Clinical Chemistry in Pregnancy


During pregnancy, a woman undergoes a multitude of normal physiochemical changes that are specific to pregnancy and with increasing frequency, challenged with pregnancy‐related conditions. Additionally, there are a number of problems affecting the unborn fetus that, in turn, affect normal maternal biochemistry, endocrinology and physiology. Furthermore, normal biochemical, hormonal and clinically relevant measurements for the nonpregnant state often no longer apply to the pregnant woman. This makes clinical laboratory measurement difficult and normal clinical diagnosis using nonpregnant values potentially dangerous, with inappropriate treatment (when it is not required) and no treatment (when it is required) being offered. Problems within early pregnancy, for example, spontaneous and recurrent miscarriage, thus become very complicated to predict or treat. Therefore, reexamining what clinical chemical tests are available and what is just emerging from the experimental laboratory (and thus becoming available in the standard clinical laboratory), should inform the unwary clinician.

Key Concepts:

  • ‘Normal’ pregnancy biochemical marker (Biomarker) concentrations fluctuate throughout pregnancy.

  • No single maternal biomarker can be used to predict gestational disease.

  • Both the concentrations of urinary, serum, plasma, salivary and amniotic fluid biomarkers and the timing of clinical sampling are critical in disease diagnosis.

  • Many new biomarkers are emerging, which may help aid the prediction/diagnosis of pregnancy‐related conditions.

Keywords: pregnancy; clinical chemistry; human chorionic gonadotrophin; human placental lactogen; oestrogen; progesterone; anandamide; endocannabinoid; PAPP‐A; alpha fetoprotein

Figure 1.

Biomarkers involved in the maintenance of early pregnancy. The diagram shows an implanted embryo (approximately 14 days after conception) and the processes necessary for the maintenance of an early pregnancy together with the important maternal biomarkers used to determine the course of successful and abnormal pregnancy. hPL, human placental lactogen; hCG, human chorionic gonadotrophin; AFP, alpha fetoprotein. Local anandamide concentrations are regulated by fatty acid amide hydrolase (FAAH) activity, which in turn is regulated by progesterone action. All of the indicated biomarkers are measurable in maternal plasma and serum, except FAAH, which can be measured in peripheral blood mononuclear cells. The image is a modification of the superb original figure produced by Norwitz E, Schust DJ and Fisher SJ (2001) Implantation and survival of early pregnancy. New England Journal of Medicine345: 1400–1408. © 2001. Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.



Akolekar R, Syngelaki A, Sarquis R, Zvanca M and Nicolaides KH (2011) Prediction of early, intermediate and late pre‐eclamsia form maternal factors, biophysical and biochemical markers at 11–13 weeks. Prenatal Diagnosis 31: 66–74.

Alfthan H, Haglund C, Dabek J and Stenman U‐H (1992) Concentrations of human chorionic gonadotropin, its b‐subunit and the core fragment of the b‐subunit in serum and urine of men and nonpregnant women. Clinical Chemistry 38: 1981–1987.

Armstrong RA, Reynolds RM, Leask R et al. (2009) Decreased serum levels of kisspeptin in early pregnancy are associated with intra‐uterine growth restriction and pre‐eclampsia. Prenatal Diagnosis 29: 982–985.

Bambang KN, Karasu T, Gebeh A et al. (2010) From fertilisation to implantation in mammalian pregnancy – modulation of early human reproduction by the endocannabinoid system. Pharmaceuticals 3: 2910–2929.

Bayes‐Genis A, Conover CA, Overgaard MT et al. (2001) Pregnancy‐associated plasma protein‐A as a marker of acute coronary syndromes. New England Journal of Medicine 345: 1022–1029.

Beischer NA and Brown JB (1972) Current status of estrogen assays in obstetrics and gynecology. 2. Estrogen assays in late pregnancy. Obstetrics and Gynecologic Surveys 27: 303–343.

Berry E, Aitken DA, Crossley JA, Macri JN and Connor JM (1997) Screening for Down's syndrome: changes in marker levels and detection rates between first and second trimesters. British Journal of Obstetrics and Gynaecology 104: 811–817.

Beta J, Akolekar R, Ventura W, Syngelaki A and Nicolaides KH (2011) Prediction of spontaneous preterm delivery from maternal factors, obstetric history and placental perfusion and function at 11–13 weeks. Prenatal Diagnosis 31: 75–83.

Brizot ML, Hyett JA, McKie AT et al. (1996) Gene expression of human pregnancy‐associated plasma protein‐A in placenta from trisomic pregnancies. Placenta 17: 33–36.

Butler SA, Khanlian SA and Cole LA (2001) Detection of early pregnancy forms of human chorionic gonadotropin by home pregnancy test devices. Clinical Chemistry 47: 2131–2136.

Canick JA and Kellner LH (1999) First trimester screening for aneuploidy: serum biochemical markers. Seminars in Perinatology 5: 359–368.

Cartwright JE and Williams PJ (2012) Altered placental expression of kisspeptin and its receptor in pre‐eclampsia. Journal of Endocrinology 214: 79–85.

Check JH, Vaze MM, Epstein R et al. (1990) 17‐hydroxyprogesterone level as a marker for corpus luteum function in aborters versus nonaborters. International Journal of Fertility 35: 112–115.

Chetty M and Elson J (2007) Biochemistry in the diagnosis and management of abnormal early pregnancy. Clinical Obstetrics and Gynecology 50: 55–66.

Dawood MY (1976) Circulating maternal serum progesterone in high‐risk pregnancies. American Journal of Obstetrics and Gynecology 125: 832–840.

Elson J, Tailor A, Salim R et al. (2005) Expectant management of miscarriage‐prediction of outcome using ultrasound and novel biochemical markers. Human Reproduction 20: 2330–2333.

El‐Talatini MR, Taylor AH, Elson JC et al. (2009b) Localisation and function of the endocannabinoid system in the human ovary. PLoS One 4: e4579.

El‐Talatini MR, Taylor AH and Konje JC (2009a) Fluctuation in anandamide levels from ovulation to early pregnancy in in‐vitro fertilization‐embryo transfer women, and its hormonal regulation. Human Reproduction 24: 1989–1998.

Florio P, Bruni L, De Falco C et al. (2008) Evaluation of endometrial urocortin secretion for prediction of pregnancy after intrauterine insemination. Clinical Chemistry 54: 350–355.

Florio P, Linton EA, Torricelli M et al. (2007) Prediction of preterm delivery based on maternal urocortin. Journal of Clinical Endocrinology and Metabolism 92: 4734–4737.

Florio P, Torricelli M, Galleri L et al. (2005) High fetal urocortin levels at term and preterm labor. Journal of Clinical Endocrinology and Metabolism 90: 5361–5365.

Folkersen J, Grudzinkas JG, Hindersson P, Teisner B and Westergaard JG (1981) Pregnancy‐associated plasma protein A: ciculating levels during normal pregnancy. American Journal of Obstetrics and Gynecology 139: 910–914.

Gall SA and Halbert SP (1972) Antigenic constituents in pregnancy plasma which are undetectable in normal non‐pregnant female or male plasma. International Archives of Allergy and Applied Immunology 42: 503–515.

Goetzl L, Krantz D, Simpson JL et al. (2004) Pregnancy‐associated plasma protein A, free beta‐hCG, nuchal translucency, and risk of pregnancy loss. Obstetrics and Gynecology 104: 30–36.

Grammatopoulos DK and Hillhouse EW (1999) Role of corticotrophin‐releasing hormone in onset of labour. Lancet 354: 1546–1549.

Habayeb OMH, Taylor AH, Evans MD et al. (2004) Plasma levels of the endocannabinoid anandamide in women – a potential role in pregnancy maintenance and labor? Journal of Clinical Endocrinology and Metabolism 89: 5482–5487.

Habayeb OMH, Taylor AH, Finney M, Evans MD and Konje JC (2008) Plasma anandamide concentration and pregnancy outcome in women with threatened miscarriage. Journal of the American Medical Association 299: 1135–1136.

Heine RP, McGregor JA and Dullien VK (1999) Accuracy of salivary estriol testing compared to traditional risk factor assessment in predicting preterm birth. American Journal of Obstetrics and Gynecology 180: S214–S218.

Heine RP, McGregor JA, Goodwin TM et al. (2000) Serial salivary estriol to detect an increased risk of preterm birth. Obstetrics and Gynecology 96: 490–497.

Johanasson SGO, Kjessler B, Sherman MS and Wahlstrom J (1977) Alpha‐fetoprotein (AFP) levels in maternal serum and amniotic fluid in singleton pregnant women in their 10th–25th week post last menstrual period. Acta Obstetrica Gynecologica Scandinavica 69(Suppl.): 20–24.

Kaplan SL, Gurpide E, Sciarra JJ and Grumbach MM (1968) Metabolic clearance rate and production rate of chorionic growth‐hormone‐prolactin in late pregnancy. Journal of Clinical Endocrinology and Metabolism 28: 1450–1460.

Kashanian M, Bahasadri S, Ghasemi A and Bathaee S (2012) Value of serum urocortin concentration in the prediction of preterm birth. Journal of Obstetrics and Gynaecology Research 28 May 2012. doi: 10.1111/j.1447‐0756.2012.01887.x. [Epub ahead of print].

Knight GJ, Palomaki GE, Haddow JE et al. (1993) Pregnancy associated plasma protein A as a marker of Down's syndrome in the second trimester of pregnancy. Prenatal Diagnosis 13: 222–223.

Kowalcyzk TD, Cabaniss ML and Cusmano L (1998) Association of low unconjugated estriol in the second trimester and adverse pregnancy outcome. Obstetrics and Gynecology 91: 396–400.

Lam PMW, Marczylo TH, El‐Talatini M et al. (2008) Ultra performance liquid chromatography tandem mass spectrometry method for the measurement of anandamide in human plasma. Analytical Biochemistry 380: 195–201.

Logie JJ, Denison FC, Riley SC et al. (2012) Evaluation of kisspeptin levels in obese patients as a biomarker for pre‐eclampsia. Clinical Endocrinology 76: 887–893.

Luisi S, Petraglia F, Benedetto C et al. (2000) Serum allopregnalone levels in pregnant women: changes in pregnancy, at delivery, and in hypertensive patients. Journal of Clinical Endocrinology and Metabolism 85: 2429–2433.

Lukes A, Thorp J, Eucker B and Pahel‐Short S (1997) Predictors of positivity for fetal fibronectin in patients with symptoms of preterm labor. American Journal of Obstetrics and Gynecology 176: 639–641.

Maccarrone M, Bisogno T, Valensise H et al. (2002) Low fatty acid amide hydrolase and high anandamide levels are associated with failure to achieve an ongoing pregnancy after IVF and embryo transfer. Molecular Human Reproduction 8: 188–195.

Maccarrone M, Valensise H, Bari M et al. (2000) Relation between decreased anandamide hydrolase concentrations in human lymphocytes and miscarriage. Lancet 355: 1326–1329.

Marjono AB, Brown DA, Horton KE et al. (2003) Macrophage inhibitory cytokine‐1 in gestational tissues and maternal serum in normal and pre‐eclamptic pregnancy. Placenta 24: 100–106.

Merkatz IR, Nitowsky HM, Macri JN and Johnson WE (1984) An association between low maternal serum α‐fetoprotein and fetal chromosomal abnormalities. American Journal of Obstetrics and Gynecology 148: 886–894.

Milunsky A, Alpert E, Neff RK and Frigoletto FD Jr. (1980) Prenatal diagnosis of neural tube defects. IV. Maternal serum α‐fetoprotein screening. Obstetrics and Gynaecology 55: 60–66.

Moore ML (1990) Biochemical markers for preterm labor and birth: what is their role in the care of pregnant women? MCN: Journal of Maternal Child Nursing 24: 80–86.

Morssink LP, Kornman LH, Hallahan TW et al. (1998) Maternal seum levels of free b‐hCG and Papp‐a in the first trimester are associated with fetal growth retardation or preterm delivery. Prenatal Diagnosis 18: 147–152.

Muttukrishna S, Bearfield C, Johns J and Jauniaux E (2004) Inhibin, activin, follistatin, activin receptors and [beta]‐glycan gene expression in the villous tissue of miscarriage patients. Molecular Human Reproduction 10: 793–798.

Nallendran V, Lam PMW, McParland P, Taylor AH and Konje JC (2009) Prediction of preterm labour among asymptomatic high risk patients using plasma anandamide levels. Reproductive Sciences 16: 220A.

Norwitz ER, Robinson JN and Challis JRG (1999) The control of labor. New England Journal of Medicine 341: 660–666.

O'Leary P, Boyne P, Flett P, Beilby J and James I (1991) Longitudinal assessment of changes in reproductive hormones during normal pregnancy. Clinical Chemistry 37: 667–672.

Parker CR Jr., Everett RB, Quirk JG Jr., Whalley PJ and Gant NF (1979) Hormone production during pregnancy in the primigravid patient. I. Plasma levels of progesterone and 5‐α‐pregnane‐3,20‐dione throughout pregnancy of normal women and women who develop pregnancy‐induced hypertension. American Journal of Obstetrics and Gynecology 135: 778–782.

Petraglia F, Florio P, Nappi C and Genazzani AR (1996) Peptide signaling in human placenta and membranes: autocrine, paracrine and endocrine mechanisms. Endocrine Reviews 17: 156–186.

Poikkeus P, Hiilesmaa V and Tiitinen A (2002) Serum HCG 12 days after embryo transfer in predicting pregnancy outcome. Human Reproduction 17: 1901–1905.

Riboni F, Vitulo A, Plebani M et al. (2012) Combination of biochemical markers in predicting pre‐term delivery. Archives of Gynecology and Obstetrics 275: 61–66.

Saruhan Z, Ozekinci M, Simsek M and Mendilcioglu I (2012) Association of first trimester low PAPP‐A levels with adverse pregnancy outcomes. Clinical and Experimental Obstetrics and Gynecology 39: 225–228.

Second Report of the UK Collaborative Study on Alpha‐fetoprotein in Relation to Neural‐tube Defects (1979) Amniotic fluid alpha‐fetoprotein measurement in antenatal diagnosis of anencephaly and spina bifida in early pregnancy. Lancet 314: 651–662.

Segerer SE, Rieger L, Kapp M et al. (2012) MIC‐1 (a multifunctional modulator of dendritic cell phenotype and function) is produced by decidual stromal cells and trophoblasts. Human Reproduction 27: 200–209.

Selenkow HA, Saxena BN, Dana CL and Emerson K Jr. (1969) Measurement and pathophysiological significance of human placental lactogen. In: Pecile A and Finzi C (eds) The Foeto–Placental Unit, pp. 340–362. Amsterdam: Netherlands Excerpta Medica.

Smith GCS, Stenhouse EJ, Crossley JA et al. (2002) Early pregnancy levels of pregnancy‐associated plasma protein A and the risk of intrauterine growth restriction, premature birth preeclampsia and stillbirth. Journal of Clinical Endocrinology and Metabolism 87: 1762–1767.

Soler NG (1974) Human placental lactogen and fetal abnormalities in infants of diabetic mothers. Lancet 304: 1389.

Stenman UH and Alfthan H (2005) Optimal sensitivity of pregnancy tests. Business Briefing: Medical Device Manufacturing & Technology.

Stenman UH, Myllynen L, Alfthan H and Seppala M (1983) Ultrarapid and highly sensitive time‐resolved fluoroimmunometric assay for chorionic gonadotrophin. Lancet 322: 647–649.

Stenman UH, Alfthan H, Ranta T et al. (1987) Serum levels of human chorionic gonadotropin in nonpregnant women and men are modulated by gonadotropin‐releasing hormone and sex hormones. Journal of Clinical Endocrinology and Metabolism 64: 730–736.

Stewart BK, Nazar‐Stewart V and Toivola B (1995) Biochemical discrimination of pathologic pregnancy from early, normal intrauterine gestation in symptomatic patients. Clinical Chemistry 103: 386–390.

Taylor AH, Amoako AA, Bambang KN et al. (2010) Endocannabinoids and pregnancy. Clinica Chimica Acta 411: 921–930.

Taylor RN and Martin MC (1997) The endocrinology of pregnancy. In: Greenspan FS and Strewler GJ (eds) Basic and Clinical Endocrinology, pp. 548–574. Stamford, CT: Appleton & Lange.

Tong S, Marjono B, Brown D et al. (2004) Serum concentrations of macrophage inhibitory cytokine 1 (MIC 1) as a predictor of miscarriage. Lancet 363: 129–130.

Tong S, Ngian G‐L, Onwade JL et al. (2012) Diagnostic accuracy of maternal serum macrophage inhibitory cytokine‐1 and pregnancy‐associated plasma protein‐A at 6–10 weeks of gestation to predict miscarriage. Obsterics and Gynecology 119: 1000–1008.

Wald NJ, Cuckle HS, Boreham J and Terzian E (1981) The effect of maternal weight on maternal serum alpha‐fetoprotein levels. British Journal of Obstetrics and Gynaecology 88: 1094–1096.

Wald NJ, Rodeck C, Hackshaw AK et al. (1994) First and second trimester antenatal screening fro Down's syndrome: the results of the serum, urine and ultrasound screening study (SURUSS). Journal of Medical Screening 10: 56–104.

Wald NJ, Smith D, Kennard A et al. (1993) Biparietal diameter and crown–rump length in fetuses with Down's syndrome: implications for antenatal serum screening for Down's syndrome. British Journal of Obstetrics and Gynaecology 100: 430–435.

Watt HC, Wald NJ, Smith D, Kennard A and Densem J (1996) Effect of allowing for ethnic group in prenatal screening for Down's syndrome. Prenatal Diagnosis 16: 691–698.

Wilcox AJ, Baird DD, Dunson D, McChesney R and Weinberg CR (2001) Natural limits of pregnancy testing in relation to the expected menstrual period. Journal of the American Medical Association 286: 1759–1761.

Yaron Y, Cherry M, Kramer RL et al. (1999) Second trimester maternal serum marker screening: maternal serum α‐fetoprotein, β‐human chorionic gonadotropin, estriol and their various combinations as predictors of pregnancy outcome. Obstetrics and Gynecology 181: 968–974.

Further Reading

Abbassi‐Ghanavati M, Greer LG and Cunningham FG (2009) Pregnancy and laboratory studies: a reference table for clinicians. Obstetrics and Gynecology 114: 1326–1331.

Beckett G (2010) Chapter 11: Pregnancy and antenatal screening. In: Beckett G, Walker S, Rae P and Ashley P (eds) Lecture Notes: Clinical Chemistry, pp. 170–178. Oxford, UK: Blackwell Publishing.

Cameron A, Brennand J, Crichton L and Gibson J (2011) Fetal Medicine for the MRCOG and beyond, 2nd edn. London: Royal College of Obstetricians and Gynaecologists Press.

DeCherney A, Spencer J, Chard T and Hutchinson KA (2007) Endocrinology of pregnancy and the placenta. In: Reece EA and Hobbins JC (eds) Clinical Obstetrics: The Fetus and Mother, 3rd edn., p. 68–82. Oxford, UK: Blackwell Publishing.

Farquharson RG and Stephenson MD (eds) (2010) Early Pregnancy. Cambridge, UK: Cambridge University Press.

Gagnon A, Wilson RD, Society of Obstetricians and Gynaecologists of Canada Genetics Committee et al. (2008) Obstetrical complications associated with abnormal maternal serum markers analytes. Journal of Obstetrics and Gynaecology Canada 30: 918–932.

Gronowski AM (ed.) (2004) Handbook of Clinical Laboratory Testing During Pregnancy. Totowa, NJ: Humana Press.

Larsson A, Palm M, Hansson L‐O and Axelsson A (2008) Reference values for clinical Chemistry tests during normal pregnancy. British Journal of Obstetrics and Gynaecology 115: 874–881.

Lind T (1980) Clinical Chemistry in Pregnancy. Advances in Clinical Chemistry 21: 1–24.

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Taylor, Anthony H, Melford, Sarah E, and Konje, Justin C(Jan 2013) Clinical Chemistry in Pregnancy. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0023397]