elastin in the human uterus during pregnancy and post-partum involution. Biochemical J 1963 Oct; 89: 75–82

    CAS  Google Scholar 

  120. Morrione TG, Seifter S. Alteration in the collagen content of the human uterus during pregnancy and post partum involution. J Exp Med 1962 Feb 1; 115: 357–65

    Article  PubMed  CAS  Google Scholar 

  121. Flo K, Wilsgaard T, Vartun A, et al. 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. BJOG 2010 Jun; 117(7): 837–44

    Article  PubMed  CAS  Google Scholar 

  122. Thaler I, Manor D, Itskovitz J, et al. Changes in uterine blood flow during human pregnancy. Am J Obstet Gynecol 1990 Jan; 162(1): 121–5

    Article  PubMed  CAS  Google Scholar 

  123. Bernstein IM, Ziegler WF, Leavitt T, et al. Uterine artery hemodynamic adaptations through the menstrual cycle into early pregnancy. Obstet Gynecol 2002 Apr; 99(4): 620–4

    Article  PubMed  Google Scholar 

  124. Dickey RP, Hower JF. Ultrasonographic features of uterine blood flow during the first 16 weeks of pregnancy. Human Reprod 1995 Sep; 10(9): 2448–52

    CAS  Google Scholar 

  125. Jeffreys RM, Stepanchak W, Lopez B, et al. Uterine blood flow during supine rest and exercise after 28 weeks of gestation. BJOG 2006 Nov; 113(11): 1239–47

    Article  PubMed  CAS  Google Scholar 

  126. Konje JC, Howarth ES, Kaufmann P, et al. Longitudinal quantification of uterine artery blood volume flow changes during gestation in pregnancies complicated by intrauterine growth restriction. BJOG 2003 Mar; 110(3): 301–5

    Article  PubMed  Google Scholar 

  127. Konje JC, Kaufmann P, Bell SC, et al. A longitudinal study of quantitative uterine blood flow with the use of color power angiography in appropriate for gestational age pregnancies. Am J Obstet Gynecol 2001 Sep; 185(3): 608–13

    Article  PubMed  CAS  Google Scholar 

  128. Metcalfe J, Romney SL, Ramsey LH, et al. Estimation of uterine blood flow in normal human pregnancy at term. J Clin Invest 1955 Nov; 34(11): 1632–8

    Article  PubMed  CAS  Google Scholar 

  129. Palmer SK, Zamudio S, Coffin C, et al. Quantitative estimation of human uterine artery blood flow and pelvic blood flow redistribution in pregnancy. Obstet Gynecol 1992 Dec; 80(6): 1000–6

    PubMed  CAS  Google Scholar 

  130. Rigano S, Ferrazzi E, Boito S, et al. Blood flow volume of uterine arteries in human pregnancies determined using 3D and bi-dimensional imaging, angio-Doppler, and fluid-dynamic modeling. Placenta 2010 Jan; 31(1): 37–43

    Article  PubMed  CAS  Google Scholar 

  131. Wilson MJ, Lopez M, Vargas M, et al. Greater uterine artery blood flow during pregnancy in multigenerational (Andean) than shorter-term (European) high-altitude residents. Am J Physiol 2007 Sep; 293(3): R1313–24

    CAS  Google Scholar 

  132. Cox DB, Kent JC, Casey TM, et al. Breast growth and the urinary excretion of lactose during human pregnancy and early lactation: endocrine relationships. Exp Physiol 1999 Mar; 84(2): 421–34

    Article  PubMed  CAS  Google Scholar 

  133. Hytten FE. Clinical and chemical studies in human lactation. VI: the functional capacity of the breast. Br Med J 1954 Apr 17; 1(4867): 912–5

    Article  PubMed  CAS  Google Scholar 

  134. Eder M, Schneider A, Feussner H, et al. Breast volume assessment based on 3D surface geometry: verification of the method using MR imaging [in German]. Biomed Tech (Berl) 2008 Jun; 53(3): 112–21

    Article  Google Scholar 

  135. Kovacs L, Eder M, Hollweck R, et al. New aspects of breast volume measurement using 3-dimensional surface imaging. Ann Plast Surg 2006 Dec; 57(6): 602–10

    Article  PubMed  CAS  Google Scholar 

  136. Thoresen M, Wesche J. Doppler measurements of changes in human mammary and uterine blood flow during pregnancy and lactation. Acta Obstet Gynecol Scand 1988; 67(8): 741–5

    Article  PubMed  CAS  Google Scholar 

  137. Hussain Z, Roberts N, Whitehouse GH, et al. Estimation of breast volume and its variation during the menstrual cycle using MRI and stereology. Br J Radiol 1999 Mar; 72(855): 236–45

    PubMed  CAS  Google Scholar 

  138. Kovacs L, Eder M, Hollweck R, et al. Comparison between breast volume measurement using 3D surface imaging and classical techniques. Breast 2007 Apr; 16(2): 137–45

    Article  PubMed  Google Scholar 

  139. Arslan AA, Zeleniuch-Jacquotte A, Lukanova A, et al. Effects of parity on pregnancy hormonal profiles across ethnic groups with a diverse incidence of breast cancer. Cancer Epidemiol Biomarkers Prev 2006 Nov; 15(11): 2123–30

    Article  PubMed  CAS  Google Scholar 

  140. Dickey RP, Hower JF. Relationship of estradiol and progesterone levels to uterine blood flow during early pregnancy. Early Pregnancy 1996 Jun; 2(2): 113–20

    PubMed  CAS  Google Scholar 

  141. Potischman N, Troisi R, Thadhani R, et al. Pregnancy hormone concentrations across ethnic groups: implications for later cancer risk. Cancer Epidemiol Biomarkers Prev 2005 Jun; 14(6): 1514–20

    Article  PubMed  CAS  Google Scholar 

  142. Risberg A, Olsson K, Lyrenas S, et al. Plasma vasopressin, oxytocin, estradiol, and progesterone related to water and sodium excretion in normal pregnancy and gestational hypertension. Acta Obstet Gynecol Scand 2009; 88(6): 639–46

    Article  PubMed  CAS  Google Scholar 

  143. Tamimi R, Lagiou P, Vatten LJ, et al. Pregnancy hormones, pre-eclampsia, and implications for breast cancer risk in the offspring. Cancer Epidemiol Biomarkers Prev 2003 Jul; 12(7): 647–50

    PubMed  CAS  Google Scholar 

  144. Tulchinsky D, Korenman SG. The plasma estradiol as an index of fetoplacental function. J Clin Invest 1971 Jul; 50(7): 1490–7

    Article  PubMed  CAS  Google Scholar 

  145. Wald A, Van Thiel DH, Hoechstetter L, et al. Effect of pregnancy on gastrointestinal transit. Dig Dis Sci 1982 Nov; 27(11): 1015–8

    Article  PubMed  CAS  Google Scholar 

  146. Fu Q, VanGundy TB, Shibata S, et al. Menstrual cycle affects renal-adrenal and hemodynamic responses during prolonged standing in the postural orthostatic tachycardia syndrome. Hypertension 2010 Jul; 56(1): 82–90

    Article  PubMed  CAS  Google Scholar 

  147. Kern Jr F, Everson GT, DeMark B, et al. Biliary lipids, bile acids, and gallbladder function in the human female: effects of pregnancy and the ovulatory cycle. J Clin Invest 1981 Nov; 68(5): 1229–42

    Article  PubMed  CAS  Google Scholar 

  148. Winkel P, Gaede P, Lyngbye J. Method for monitoring plasma progesterone concentrations in pregnancy. Clin Chem 1976 Apr; 22(4): 422–8

    PubMed  CAS  Google Scholar 

  149. Jones TB, Price RR, Gibbs SJ. Volumetric determination of placental and uterine growth relationships from B-mode ultrasound by serial area-volume determinations. Invest Radiol 1981 Mar–Apr; 16(2): 101–6

    Article  PubMed  CAS  Google Scholar 

  150. Geirsson RT, Ogston SA, Patel NB, et al. Growth of total intrauterine, intra-amniotic and placental volume in normal singleton pregnancy measured by ultrasound. Br J Obstet Gynaecol 1985 Jan; 92(1): 46–53

    Article  PubMed  CAS  Google Scholar 

  151. Falcon O, Wegrzyn P, Faro C, et al. Gestational sac volume measured by three-dimensional ultrasound at 11 to 13+6 weeks of gestation: relation to chromosomal defects. Ultrasound Obstet Gynecol 2005 Jun; 25(6): 546–50

    Article  PubMed  CAS  Google Scholar 

  152. Lee W, Deter RL, McNie B, et al. Quantitative and morphological assessment of early gestational sacs using three-dimensional ultrasonography. Ultrasound Obstet Gynecol 2006 Sep; 28(3): 255–60

    Article  PubMed  CAS  Google Scholar 

  153. Muller T, Sutterlin M, Pohls U, et al. Transvaginal volumetry of first trimester gestational sac: a comparison of conventional with three-dimensional ultrasound. J Perinat Med 2000; 28(3): 214–20

    Article  PubMed  CAS  Google Scholar 

  154. Steiner H, Gregg AR, Bogner G, et al. First trimester three-dimensional ultrasound volumetry of the gestational sac. Arch Gynecol Obstet 1994; 255(4): 165–70

    Article  PubMed  CAS  Google Scholar 

  155. Jirasek JE, Uher J, Uhrova M. Water and nitrogen content of the body of young human embryos. Am J Obstet Gynecol 1966 Nov 15; 96(6): 868–71

    PubMed  CAS  Google Scholar 

  156. Thomson AM, Billewicz WZ, Hytten FE. The weight of the placenta in relation to birthweight. J Obstet Gynaecol Br Commonw 1969 Oct; 76(10): 865–72

    Article  PubMed  CAS  Google Scholar 

  157. Bonellie S, Chalmers J, Gray R, et al. Centile charts for birthweight for gestational age for Scottish singleton births. BMC Pregnancy Childbirth 2008; 8: 5

    Article  PubMed  Google Scholar 

  158. Abramovich DR. The volume of amniotic fluid in early pregnancy. J Obstet Gynaecol Br Commonw 1968 Jul; 75(7): 728–31

    Article  PubMed  CAS  Google Scholar 

  159. Lind T, Kendall A, Hytten FE. The role of the fetus in the formation of amniotic fluid. J Obstet Gynaecol Br Commonw 1972 Apr; 79(4): 289–98

    Article  PubMed  CAS  Google Scholar 

  160. Smith DL. Amniotic fluid volume. A measurement of the amniotic fluid present in 72 pregnancies during the first half of pregnancy. Am J Obstet Gynecol 1971 May 15; 110(2): 166–72

    PubMed  CAS  Google Scholar 

  161. Clapp JF, Rizk KH, Appleby-Wineberg SK, et al. Second-trimester placental volumes predict birth weight at term. J Soc Gynecol Invest 1995 Jan–Feb; 2(1): 19–22

    Article  Google Scholar 

  162. Hafner E, Schuchter K, van Leeuwen M, et al. Three-dimensional sonographic volumetry of the placenta and the fetus between weeks 15 and 17 of gestation. Ultrasound Obstet Gynecol 2001 Aug; 18(2): 116–20

    Article  PubMed  CAS  Google Scholar 

  163. Hertig AT, Rock J, Adams EC. A description of 34 human ova within the first 17 days of development. Am J Anat 1956 May; 98(3): 435–93

    Article  PubMed  CAS  Google Scholar 

  164. Jackson CM. On the prenatal growth of the human body and the relative growth of the various organs and parts. Am J Anat 1909; 9(1): 119–65

    Article  Google Scholar 

  165. McKeown T, Record RG. The influence of placental size on foetal growth according to sex and order of birth. J Endocrinol 1953 Nov; 10(1): 73–81

    Article  PubMed  CAS  Google Scholar 

  166. Molteni RA, Stys SJ, Battaglia FC. Relationship of fetal and placental weight in human beings: fetal/placental weight ratios at various gestational ages and birth weight distributions. J Reproduct Med 1978 Nov; 21(5): 327–34

    CAS  Google Scholar 

  167. Osei EK, Faulkner K. Fetal position and size data for dose estimation. Br J Radiol 1999 Apr; 72(856): 363–70

    PubMed  CAS  Google Scholar 

  168. Verburg BO, Jaddoe VW, Wladimiroff JW, et al. Fetal hemodynamic adaptive changes related to intrauterine growth: the Generation R Study. Circulation 2008 Feb 5; 117(5): 649–59

    Article  PubMed  Google Scholar 

  169. Mayhew TM, Sorensen FB, Klebe JG, et al. The effects of mode of delivery and sex of newborn on placental morphology in control and diabetic pregnancies. J Anat 1993 Dec; 183(Pt 3): 545–52

    PubMed  Google Scholar 

  170. Wilcox M, Gardosi J, Mongelli M, et al. Birth weight from pregnancies dated by ultrasonography in a multicultural British population. BMJ 1993 Sep 4; 307(6904): 588–91

    Article  PubMed  CAS  Google Scholar 

  171. Wolf H, Oosting H, Treffers PE. Placental volume measurement by ultrasonography: evaluation of the method. Am J Obstet Gynecol 1987 May; 156(5): 1191–4

    PubMed  CAS  Google Scholar 

  172. Hellman LM, Kobayashi M, Tolles WE, et al. Ultrasonic studies on the volumetric growth of the human placenta. Am J Obstet Gynecol 1970 Nov 1; 108(5): 740–50

    PubMed  CAS  Google Scholar 

  173. Bozkurt N, Basgul Yigiter A, Gokaslan H, et al. Correlations of fetal-maternal outcomes and first trimester 3-D placental volume/3-D power Doppler calculations. Clin Exp Obstet Gynecol 2010; 37(1): 26–8

    PubMed  CAS  Google Scholar 

  174. Bujold E, Effendi M, Girard M, et al. Reproducibility of first trimester three-dimensional placental measurements in the evaluation of early placental insufficiency. J Obstet Gynaecol Can 2009 Dec; 31(12): 1144–8

    PubMed  Google Scholar 

  175. Howe D, Wheeler T, Perring S. Measurement of placental volume with real-time ultrasound in mid-pregnancy. J Clin Ultrasound 1994 Feb; 22(2): 77–83

    Article  PubMed  CAS  Google Scholar 

  176. Pardi G, Cetin I. Human fetal growth and organ development: 50 years of discoveries. Am J Obstet Gynecol 2006 Apr; 194(4): 1088–99

    Article  PubMed  Google Scholar 

  177. Perry IJ, Beevers DG, Whincup PH, et al. Predictors of ratio of placental weight to fetal weight in multiethnic community. BMJ 1995 Feb 18; 310(6977): 436–9

    Article  PubMed  CAS  Google Scholar 

  178. Wegrzyn P, Faro C, Falcon O, et al. Placental volume measured by three-dimensional ultrasound at 11 to 13+6 weeks of gestation: relation to chromosomal defects. Ultrasound Obstet Gynecol 2005 Jul; 26(1): 28–32

    Article  PubMed  CAS  Google Scholar 

  179. Wolf H, Oosting H, Treffers PE. Second-trimester placental volume measurement by ultrasound: prediction of fetal outcome. Am J Obstet Gynecol 1989 Jan; 160(1): 121–6

    Article  PubMed  CAS  Google Scholar 

  180. Rhodes P. The volume of liquor amnii in early pregnancy. J Obstet Gynaecol Br Commonw 1966 Feb; 73(1): 23–6

    Article  PubMed  CAS  Google Scholar 

  181. Fuchs F. Volume of amniotic fluid at various stages of pregnancy. Clin Obstet Gynecol 1966 Jun; 9(2): 449–60

    Article  PubMed  CAS  Google Scholar 

  182. Charles D, Jacoby HE, Burgess F. Amniotic fluid volumes in the second half of pregnancy. Am J Obstet Gynecol 1965 Dec 1; 93(7): 1042–7

    PubMed  CAS  Google Scholar 

  183. Elliott PM, Inman WH. Volume of liquor amnii in normal and abnormal pregnancy. Lancet 1961 Oct 14; 2(7207): 835–40

    Article  PubMed  CAS  Google Scholar 

  184. Gadd RL. The volume of the liquor amnii. Proc. Royal Soc Med 1966 Nov; 59(11 Part 1): 1131–3

    CAS  Google Scholar 

  185. Gillibrand PN. Changes in amniotic fluid volume with advancing pregnancy. J Obstet Gynaecol Br Commonw 1969 Jun; 76(6): 527–9

    Article  PubMed  CAS  Google Scholar 

  186. Lind T, Hytten FE. Relation of amniotic fluid volume to fetal weight in the first half of pregnancy. Lancet 1970 May 30; 1(7657): 1147–9

    Article  PubMed  CAS  Google Scholar 

  187. Office for National Statistics. Conception statistics, England and Wales, 2008 [online]. Available from URL: http://www.ons.gov.uk [Accessed 2012 Mar 16]

  188. Macfarlane A, Mugford M. Birth counts: statistics of pregnancy and childbirth. 2nd ed. London: The Stationery Office, 2000

    Google Scholar 

  189. Chow YH, Dattani N. Estimating conception statistics using gestational age information from NHS Numbers for Babies data. Health Stat Q 2009 Spring; (41): 21–7

    Article  PubMed  Google Scholar 

  190. Papageorghiou AT, Bakoulas V, Sebire NJ, et al. Intrauterine growth in multiple pregnancies in relation to fetal number, chorionicity and gestational age. Ultrasound Obstet Gynecol 2008 Dec; 32(7): 890–3

    Article  PubMed  CAS  Google Scholar 

  191. Bergsjo P, Denman DW, Hoffman HJ, et al. Duration of human singleton pregnancy: a population-based study. Acta Obstet Gynecol Scand 1990; 69(3): 197–207

    Article  PubMed  CAS  Google Scholar 

  192. NHS Maternity Statistics. Live born singleton taking place in NHS hospitals in England during 2009–2010 [online]. Available from URL: http://www.hesonline.nhs.uk [Accessed 2011 Mar]

  193. Rasmussen K, Yaktine A, editors. Weight gain during pregnancy: reexamining the guidelines. Washington, DC: National Academies Press, 2009

    Google Scholar 

  194. Billewicz WC, Thomson AM. Clinical significance of weight trends during pregnancy. Br Med J 1957 Feb 2; 1(5013): 243–7

    Article  PubMed  CAS  Google Scholar 

  195. Institute of Medicine. Nutrition during pregnancy. Washington, DC: National Academies Press, 1990

    Google Scholar 

  196. Cedergren M. Effects of gestational weight gain and body mass index on obstetric outcome in Sweden. Int J Gynaecol Obstet 2006 Jun; 93(3): 269–74

    Article  PubMed  CAS  Google Scholar 

  197. Nohr EA, Bech BH, Vaeth M, et al. Obesity, gestational weight gain and preterm birth: a study within the Danish National Birth Cohort. Paediatr Perinat Epidemiol 2007 Jan; 21(1): 5–14

    Article  PubMed  Google Scholar 

  198. Schubring C, Englaro P, Siebler T, et al. Longitudinal analysis of maternal serum leptin levels during pregnancy, at birth and up to six weeks after birth: relation to body mass index, skinfolds, sex steroids and umbilical cord blood leptin levels. Hormone Res 1998; 50(5): 276–83

    Article  PubMed  CAS  Google Scholar 

  199. Okereke NC, Huston-Presley L, Amini SB, et al. Longitudinal changes in energy expenditure and body composition in obese women with normal and impaired glucose tolerance. Am J Physiol Endocrinol Metab 2004 Sep; 287(3): E472–9

    Article  PubMed  CAS  Google Scholar 

  200. Lederman SA. Pregnancy. In: Hyeymsfield SB, Lohman TG, Wang Z, et al., editors. Human body composition. 2nd ed. Champaign (IL): Human Kinetics, 2005: 299–312

    Google Scholar 

  201. Lederman SA, Pierson Jr RN, Wang J, et al. Body composition measurements during pregnancy. Basic Life Sci 1993; 60: 193–5

    PubMed  CAS  Google Scholar 

  202. van Raaij JM, Peek ME, Vermaat-Miedema SH, et al. New equations for estimating body fat mass in pregnancy from body density or total body water. Am J Clin Nutr 1988 Jul; 48(1): 24–9

    PubMed  Google Scholar 

  203. Duffus GM, MacGillivray I, Dennis KJ. The relationship between baby weight and changes in maternal weight, total body water, plasma volume, electrolytes and proteins and urinary estriol excretion. J Obstet Gynecol Br Commonw 1971; 78: 97–104

    Article  CAS  Google Scholar 

  204. Stachenfeld NS, Taylor HS. Progesterone increases plasma volume independent of estradiol. J Appl Physiol 2005 Jun; 98(6): 1991–7

    Article  PubMed  CAS  Google Scholar 

  205. Simmons LA, Gillin AG, Jeremy RW. Structural and functional changes in left ventricle during normotensive and preeclamptic pregnancy. Am J Physiol Heart Circ Physiol 2002 Oct; 283(4): H1627–33

    PubMed  CAS  Google Scholar 

  206. Hunter S, Robson SC. Adaptation of the maternal heart in pregnancy. Br Heart J 1992 Dec; 68(6): 540–3

    Article  PubMed  CAS  Google Scholar 

  207. Ueland K, Novy MJ, Peterson EN, et al. Maternal cardiovascular dynamics. IV: the influence of gestational age on the maternal cardiovascular response to posture and exercise. Am J Obstet Gynecol 1969 Jul 15; 104(6): 856–64

    PubMed  CAS  Google Scholar 

  208. Brown MA, Gallery ED. Volume homeostasis in normal pregnancy and pre-eclampsia: physiology and clinical implications. Bailliere’s Clin Obstet Gynaecol 1994 Jun; 8(2): 287–310

    Article  CAS  Google Scholar 

  209. Lee W. Cardiorespiratory alterations during normal pregnancy. Crit Care Clin 1991 Oct; 7(4): 763–75

    PubMed  CAS  Google Scholar 

  210. Katz R, Karliner JS, Resnik R. Effects of a natural volume overload state (pregnancy) on left ventricular performance in normal human subjects. Circulation 1978 Sep; 58(3 Pt 1): 434–41

    Article  PubMed  CAS  Google Scholar 

  211. Mabie WC, DiSessa TG, Crocker LG, et al. A longitudinal study of cardiac output in normal human pregnancy. Am J Obstet Gynecol 1994 Mar; 170(3): 849–56

    Article  PubMed  CAS  Google Scholar 

  212. Desai DK, Moodley J, Naidoo DP. Echocardiographic assessment of cardiovascular hemodynamics in normal pregnancy. Obstet Gynecol 2004 Jul; 104(1): 20–9

    Article  PubMed  Google Scholar 

  213. van Oppen AC, van der Tweel I, Alsbach GP, et al. A longitudinal study of maternal hemodynamics during normal pregnancy. Obstet Gynecol 1996 Jul; 88(1): 40–6

    Article  PubMed  Google Scholar 

  214. Lees MM, Scott DB, Kerr MG, et al. The circulatory effects of recumbent postural change in late pregnancy. Clin Sci 1967 Jun; 32(3): 453–65

    PubMed  CAS  Google Scholar 

  215. Kinsella SM, Lee A, Spencer JA. Maternal and fetal effects of the supine and pelvic tilt positions in late pregnancy. Eur J Obstet Gynecol Reprod Biol 1990 Jul–Aug; 36(1–2): 11–7

    Article  PubMed  CAS  Google Scholar 

  216. Fujitani S, Baldisseri MR. Hemodynamic assessment in a pregnant and peripartum patient. Crit Care Med 2005 Oct; 33 (10 Suppl.): S354–61

    Article  PubMed  Google Scholar 

  217. Faupel-Badger JM, Hsieh CC, Troisi R, et al. Plasma volume expansion in pregnancy: implications for biomarkers in population studies. Cancer Epidemiol Biomarkers Prev 2007 Sep; 16(9): 1720–3

    Article  PubMed  CAS  Google Scholar 

  218. Metcalfe J, Ueland K. Maternal cardiovascular adjustments to pregnancy. Prog Cardiovasc Dis 1974 Jan–Feb; 16(4): 363–74

    Article  PubMed  CAS  Google Scholar 

  219. Chesley LC. Plasma and red cell volumes during pregnancy. Am J Obstet Gynecol 1972 Feb 1; 112(3): 440–50

    PubMed  CAS  Google Scholar 

  220. Jepson JH. Endocrine control of maternal and fetal erythropoiesis. Can Med Assoc J 1968 May 4; 98(18): 844–7

    PubMed  CAS  Google Scholar 

  221. Ervasti M, Kotisaari S, Heinonen S, et al. Elevated serum erythropoietin concentration is associated with coordinated changes in red blood cell and reticulocyte indices of pregnant women at term. Scand J Clin Lab Invest 2008; 68(2): 160–5

    Article  PubMed  CAS  Google Scholar 

  222. Jepson JH, Lowenstein L. Inhibition of the stem-cell action of erythropoietin by estradiol. Proc Soc Exp Biol Med 1966 Nov; 123(2): 457–60

    Article  PubMed  CAS  Google Scholar 

  223. Jepson JH, Lowenstein L. Role of erythropoietin and placental lactogen in the control of erythropoiesis during pregnancy. Can J Physiol Pharmacol 1968 Jul; 46(4): 573–6

    Article  PubMed  CAS  Google Scholar 

  224. Jepson JH, McGarry EE, Lowenstein L. Erythropoietin excretion in a hypopituitary patient: effects of testosterone and vasopressin. Arch Int Med 1968 Sep; 122(3): 265–70

    Article  CAS  Google Scholar 

  225. Mukundan H, Resta TC, Kanagy NL. 17-Beta estradiol independently regulates erythropoietin synthesis and NOS activity during hypoxia. J Cardiovasc Pharmacol 2004 Feb; 43(2): 312–7

    Article  PubMed  CAS  Google Scholar 

  226. Otto SJ, van Houwelingen AC, Badart-Smook A, et al. Changes in the maternal essential fatty acid profile during early pregnancy and the relation of the profile to diet. Am J Clin Nutr 2001 Feb; 73(2): 302–7

    PubMed  CAS  Google Scholar 

  227. Ulmsten U, Sundstrom G. Esophageal manometry in pregnant and non-pregnant women. Am J Obstet Gynecol 1978 Oct 1; 132(3): 260–4

    PubMed  CAS  Google Scholar 

  228. Van Thiel DH, Gavaler JS, Joshi SN, et al. Heartburn of pregnancy. Gastroenterology 1977 Apr; 72(4 Pt 1): 666–8

    PubMed  Google Scholar 

  229. O’Sullivan GM, Bullingham RE. The assessment of gastric acidity and antacid effect in pregnant women by a non-invasive radiotelemetry technique. Br J Obstet Gynaecol 1984 Oct; 91(10): 973–8

    Article  PubMed  Google Scholar 

  230. Dawes M, Chowienczyk PJ. Drugs in pregnancy. Pharmacokinetics in pregnancy. Best Pract Res 2001 Dec; 15(6): 819–26

    Article  CAS  Google Scholar 

  231. Wong CA, Loffredi M, Ganchiff JN, et al. Gastric emptying of water in term pregnancy. Anesthesiology 2002 Jun; 96(6): 1395–400

    Article  PubMed  Google Scholar 

  232. Chiloiro M, Darconza G, Piccioli E, et al. Gastric emptying and orocecal transit time in pregnancy. J Gastroenterol 2001 Aug; 36(8): 538–43

    Article  PubMed  CAS  Google Scholar 

  233. Macfie AG, Magides AD, Richmond MN, et al. Gastric emptying in pregnancy. Br J Anaesth 1991 Jul; 67(1): 54–7

    Article  PubMed  CAS  Google Scholar 

  234. Whitehead EM, Smith M, Dean Y, et al. An evaluation of gastric emptying times in pregnancy and the puerperium. Anaesthesia 1993 Jan; 48(1): 53–7

    Article  PubMed  CAS  Google Scholar 

  235. Braverman DZ, Johnson ML, Kern Jr F. Effects of pregnancy and contraceptive steroids on gallbladder function. N Engl J Med 1980 Feb 14; 302(7): 362–4

    Article  PubMed  CAS  Google Scholar 

  236. Van Bodegraven AA, Bohmer CJ, Manoliu RA, et al. Gallbladder contents and fasting gallbladder volumes during and after pregnancy. Scand J Gastroenterol 1998 Sep; 33(9): 993–7

    Article  PubMed  Google Scholar 

  237. Kapicioglu S, Gurbuz S, Danalioglu A, et al. Measurement of gallbladder volume with ultrasonography in pregnant women. Can J Gastroenterol 2000 May; 14(5): 403–5

    PubMed  CAS  Google Scholar 

  238. Hahm JS, Park JY, Song SC, et al. Gallbladder motility change in late pregnancy and after delivery. Korean J Intern Med 1997 Jan; 12(1): 16–20

    PubMed  CAS  Google Scholar 

  239. Bacq Y, Zarka O, Brechot JF, et al. Liver function tests in normal pregnancy: a prospective study of 103 pregnant women and 103 matched controls. Hepatology 1996 May; 23(5): 1030–4

    Article  PubMed  CAS  Google Scholar 

  240. Jamjute P, Ahmad A, Ghosh T, et al. Liver function test and pregnancy. J Matern Fetal Neonatal Med 2009 Mar; 22(3): 274–83

    Article  PubMed  CAS  Google Scholar 

  241. Knox TA. Evaluation of abnormal liver function in pregnancy. Semin Perinatol 1998 Apr; 22(2): 98–103

    Article  PubMed  CAS  Google Scholar 

  242. Tindall VR. The liver in pregnancy. Clin Obstet Gynaecol 1975; 2(2): 441–62

    Google Scholar 

  243. Munnell EW, Taylor HC. Liver blood flow in pregnancy-hepatic vein catheterization. J Clin Invest 1947 Sep; 26(5): 952–6

    Article  PubMed  CAS  Google Scholar 

  244. Clapp JF, Stepanchak W, Tomaselli J, et al. Portal vein blood flow-effects of pregnancy, gravity, and exercise. Am J Obstet Gynecol 2000 Jul; 183(1): 167–72

    PubMed  Google Scholar 

  245. Roobottom CA, Hunter JD, Weston MJ, et al. Hepatic venous Doppler waveforms: changes in pregnancy. J Clin Ultrasound 1995 Oct; 23(8): 477–82

    Article  PubMed  CAS  Google Scholar 

  246. Gyselaers W, Molenberghs G, Mesens T, et al. Maternal hepatic vein Doppler velocimetry during uncomplicated pregnancy and pre-eclampsia. Ultrasound Med Biol 2009 Aug; 35(8): 1278–83

    Article  PubMed  Google Scholar 

  247. Lui EY, Steinman AH, Cobbold RS, et al. Human factors as a source of error in peak Doppler velocity measurement. J Vasc Surg 2005 Nov; 42(5): 972–9

    Article  PubMed  Google Scholar 

  248. Yzet T, Bouzerar R, Allart JD, et al. Hepatic vascular flow measurements by phase contrast MRI and doppler echography: a comparative and reproducibility study. J Magn Reson Imaging 2010 Mar; 31(3): 579–88

    Article  PubMed  Google Scholar 

  249. Mesens T, Tomsin K, Molenberghs G, et al. Reproducibility and repeatability of maternal venous Doppler flow measurements in renal interlobar and hepatic veins. Ultrasound Obstet Gynecol 2010 Jul; 36(1): 120–1

    Article  PubMed  CAS  Google Scholar 

  250. Hogstedt S, Lindberg B, Rane A. Increased oral clearance of metoprolol in pregnancy. Eur J Clin Pharmacol 1983; 24(2): 217–20

    Article  PubMed  CAS  Google Scholar 

  251. Hogstedt S, Rane A. Plasma concentration-effect relationship of metoprolol during and after pregnancy. Eur J Clin Pharmacol 1993; 44(3): 243–6

    Article  PubMed  CAS  Google Scholar 

  252. Sandstrom B, Lindeberg S, Lundborg P, et al. Disposition of the adrenergic blocker metoprolol in the late pregnant women, the amniotic fluid, the cord blood and the neonate. Clin Exp Hypertension 1983; 2(1): 75–82

    CAS  Google Scholar 

  253. Wadelius M, Darj E, Frenne G, et al. Induction of CYP2D6 in pregnancy. Clin Pharmacol Ther 1997 Oct; 62(4): 400–7

    Article  PubMed  CAS  Google Scholar 

  254. Abduljalil K, Frank D, Gaedigk A, et al. Assessment of activity levels for CYP2D6*1, CYP2D6*2, and CYP2D6*41 genes by population pharmaco-kinetics of dextromethorphan. Clin Pharmacol Ther 2010 Nov; 88(5): 643–51

    Article  PubMed  CAS  Google Scholar 

  255. Jeong H, Choi S, Song JW, et al. Regulation of UDP-glucuronosyltransferase (UGT) 1A1 by progesterone and its impact on labetalol elimination. Xenobiotica 2008 Jan; 38(1): 62–75

    Article  PubMed  CAS  Google Scholar 

  256. Urquhart BL, Tirona RG, Kim RB. Nuclear receptors and the regulation of drug-metabolizing enzymes and drug transporters: implications for inter-individual variability in response to drugs. J Clin Pharmacol 2007 May; 47(5): 566–78

    Article  PubMed  CAS  Google Scholar 

  257. Aldridge A, Bailey J, Neims AH. The disposition of caffeine during and after pregnancy. Semin Perinatol 1981 Oct; 5(4): 310–4

    PubMed  CAS  Google Scholar 

  258. Brazier JL, Ritter J, Berland M, et al. Pharmacokinetics of caffeine during and after pregnancy. Dev Pharmacol Ther 1983; 6(5): 315–22

    PubMed  CAS  Google Scholar 

  259. Knutti R, Rothweiler H, Schlatter C. Effect of pregnancy on the pharmacokinetics of caffeine. Eur J Clin Pharmacol 1981; 21(2): 121–6

    Article  PubMed  CAS  Google Scholar 

  260. Gardner MJ, Schatz M, Cousins L, et al. Longitudinal effects of pregnancy on the pharmacokinetics of theophylline. Eur J Clin Pharmacol 1987; 32(3): 289–95

    Article  PubMed  CAS  Google Scholar 

  261. Dempsey D, Jacob 3rd P, Benowitz NL. Accelerated metabolism of nicotine and cotinine in pregnant smokers. J Pharmacol Exp Ther 2002 May; 301(2): 594–8

    Article  PubMed  CAS  Google Scholar 

  262. Lander CM, Smith MT, Chalk JB, et al. Bioavailability and pharmacokinetics of phenytoin during pregnancy. Eur J Clin Pharmacol 1984; 27(1): 105–10

    PubMed  CAS  Google Scholar 

  263. Dickinson RG, Hooper WD, Wood B, et al. The effect of pregnancy in humans on the pharmacokinetics of stable isotope labelled phenytoin. Br J Clin Pharmacol 1989 Jul; 28(1): 17–27

    Article  PubMed  CAS  Google Scholar 

  264. Hebert MF, Ma X, Naraharisetti SB, et al. Are we optimizing gestational diabetes treatment with glyburide? The pharmacologic basis for better clinical practice. Clin Pharmacol Ther 2009 Jun; 85(6): 607–14

    Article  PubMed  CAS  Google Scholar 

  265. McGready R, Stepniewska K, Seaton E, et al. Pregnancy and use of oral contraceptives reduces the biotransformation of proguanil to cycloguanil. Eur J Clin Pharmacol 2003 Oct; 59(7): 553–7

    Article  PubMed  CAS  Google Scholar 

  266. Wangboonskul J, White NJ, Nosten F, et al. Single dose pharmacokinetics of proguanil and its metabolites in pregnancy. Eur J Clin Pharmacol 1993; 44(3): 247–51

    Article  PubMed  CAS  Google Scholar 

  267. Heikkinen T, Ekblad U, Palo P, et al. Pharmacokinetics of fluoxetine and norfluoxetine in pregnancy and lactation. Clin Pharmacol Ther 2003 Apr; 73(4): 330–7

    Article  PubMed  CAS  Google Scholar 

  268. Heikkinen T, Ekblad U, Kero P, et al. Citalopram in pregnancy and lactation. Clin Pharmacol Ther 2002 Aug; 72(2): 184–91

    Article  PubMed  CAS  Google Scholar 

  269. Buchanan ML, Easterling TR, Carr DB, et al. Clonidine pharmacokinetics in pregnancy. Drug Metab Dispos 2009 Apr; 37(4): 702–5

    Article  PubMed  CAS  Google Scholar 

  270. Kanto J, Sjovall S, Erkkola R, et al. Placental transfer and maternal midazolam kinetics. Clin Pharmacol Ther 1983 Jun; 33(6): 786–91

    Article  PubMed  CAS  Google Scholar 

  271. Prevost RR, Akl SA, Whybrew WD, et al. Oral nifedipine pharmacokinetics in pregnancy-induced hypertension. Pharmacotherapy 1992; 12(3): 174–7

    PubMed  CAS  Google Scholar 

  272. Jarvis MA, Wu-Pong S, Kniseley JS, et al. Alterations in methadone metabolism during late pregnancy. J Addict Dis 1999; 18(4): 51–61

    Article  PubMed  CAS  Google Scholar 

  273. Wolff K, Boys A, Rostami-Hodjegan A, et al. Changes to methadone clearance during pregnancy. Eur J Clin Pharmacol 2005 Nov; 61(10): 763–8

    Article  PubMed  CAS  Google Scholar 

  274. Hardman J, Endres L, Fischer P, et al. Pharmacokinetics of labetalol in pregnancy. Pharmacotherapy 2005; 25(10): 1493

    Google Scholar 

  275. Fotopoulou C, Kretz R, Bauer S, et al. Prospectively assessed changes in lamotrigine-concentration in women with epilepsy during pregnancy, lactation and the neonatal period. Epilepsy Res 2009 Jul; 85(1): 60–4

    Article  PubMed  CAS  Google Scholar 

  276. Franco V, Mazzucchelli I, Gatti G, et al. Changes in lamotrigine pharmacokinetics during pregnancy and the puerperium. Ther Drug Monit 2008 Aug; 30(4): 544–7

    PubMed  CAS  Google Scholar 

  277. Tran TA, Leppik IE, Blesi K, et al. Lamotrigine clearance during pregnancy. Neurology 2002 Jul 23; 59(2): 251–5

    Article  PubMed  CAS  Google Scholar 

  278. Rostami-Hodjegan A, Kroemer HK, Tucker GT. In-vivo indices of enzyme activity: the effect of renal impairment on the assessment of CYP2D6 activity. Pharmacogenetics 1999 Jun; 9(3): 277–86

    Article  PubMed  CAS  Google Scholar 

  279. Johnson TN, Tucker GT, Rostami-Hodjegan A. Development of CYP2D6 and CYP3A4 in the first year of life. Clin Pharmacol Ther 2008 May; 83(5): 670–1

    Article  PubMed  CAS  Google Scholar 

  280. Anderson GD, Carr DB. Effect of pregnancy on the pharmacokinetics of antihypertensive drugs. Clin Pharmacokinet 2009; 48(3): 159–68

    Article  PubMed  CAS  Google Scholar 

  281. Anderson GD. Using pharmacokinetics to predict the effects of pregnancy and maternal-infant transfer of drugs during lactation. Expert Opin Drug Metab Toxicol 2006 Dec; 2(6): 947–60

    Article  PubMed  CAS  Google Scholar 

  282. Lind AB, Wadelius M, Darj E, et al. Gene expression of cytochrome P450 1B1 and 2D6 in leukocytes in human pregnancy. Pharmacol Toxicol 2003 Jun; 92(6): 295–9

    Article  PubMed  CAS  Google Scholar 

  283. Christensen T, Klebe JG, Bertelsen V, et al. Changes in renal volume during normal pregnancy. Acta Obstet Gynecol Scand 1989; 68(6): 541–3

    PubMed  CAS  Google Scholar 

  284. Bailey RR, Rolleston GL. Kidney length and ureteric dilatation in the puerperium. J Obstet Gynaecol Br Commonw 1971 Jan; 78(1): 55–61

    Article  PubMed  CAS  Google Scholar 

  285. Davison JM. The effect of pregnancy on kidney function in renal allograft recipients. Kidney Int 1985 Jan; 27(1): 74–9

    Article  PubMed  CAS  Google Scholar 

  286. Conrad KP. Emerging role of relaxin in the maternal adaptations to normal pregnancy: implications for preeclampsia. Semin Nephrol 2011 Jan; 31(1): 15–32

    Article  PubMed  CAS  Google Scholar 

  287. Fried AM, Woodring JH, Thompson DJ. Hydronephrosis of pregnancy: a prospective sequential study of the course of dilatation. J Ultrasound Med 1983 Jun; 2(6): 255–9

    PubMed  CAS  Google Scholar 

  288. Grenier N, Pariente JL, Trillaud H, et al. Dilatation of the collecting system during pregnancy: physiologic vs obstructive dilatation. Eur Radiol 2000; 10(2): 271–9

    Article  PubMed  CAS  Google Scholar 

  289. Hebert MF, Carr DB, Anderson GD, et al. Pharmacokinetics and pharmacodynamics of atenolol during pregnancy and postpartum. J Clin Pharmacol 2005 Jan; 45(1): 25–33

    Article  PubMed  CAS  Google Scholar 

  290. Oatridge A, Holdcroft A, Saeed N, et al. Change in brain size during and after pregnancy: study in healthy women and women with preeclampsia. Am J Neuroradiol 2002 Jan; 23(1): 19–26

    PubMed  Google Scholar 

  291. McCall M. Cerebral blood flow and metabolism in toxemias of pregnancy. Surg Gynecol Obstet 1949 Dec; 89(6): 715–21, illust

    PubMed  CAS  Google Scholar 

  292. Benacerraf BR, Shipp TD, Lyons JG, et al. Width of the normal uterine cavity in premenopausal women and effect of parity. Obstet Gynecol 2010 Aug; 116(2 Pt 1): 305–10

    Article  PubMed  Google Scholar 

  293. ICPR. International Commission on Radiological Protection. Report of the Task Group on Reference Man. Oxford: Pergammon Press, 1975. ICRP publication no. 23

    Google Scholar 

  294. Milligan D, Drife JO, Short RV. Changes in breast volume during normal menstrual cycle and after oral contraceptives. Br Med J 1975 Nov 29; 4(5995): 494–6

    Article  PubMed  CAS  Google Scholar 

  295. Hegenbart L, Na YH, Zhang JY, et al. A Monte Carlo study of lung counting efficiency for female workers of different breast sizes using deformable phantoms. Phys Med Biol 2008 Oct 7; 53(19): 5527–38

    Article  PubMed  CAS  Google Scholar 

  296. Loughry CW, Sheffer DB, Price TE, et al. Breast volume measurement of 598 women using biostereometric analysis. Ann Plast Surg 1989 May; 22(5): 380–5

    Article  PubMed  CAS  Google Scholar 

  297. Malini S, Smith EO, Goldzieher JW. Measurement of breast volume by ultrasound during normal menstrual cycles and with oral contraceptive use. Obstet Gynecol 1985 Oct; 66(4): 538–41

    PubMed  CAS  Google Scholar 

  298. Pickles VR. Blood-flow estimations as indices of mammary activity. J Obstet Gynaecol Br Emp 1953 Jun; 60(3): 301–11

    Article  PubMed  CAS  Google Scholar 

  299. Burd LI, Dorin M, Philipose V, et al. The relationship of mammary temperature to parturition in human subjects. Am J Obstet Gynecol 1977 Jun 1; 128(3): 272–8

    PubMed  CAS  Google Scholar 

  300. Sambrook M, Bamber JC, Minasian H, et al. Ultrasonic Doppler study of the hormonal response of blood flow in the normal human breast. Ultrasound Med Biol 1987 Mar; 13(3): 121–9

    Article  PubMed  CAS  Google Scholar 

  301. Jensen D, Webb KA, O’Donnell DE. Chemical and mechanical adaptations of the respiratory system at rest and during exercise in human pregnancy. Appl Physiol Nutr Metab 2007 Dec; 32(6): 1239–50

    Article  PubMed  Google Scholar 

  302. Hegewald MJ, Crapo RO. Respiratory physiology in pregnancy. Clin Chest Med 2011 Mar; 32(1): 1–13

    Article  PubMed  Google Scholar 

  303. Elkus R, Popovich Jr J. Respiratory physiology in pregnancy. Clin Chest Med 1992 Dec; 13(4): 555–65

    PubMed  CAS  Google Scholar 

  304. Contreras G, Gutierrez M, Beroiza T, et al. Ventilatory drive and respiratory muscle function in pregnancy. Am Rev Respir Dis 1991 Oct; 144(4): 837–41

    Article  PubMed  CAS  Google Scholar 

  305. McAuliffe F, Kametas N, Costello J, et al. Respiratory function in singleton and twin pregnancy. BJOG 2002 Jul; 109(7): 765–9

    Article  PubMed  Google Scholar 

  306. Gardner MO, Doyle NM. Asthma in pregnancy. Obstet Gynecol Clin North Am 2004 Jun; 31(2): 385–413, vii

    Article  PubMed  Google Scholar 

  307. Spatling L, Fallenstein F, Huch A, et al. The variability of cardiopulmonary adaptation to pregnancy at rest and during exercise. Br J Obstet Gynaecol 1992 Jul; 99 Suppl. 8: 1–40

    PubMed  Google Scholar 

  308. Rees GB, Broughton Pipkin F, Symonds EM, et al. A longitudinal study of respiratory changes in normal human pregnancy with cross-sectional data on subjects with pregnancy-induced hypertension. Am J Obstet Gynecol 1990 Mar; 162(3): 826–30

    Article  PubMed  CAS  Google Scholar 

  309. Knuttgen HG, Emerson Jr K. Physiological response to pregnancy at rest and during exercise. J Appl Physiol 1974 May; 36(5): 549–53

    PubMed  CAS  Google Scholar 

  310. Pernoll ML, Metcalfe J, Kovach PA, et al. Ventilation during rest and exercise in pregnancy and postpartum. Respir Physiol 1975 Dec; 25(3): 295–310

    Article  PubMed  CAS  Google Scholar 

  311. Pernoll ML, Metcalfe J, Schlenker TL, et al. Oxygen consumption at rest and during exercise in pregnancy. Respir Physiol 1975 Dec; 25(3): 285–93

    Article  PubMed  CAS  Google Scholar 

  312. Emerson Jr K, Saxena BN, Poindexter EL. Caloric cost of normal pregnancy. Obstet Gynecol 1972 Dec; 40(6): 786–94

    PubMed  Google Scholar 

  313. De Swiet M. The respiratory system. 2nd ed. Oxford: Blackwell Science Ltd, 1991

    Google Scholar 

  314. Bronstein MN, Mak RP, King JC. Unexpected relationship between fat mass and basal metabolic rate in pregnant women. Br J Nutr 1996 May; 75(5): 659–68

    Article  PubMed  CAS  Google Scholar 

  315. Liu JH. Endocrinology of pregnancy. In: Creasy RK, Resnik R, Iams JD, editors. Maternal-fetal medicine: principles and practice. 5th ed. Philadelphia (PA): Saunders, 2004: 121–34

    Google Scholar 

  316. Holmdahl TH, Johansson ED, Wide L. The site of progesterone production in early pregnancy. Acta Endocrinol 1971 Jun; 67(2): 353–61

    PubMed  CAS  Google Scholar 

  317. Bernstein L, Lipworth L, Ross RK, et al. Correlation of estrogen levels between successive pregnancies. Am J Epidemiol 1995 Sep 15; 142(6): 625–8

    PubMed  CAS  Google Scholar 

  318. Blackburn ST. Fetal, and neonatal physiology: a clinical perspective. 3rd ed. St Louis (MO): Saunders, 2007

    Google Scholar 

  319. Hytten F, Chamberlain G. Clinical physiology in obstetrics. 2nd ed. Oxford: Blackwell Scientific, 1980

    Google Scholar 

  320. Berghout A, Endert E, Ross A, et al. Thyroid function and thyroid size in normal pregnant women living in an iodine replete area. Clin Endocrinol 1994 Sep; 41(3): 375–9

    Article  CAS  Google Scholar 

  321. Fister P, Gaberscek S, Zaletel K, et al. Thyroid volume changes during pregnancy and after delivery in an iodine-sufficient Republic of Slovenia. Eur J Obstet Gynecol Reproduct Biol 2009 Jul; 145(1): 45–8

    Article  Google Scholar 

  322. Vila L, Legaz G, Barrionuevo C, et al. Iodine status and thyroid volume changes during pregnancy: results of a survey in Aran Valley (Catalan Pyrenees). J Endocrinol Invest 2008 Oct; 31(10): 851–5

    PubMed  CAS  Google Scholar 

  323. Antonangeli L, Maccherini D, Cavaliere R, et al. Comparison of two different doses of iodide in the prevention of gestational goiter in marginal iodine deficiency: a longitudinal study. Eur J Endocrinol 2002 Jul; 147(1): 29–34

    Article  PubMed  CAS  Google Scholar 

  324. Kumari R, Jaisankar TJ, Thappa DM. A clinical study of skin changes in pregnancy. Indian J Dermatol Venereol Leprol 2007 Mar–Apr; 73(2): 141

    PubMed  Google Scholar 

  325. Muallem MM, Rubeiz NG. Physiological and biological skin changes in pregnancy. Clinics Dermatol 2006 Mar–Apr; 24(2): 80–3

    Article  Google Scholar 

  326. Wade TR, Wade SL, Jones HE. Skin changes and diseases associated with pregnancy. Obstet Gynecol 1978 Aug; 52(2): 233–42

    PubMed  CAS  Google Scholar 

  327. Ginsburg J, Duncan SL. Peripheral blood flow in normal pregnancy. Cardiovascular Res 1967 Apr; 1(2): 132–7

    Article  CAS  Google Scholar 

  328. Beinder E, Huch A, Huch R. Peripheral skin temperature and micro-circulatory reactivity during pregnancy: a study with thermography. J Perinatal Med 1990; 18(5): 383–90

    Article  CAS  Google Scholar 

  329. Ashton H. Cigarette smoking in pregnancy: differences in peripheral circulation between smokers and non-smokers. Br J Obstet Gynaecol 1975 Nov; 82(11): 868–81

    Article  PubMed  CAS  Google Scholar 

  330. Katz M, Sokal MM. Skin perfusion in pregnancy. Am J Obstet Gynecol 1980 May 1; 137(1): 30–3

    PubMed  CAS  Google Scholar 

  331. de Mul FF, Blaauw J, Aarnoudse JG, et al. Diffusion model for iontophoresis measured by laser-Doppler perfusion flowmetry, applied to normal and preeclamptic pregnancies. J Biomed Optics 2007 Jan–Feb; 12(1): 014032

    Article  Google Scholar 

  332. Pitkin RM. Nutritional support in obstetrics and gynecology. Clin Obstet Gynecol 1976 Sep; 19(3): 489–513

    Article  PubMed  CAS  Google Scholar 

  333. Rodeck CH, Whittle MJ. Fetal medicine: basic science and clinical practice. 2nd ed. Oxford: Churchill Livingstone, 2008

    Google Scholar 

  334. Friis-Hansen B. The body density of newborn infants. Acta Paediatrica 1963 Sep; 52: 513–21

    Article  PubMed  CAS  Google Scholar 

  335. Levine D. Three-dimensional fetal MR imaging: will it fulfill its promise? Radiology 2001 May; 219(2): 313–5

    PubMed  CAS  Google Scholar 

  336. Luecke RH, Wosilait WD, Young JF. Mathematical modeling of human embryonic and fetal growth rates. Growth Dev Aging 1999 Spring-Summer; 63(1–2): 49–59

    PubMed  CAS  Google Scholar 

  337. Wosilait WD, Luecke RH, Young JF. A mathematical analysis of human embryonic and fetal growth data. Growth Dev Aging 1992 Winter; 56(4): 249–57

    PubMed  CAS  Google Scholar 

  338. Wilcox MA, Johnson IR, Maynard PV, et al. The individualised birthweight ratio: a more logical outcome measure of pregnancy than birthweight alone. Br J Obstet Gynaecol 1993 Apr; 100(4): 342–7

    Article  PubMed  CAS  Google Scholar 

  339. Blair EM, Liu Y, de Klerk NH, et al. Optimal fetal growth for the Caucasian singleton and assessment of appropriateness of fetal growth: an analysis of a total population perinatal database. BMC Pediatrics 2005; 5(1): 13

    Article  PubMed  Google Scholar 

  340. Bertino E, Di Battista E, Bossi A, et al. Fetal growth velocity: kinetic, clinical, and biological aspects. Arch Dis Child 1996 Jan; 74(1): F10–5

    Article  CAS  Google Scholar 

  341. Enders AC, Blankenship TN. Comparative placental structure. Adv Drug Deliv Rev 1999 Jun 14; 38(1): 3–15

    Article  PubMed  CAS  Google Scholar 

  342. Jones CJ, Fox H. Ultrastructure of the normal human placenta. Electron Microsc Rev 1991; 4(1): 129–78

    Article  PubMed  CAS  Google Scholar 

  343. Stoz F, Schuhmann RA, Schebesta B. The development of the placental villus during normal pregnancy: morphometric data base. Arch Gynecol Obstet 1988; 244(1): 23–32

    Article  PubMed  CAS  Google Scholar 

  344. Pollex EK, Hutson JR. Genetic polymorphisms in placental transporters: implications for fetal drug exposure to oral antidiabetic agents. Expert Opin Drug Metab Toxicol 2011 Mar; 7(3): 325–39

    Article  PubMed  CAS  Google Scholar 

  345. Prouillac C, Lecoeur S. The role of the placenta in fetal exposure to xenobiotics: importance of membrane transporters and human models for transfer studies. Drug Metab Dispos 2010 Oct; 38(10): 1623–35

    Article  PubMed  CAS  Google Scholar 

  346. Zharikova OL, Fokina VM, Nanovskaya TN, et al. Identification of the major human hepatic and placental enzymes responsible for the biotransformation of glyburide. Biochem Pharmacol 2009 Dec 15; 78(12): 1483–90

    Article  PubMed  CAS  Google Scholar 

  347. Ceckova-Novotna M, Pavek P, Staud F. P-glycoprotein in the placenta: expression, localization, regulation and function. Reproduct Toxicol 2006 Oct; 22(3): 400–10

    Article  CAS  Google Scholar 

  348. Syme MR, Paxton JW, Keelan JA. Drug transfer and metabolism by the human placenta. Clin Pharmacokinet 2004; 43(8): 487–514

    Article  PubMed  CAS  Google Scholar 

  349. Hakkola J, Pelkonen O, Pasanen M, et al. Xenobiotic-metabolizing cytochrome P450 enzymes in the human feto-placental unit: role in intrauterine toxicity. Crit Rev Toxicol 1998 Jan; 28(1): 35–72

    Article  PubMed  CAS  Google Scholar 

  350. Kuhlmann RS, Warsof S. Ultrasound of the placenta. Clin Obstet Gynecol 1996 Sep; 39(3): 519–34

    Article  PubMed  CAS  Google Scholar 

  351. Younoszai MK, Haworth JC. Chemical composition of the placenta in normal preterm, term, and intrauterine growth-retarded infants. Am J Obstet Gynecol 1969 Jan 15; 103(2): 262–4

    PubMed  CAS  Google Scholar 

  352. Younoszai MK, Haworth JC. Placental dimensions and relations in preterm, term, and growth-retarded infants. Am J Obstet Gynecol 1969 Jan 15; 103(2): 265–71

    PubMed  CAS  Google Scholar 

  353. Garrow JS. The relationship of foetal growth to size and composition of the placenta. Proc Royal Soc Med 1970 May; 63(5): 498–500

    CAS  Google Scholar 

  354. Leary SD, Godfrey KM, Greenaway LJ, et al. Contribution of the umbilical cord and membranes to untrimmed placental weight. Placenta 2003 Feb–Mar; 24(2–3): 276–8

    Article  PubMed  CAS  Google Scholar 

  355. Yao AC, Moinian M, Lind J. Distribution of blood between infant and placenta after birth. Lancet 1969 Oct 25; 2(7626): 871–3

    Article  PubMed  CAS  Google Scholar 

  356. Brace RA. Progress toward understanding the regulation of amniotic fluid volume: water and solute fluxes in and through the fetal membranes. Placenta 1995 Jan; 16(1): 1–18

    Article  PubMed  CAS  Google Scholar 

  357. Wagner G, Fuchs F. The volume of amniotic fluid in the first half of human pregnancy. J Obstet Gynaecol Br Empire 1962 Feb; 69: 131–6

    Article  CAS  Google Scholar 

  358. Touboul C, Boulvain M, Picone O, et al. Normal fetal urine production rate estimated with 3-dimensional ultrasonography using the rotational technique (virtual organ computer-aided analysis). Am J Obstet Gynecol 2008 Jul; 199(1): 57e1–5

    Article  Google Scholar 

  359. Garby L. Studies on transfer of matter across membranes with special reference to the isolated human amniotic membrane and the exchange of amniotic fluid. Acta Physiol Scand 1957; 40(137): 1–84

    CAS  Google Scholar 

  360. Dildy GA, Lira N, Moise Jr KJ, et al. Amniotic fluid volume assessment: comparison of ultrasonographic estimates versus direct measurements with a dye-dilution technique in human pregnancy. Am J Obstet Gynecol 1992 Oct; 167(4 Pt 1): 986–94

    Article  PubMed  Google Scholar 

  361. Gramellini D, Fieni S, Verrotti C, et al. Ultrasound evaluation of amniotic fluid volume: methods and clinical accuracy. Acta Biomed 2004; 75 Suppl. 1: 40–4

    PubMed  Google Scholar 

  362. Lukaski HC. Methods for the assessment of human body composition: traditional and new. Am J Clin Nutr 1987 Oct; 46(4): 537–56

    PubMed  CAS  Google Scholar 

  363. Siri WE. Gross composition of the body. In: Tobias CA, Lawrence JH, editors. Advances in biological and medical physics. New York: Academic, 1956: 239–80

    Google Scholar 

  364. Hopkinson JM, Butte NF, Ellis KJ, et al. Body fat estimation in late pregnancy and early postpartum: comparison of two-, three-, and four-component models. Am J Clin Nutr 1997 Feb; 65(2): 432–8

    PubMed  CAS  Google Scholar 

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Acknowledgements

This project was funded by an FSA (Food Standards Agency) grant (T01065) of the UK Government. We thank Mr James Kay for assistance with collecting the references and preparation of the manuscript. We also would like to thank Mrs Melanie Gee (Information Scientist from Learning and Information Services, Sheffield Hallam University) for her help in developing and running the literature search strategies. The authors have no conflicts of interest that are directly relevant to the content of this study.

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Abduljalil, K., Furness, P., Johnson, T.N. et al. Anatomical, Physiological and Metabolic Changes with Gestational Age during Normal Pregnancy. Clin Pharmacokinet 51, 365–396 (2012). https://doi.org/10.2165/11597440-000000000-00000

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