Biochemical tests in pregnancy

Pregnancy is a normal physiological phenomenon with many biochemical changes ranging from alterations in electrolyte concentrations to more complex changes in cortisol and calcium metabolism. The results of biochemical tests during pregnancy may therefore differ from the normal reference ranges so they may be mistakenly interpreted as abnormal. This can lead to unnecessary and potentially dangerous therapeutic actions. If there is doubt about a result, contact the laboratory to ask if the result reflects the physiological changes that occur during pregnancy. Further investigation and treatment can be recommended if appropriate.

Pregnancy is associated with normal physiological changes that assist the nurturing and survival of the fetus. Biochemical parameters reflect these adaptive changes and are clearly distinct from the non-pregnant state. The woman's renal function, carbohydrate and protein metabolism, and particularly the hormonal pattern are affected. It is critical to appreciate both normal and abnormal changes as laboratory results can influence the management of both mother and child.

During pregnancy the serum sodium is about 3-5 mmol/L lower than normal because of an increase in intravascular volume and the resetting of the osmostat. Cardiac output and renal blood flow are also increased. This leads to an increased glomerular filtration rate (GFR) with resultant decrease in concentrations of serum urea, creatinine and uric acid (Table 1).

In most cases, renal function during pregnancy can be adequately assessed by the serum urea and creatinine. If required, the GFR can be calculated using the Cockcroft-Gault or Method of Disease Renal Diet formulae.¹ but it is necessary to take into account the pregnant state specifically. The GFR can also be calculated using urinary volume, urinary and serum creatinine. Radioactive studies of urinary excretion are clearly not appropriate.

The renal tubular threshold is also lowered in pregnancy. This results in an increased excretion of uric acid, amino acids and glucose. Urinary testing for glycosuria can therefore be misleading. Similarly, urinary testing to assess metabolic changes should not be used during pregnancy and is best delayed well into the post-partum period. The best practical uses of urine testing during pregnancy are to diagnose pregnancy itself, to detect asymptomatic bacteruria and to warn of imminent pre-eclampsia when protein excretion rises.

All markers of liver function are generally reduced or low during pregnancy due to the expansion of extracellular fluid. Hence serum albumin, transaminases (AST and ALT) and total bilirubin are low compared with the non-pregnant state. The only exception is serum alkaline phosphatase (ALP) which is elevated due to ALP of placental origin.

Causes of abnormal liver function tests specific to pregnancy include intrahepatic cholestasis of pregnancy, pre-eclampsia, haemolysis-elevated liver enzymes-low platelets (HELLP) and rarely acute fatty liver of pregnancy (Table 1). All of these can cause significant fetal and maternal morbidity and mortality. Newly acquired hepatitides during pregnancy and adverse drug reactions should also be considered when assessing abnormal liver function tests.

During pregnancy, serum total calcium, phosphate and magnesium tend to be low due to the expanded intravascular space. Concentrations of calcium are also affected by the reduced albumin concentration. However, results all remain within the reference range. If there is any doubt regarding the calcium result measure the ionized calcium concentration as it remains unchanged during normal pregnancy despite changes in vascular volume and binding proteins. The concentration of serum parathyroid hormone tends to be 50% lower in pregnancy, despite the increased urinary excretion of calcium as a result of the increased GFR.² Although primary hyperparathyroidism is rare, it remains the commonest cause of hypercalcaemia during pregnancy. However, differentiating it biochemically from familial hypocalciuria hypercalcaemia (which has non-surgical management) is difficult and evaluation at a specialist endocrinology clinic is recommended.

The concentration of fasting glucose is reduced during pregnancy because of increased substrate utilisation (Table 1). With the increasing incidence of obesity, there will be an increased prevalence of gestational diabetes and type 2 diabetes developing during pregnancy. It is therefore prudent to be familiar with the diagnostic criteria.³ It is essential to screen for gestational diabetes at 26-28 weeks of gestation so that the correct interpretation can be made. The test is positive if the plasma glucose concentration is 7.8 mmol/L or more one hour after a 50 g glucose load.³

Pregnancy causes a remarkable number of hormonal changes that continue to evolve throughout the gestational period. This makes the interpretation of biochemical and hormonal results a challenging task. The changes are a continuation of the luteal phase of the menstrual cycle. Once pregnancy has occurred, concentrations of progesterone and oestrogen continue to rise suppressing the secretion of luteinising hormone and follicle stimulating hormone. However, these changes are non-specific and should not be used to confirm pregnancy.

To confirm pregnancy, serum human chorionic gonadotrophin (HCG) is the test of choice. The concentration of HCG is likely to be elevated by trophoblastic activity as early as day eight after implantation. Concentrations peak at approximately 10 weeks and then decline to plateau out at a lower level.

Thyroid function

Thyroid function tests are not uncommonly ordered during pregnancy and interpreting the results is challenging. Physiologically, the concentration of thyroid stimulating hormone (TSH) normally decreases during the first trimester of pregnancy during which there is maximal cross-stimulation of the TSH receptor by HCG. The TSH concentration then returns to its pre-pregnancy level in the second trimester and then rises slightly in the third. However, most of the changes still occur within the normal non-pregnant range. Serum free tri-and tetra-iodothyronine concentrations essentially remain unchanged during pregnancy but total concentrations, which include both free and protein-bound fractions, are significantly elevated due to increased circulating binding globulins.⁴ Clinical indicators are usually confounding due to symptoms of pregnancy that can mimic thyrotoxicosis such as nausea, vomiting, heat intolerance, fatigue, anxiety and palpitations. The presence of a goitre, especially in patients with a borderline iodine deficiency, can further confound the diagnosis.

Graves' disease is the commonest cause of true thyrotoxicosis in pregnancy. Where there is prolonged and intractable nausea and vomiting, Graves' disease should be distinguished from hyperemesis gravidarum of pregnancy and transient hyperthyroxinaemia of pregnancy. It is important that they are distinguished from Graves' disease as the prognoses and management are distinctly different (Table 2). Hyperemesis gravidarum and transient hyperthyroxinaemia of pregnancy are often self-limiting and can be treated expectantly with general support and/or beta blockade.⁵ Graves' disease needs to be rigorously controlled in order to optimise both fetal and maternal outcome.⁴

In pregnancy, there is a gradual increase in circulating blood volume of up to 1.5 L by the third trimester. As there is a relatively smaller increase in red cell mass there is a decrease in haematocrit and haemoglobin concentrations. The white blood cell and platelet concentrations remain essentially stable throughout (Table 1).⁶

Pregnancy results in many changes to laboratory tests which can be misinterpreted as abnormal. In general, most of the analytes have lower concentrations than in the non-pregnant state due to increased intravascular volume while the free active fractions, such as ionized calcium, remain unchanged. It is uncommon for a particular analyte to become elevated and thus this is a useful pointer to recognising abnormal laboratory results during pregnancy. When there are clinically discrepant results, it is prudent to seek further advice from the laboratory.