Usefulness of Urine Tests in the Prevention, Diagnosis, Treatment and Prognosis of Pathologies Present during Pregnancy

Abstract

Pregnancy produces physiological changes in the woman necessary to be able to bring it to a happy term. However, they can favor the development of pathologies in various organs and systems, ranging from urinary infections, diabetes mellitus or gestational to hypertensive disorders of pregnancy. Which produce substances that are excreted through the urine. There is also excretion of metabolites which can be evaluated for the diagnosis and prognosis of certain chromosomopathies. These substances, when measured or quantified, provide bases for diagnosis, prevention, and allow decisions to be made regarding timely treatment in many of them.

1. Introduction

Pregnancy (EMB) is considered a physiological state where the maternal organism must adapt to the allograft it carries in its body [1]. To do this, it undergoes a series of modifications or physiological changes that allow it to adapt to the EMB in a continuous and dynamic way, which occur at the level of all organs and systems, and in turn are influenced by multiple factors that include the age of the woman, previous pregnancies, physical and nutritional status, presence of previous diseases or pathologies, among others [2]. These changes regress after the birth of the fetus in a period of approximately 40 days or until the moment the menstrual cycle resumes, returning the mother to the state prior to pregnancy and preparing her body for a new pregnancy [1, 2].

These changes known as gravid or physiological modifications of pregnancy (MFE) can be monitored through laboratory tests and diagnostic aid images (such as ultrasound) which can be routinely performed quarterly in normal EMB or vary their frequency in those cases in which complications or pathologies associated with it appear, which are capable of modifying its course or aggravating or unmasking a pre-existing problem [3].

1.1 MFEs comprise

1. Changes observable by the mother that are capable of producing specific symptoms such as weight gain, abdominal volume increase, breast growth, frequency, constipation, vaginal discharge, heartburn, skin hyperpigmentation [2].

2. Changes that can be assessed through physical examination by health personnel, such as blood pressure, changes in heart rate, changes in respiratory rate, and the presence of a noise in S3 on auscultation [2].

3. Changes detected through diagnostic aid studies in images such as basic ultrasound or the use of Doppler and through laboratory tests that include hematology, blood chemistry, serology and urinalysis or urine test [2].

The kidney is one of the organs that undergo important changes with the EMB which begin from the 6th week beginning with anatomical changes that include dilation of the pelvis and renal calyces and ureters, all this under the action of pregnancy hormones. Progesterone and estrogens [1, 2]. This causes an increase in urinary dead space, at the same time that renal vascularization increases with an increase in interstitial volume, which in turn causes an increase in kidney length of approximately 1 to 1.5 cm. compared to a normal adult (4.5). The kidney recovers its normal size approximately 6 months postpartum, even when the puerperium has already ended.

All of this leads to changes in renal physiology from the hemodynamic point of view, glomerular filtration, water and electrolyte management, and changes in the renin-angiotensin-aldosterone system [4].

A predisposition to the appearance of urinary tract infections (UI) occurs due to compression of the right ureter by dextrorotation of the uterus, to which the sigmoid colon contributes, which compresses the right ureter, and to the decrease in its peristalsis due to the action of progesterone, which favors the appearance of hydronephrosis. in the right kidney, slowing of urine transit through the ureter causing retrograde stasis. Contributing to this is the fact of the residual presence of urine in the urinary bladder, with a decrease in its tone, and a relative increase in its capacity as the EMB progresses due to uterine compression, which even produces reflux into the ureter, and may be up to be for 24 hours or more without being eliminated properly. Its mucosa becomes hyperemic and edematous, making it susceptible to infections and trauma [4].

Renal blood flow increases between 35 and 60%, therefore glomerular filtration increases between 50 and 60% together with the reabsorption of water and electrolytes to maintain the hydroelectrolytic balance [4, 5, 6].

During EMB, amino acids and water-soluble vitamins are lost in greater amounts than in non-EMB. Creatinine and uric acid decrease so that normal values for pregnant women are considered normal at 0.8 mgrs.%, and a greater increase is considered suspicious of kidney disease. Creatinine clearance increases by 30%. therefore, values less than 1 37 ml must be evaluated. Glycosuria is not necessarily abnormal and there may be non-significant proteinuria of 115 to 260 mg/day [1].

2. Utilization of urinalysis during pregnancy

2.1 Urinary tract infections

The appearance of urinary tract infections (UTI) is possibly the most frequent pathology during EMB, with a prevalence ranging between 14 and 48% [7], favored by the MFE that occur in the urinary tract and the alkalinization of the urinary tract. Urine [8, 9]. It is associated with other complications of EMB including pyelonephritis, preterm delivery, low birth weight newborns, and increased perinatal mortality [10, 11].

Preterm delivery (PP) is the main complication associated with UTIs, since bacterial infection in maternal and fetal tissues causes the release of endotoxins and exotoxins, cytokines, tumor necrosis factor, interleukin-1 beta, interleukins 6 and 8, granulocyte colony-stimulating factor and other factors, which stimulate the production and release of prostaglandins, leading to uterine contractions and neutrophil activity, which in turn stimulate the synthesis and production of metalloproteinases, causing membrane rupture and collagen remodeling of the cervix [12].

UTI is defined as the presence of 100,000 germs per cubic centimeter (cc) of urine in asymptomatic patients, or greater than 100,000 germs per cc of urine and leukocytes greater than 7 leukocytes per cc of urine in a symptomatic patient [10]. In most cases, it begins in the urinary bladder, favored by MGE, which in turn will allow it to ascend to the kidney [7].

2.1.1 Types of urinary tract infection

Asymptomatic bacteriuria: It is the presence of 100,000 organisms per milliliter (ml) in 2 consecutive cultures with the absence of symptoms, constituting a 40% risk factor for acute cystitis and 25 to 30% for pyelonephritis in pregnancy [9].

UTI: Presence of 100,000 organisms per ml of urine in asymptomatic patients or more than 100,000 accompanied by more than 7 cells in a symptomatic patient [9].

Cystitis: It constitutes the lower UTI characterized by inflammation of the urinary bladder due to bacterial causes or not (radiation) or viral. It occurs in 1 to 2% of pregnant women, being negative in 60% in the first screenings. It is complicated between 15 to 50% with pyelonephritis [9].

Pyelonephritis: upper UTI occurs in approximately 0.5 to 2% of all pregnancies [7, 9].

Now, what should we study in the urine test to help us diagnose UTIs or other pathologies.

2.2 Urinary sediment

The urinary sediment is obtained from a urine sample centrifuged at 2000 revolutions per minute, from which different types of cells originating from the urinary tract epithelium, or other cells such as leukocytes, red blood cells, platelets, renal cells, hyaline casts, are obtained. Leukocyte casts, amorphous phosphates, calcium crystals, uric acid, urates, lipid droplets, cholesterol crystals, proteins [13].

The presence of organisms such as bacteria, which can be typical of the urinary tract or contamination of the vagina, is frequent, as well as protozoa (vaginal trichomonas) and fungi such as candida vaginalis, as well as menstrual products and even spermatozoa [13]. Always contamination vaginal is accompanied by leukocytes and vaginal epithelial cells, so it is necessary to examine the patient’s vagina with a speculum when we have these results. Gardnerella vaginalis is another germ that causes infections and vaginal discharges that easily contaminate the urine test.

In the urine analysis, the presence of leucocyte esterase can be evaluated, which is an enzyme secreted by neutrophils, constituting a marker of infection [14, 15]. It has a sensitivity of 83% and a specificity of 78% [16].

Another test used is the nitrite test. It is based on the reduction of nitrates to nitrites carried out by enterobacteria by action of the enzyme nitrite reductase, for which it is necessary that the urine be found without mobilizing for 4 hours, its specificity being that it does not react with other substances [17]. Its sensitivity is 53% and a specificity of 78% [16, 18].

When both studies are combined, they reach a sensitivity of 98% and a specificity of 95%, which makes them very useful in the diagnosis of urinary tract infections [17].

2.3 Ph in urine

The pH of the urine covers the limits of acidity and alkalinity from 5.0 to 8.8. Ph greater than or equal to 6.0 is considered altered [17]. Its determination is a reflection of the buffered ion concentration and not a net measure of acids [18].

Acidic urine, with a pH less than 4.5, may be a reflection of metabolic acidosis, such as diabetic ketoacidosis, which can affect a patient with poorly controlled gestational diabetes or type I or II diabetes during pregnancy. Cases of patients with chronic diarrhea, a diet rich in meat, or in cases of chronic respiratory failure [18].

In contrast, alkaline urine presents with a pH greater than 8.0 and may be due to renal tubular acidosis, metabolic alkalosis which may be caused by pregnancy vomiting in the first trimester or in the case of hyperemesis gravidarum, or in the case administration of diuretics, in respiratory alkalosis or in cases of urinary infections by urease-producing germs such as Proteus miriabilis or in cases of a vegetarian diet [18].

In patients with alkanuria an alkaline pH is reported, which occurs in the presence of bacteria, urinary infection or diets rich in citrus or vegetables or the presence of certain drugs. It is also the product of the presence of lithiasis due to calcium carbonate, calcium phosphate and magnesium phosphate. However, the presence of acid urine is identified with aciduria, the product of respiratory or metabolic acidosis. When there is tubular acidosis, the urine is alkaline and the blood pH shows acidity [19].

During the pregnancy motivated by the MFE, changes in the breathing of the pregnant woman begin to appear from the eighth week, they begin with hyperventilation and a slight dyspnea which increases gradually throughout the pregnancy due to anatomical modifications by increasing the internal vertical diameters. and circumference of the ribcage when the uterus increases in size and volume, which in turn compresses the abdominal viscera against the diaphragm, thereby limiting its mobility, thereby increasing intra-abdominal pressure, which has its impact at the of lung volumes. This in turn causes the reduction of PCO2 to 30 mmHg by the action of progesterone, while increasing PO2 to 107 mmHg. Serum bicarbonate decreases to 20 mEq/L. By increasing renal excretion, it modifies the pH from 0.02 to 0.06 as a metabolic compensation for respiratory alkalosis (4.5).

All of this has as a consequence that the urine tends to become alkaline with a Ph of 6.0 or more, which, together with the gravid changes that affect the urinary system, will favor the appearance of UTI.

2.4 Hormonal study in a urine sample

Human chorionic gonatropin (HCG) is a protein synthesized by embryonic tissues, made up of 2 amino acid chains called alpha and beta. Its secretion is related to the growth of trophoblastic tissue during pregnancy, reaching its maximum levels between weeks 3 and 9 of the same [20].

Its concentration varies substantially in serum and urine [20]. For this reason, excretion in urine has allowed the development of pregnancy tests due to their levels in urine to make a diagnosis of it in a simple way, which can be carried out by patients without the need to go to a laboratory, but without specifying the conditions. Weeks of gestation, which is done by evaluating the plasmatic levels of its beta fraction.

It is considered responsible for the nausea and vomiting of pregnancy. Its presence, in addition to allowing the diagnosis of normal pregnancy, allows the diagnosis of ectopic pregnancy or gestational trophoblastic disease in any of its forms, which in most cases can occur with hypertensive disorders of pregnancy when its levels quadruple the values of the normal pregnancies. However, it can give false negatives when performed between weeks 41 and 109 of pregnancy, due to the decrease in trophoblastic tissue that produces it [20].

2.5 Presence of metabolites in urine

2.5.1 Ketone bodies

The presence of ketone bodies in urine during EMB may be related to the presence of diabetes mellitus. It must be known if this diabetes was type I or II and was present before it or if it is gestational diabetes that develops during it from the 24th week of pregnancy and which can disappear after it or the patient remains diabetic. Type II [21].

The MFE that leads to changes in energy distribution during pregnancy must be taken into account [21]. At the beginning of EMB, there is an increase in insulin sensitivity with a decrease in fasting plasma glucose levels and a slight decrease in hepatic glucose production. At the end of the first trimester and during the second trimester of gestation, insulin sensitivity decreases, finding its highest level in the third trimester, with a 30% increase in hepatic glucose secretion and a 40–50% decrease in glucose mediated by insulin, leading to decreased insulin sensitivity with a predisposition to accelerated fasting ketosis and increased fasting maternal glycemia and fatty acids [21].

Gestational diabetes is a common disorder that can affect pregnancy, capable of causing maternal and fetal complications such as neural tube malformations that include anencephaly, spina bifida, renal agenesis and hypoplasia, cardiac disorders such as tetralogy of Fallot, atrioventricular septal defects., coarctation of the aorta, ventricular septal defect, and musculoskeletal diseases and injuries such as agenesis of the sacrum, cleft palate, and high risk of preeclampsia, preterm delivery, fetal malformations, and cesarean sections due to the presence of fetal macrosomia [21, 22, 23].

Diabetic ketoacidosis in gestational diabetes has an incidence of 0.3 to 5%, so it is always necessary to rule out a history of type I and II diabetes, which are more easily and severely complicated than in non-pregnant patients [24].

2.5.2 Proteinuria

A separate chapter is constituted by proteinuria in pregnancy, which is extremely important for the diagnosis, evaluation, and prognosis of hypertensive disorders of pregnancy, preeclampsia-eclampsia, and its complications. It occurs in 2 to 10% of pregnancies [25] and is responsible for 26% of maternal deaths in Latin America and 9% in Africa and Asia.

Preeclampsia affects the endothelium systemically, proving a generalized endotheliosis that reaches all organs of the economy. In the kidney, at the level of the renal glomerulus, it produces glomeruloendotheliosis, which is manifested by proteinuria and oliguria that improves after fetal extraction [25].

It is necessary and important to know the classification of hypertensive disorders of pregnancy:

1. Chronic arterial hypertension: that which occurs before 20 weeks of gestation. It may or may not have been previously diagnosed [26].

2. Gestational hypertension: It occurs after the 20th week of gestation with the absence of proteinuria and without biochemical or hematological alterations and without repercussions on fetal growth [26].

3. White coat hypertension: It appears during the visit of the patients to be checked by their doctor either in the hospital or clinic where it can reach 140/90 mmHg and when they get home it returns to levels of 120/70 mmHg [26].

4. Transient gestational hypertension: Hypertension that appears from the 2nd trimester of pregnancy, without proteinuria, which normalizes after several repeated doses at rest without persistence in the puerperium [26].

5. Pre-Eclampsia: Hypertension diagnosed after 20 weeks of gestation accompanied by proteinuria with or without renal damage, liver dysfunction, neurological abnormalities, hemolysis, thrombocytopenia and fetal growth restriction [26].

It is necessary to consider the presence of renal disease prior to pregnancy, which can cause proteinuria, for which it is necessary that it be present before the 20th week of gestation [27]. Its appearance after week 20 may constitute one of the first signs of the appearance of hypertensive disorders of pregnancy: preeclampsia [26].

For the diagnosis of proteinuria it is necessary to collect 24-hour urine with values equal to or greater than 300 mg/day [26].

In the presence of proteinuria, it is necessary to rule out different nephropathies ranging from chronic kidney disease in which a progression of kidney disease is considered [28], diabetes mellitus, human immunodeficiency virus (HIV) infection or autoimmune diseases such as Lupus. systemic erythematosus [29]. For this reason, any proteinuria greater than 300 mg/day needs to be evaluated and the respective differential diagnoses made, especially in the presence of autoimmune diseases.

Since preeclampsia is a cause of maternal morbidity and mortality in many countries [25], methods have been sought to simplify the diagnosis of proteinuria in pregnancy. One of the simplest is using Robert’s reagent which produces protein precipitation forming a clear halo in a test tube which contains a urine sample. Densitometers have also been used to measure the increase in urinary density due to the increase in the proteins present in them. Its biggest disadvantage is that it can produce false positives, in which case it is necessary to resort to other tests to verify its results.

At present, test strips are used for a quick and simple diagnosis of proteinuria, easy to handle and apply both by primary health personnel in a prenatal consultation, and for use by the patient at home [30]. Although they can give results as false positives or negatives, motivated by the fact that the presence of pathologies prior to pregnancy or not must be known, it is useful in patients with blood pressures of 140/90 mmHg, for monitoring at home, which allows go to a care center if they are positive [30].

Another method that has been used to diagnose proteinuria in hypertensive disorders of pregnancy is the use of sulfosalicylic acid, looking for a fast, simple, economical and reproducible method for health personnel at any level. This chemical reagent is capable of producing protein precipitation through urine acidification. It has a sensitivity of 41.1% and a specificity of 97.7% [27].

Gestational proteinuria has been described in the absence of hypertensive disorders of pregnancy, which appears after 20 weeks of pregnancy. A careful evaluation of the same is necessary [31] motivated by the fact that previous pathologies must be ruled out, and take into account that it may be an early sign of preeclampsia [32].

Investigators have been looking for another method for the diagnosis of preeclampsia through urinalysis, which is why the presence of podocytes in urine or podocyturia has been described [33]. The podocyte is a cell that forms part of the basal epithelium of the glomerulus which is affected by renal pathologies, but it was thought that it was not altered in preeclampsia, but when the glomeruloendotheliosis of preeclampsia develops, these are affected. For this reason, the study of podocyturia as a diagnostic method for preeclampsia has been proposed. However, it is also present in cases of chronic arterial hypertension, diabetes mellitus and gestational diabetes, lupus nephritis, and chronic membranous nephropathy [30, 33]. For its study, synaptopodin is used as a marker, which is a protein that binds the actin of the podocytes with the cytoskeleton of the cells [33, 34].

2.5.3 Other analyzable metabolites in urine samples

Another method used for the diagnosis, evolution and prognosis of hypertensive disorders of pregnancy is the creatinine protein index. It is used as a simpler and faster option to perform proteinuria in 24 hours. It has a sensitivity of 90% and a specificity of 80% [35, 36].

Studies are underway to develop other methods for examining urine samples and using nuclear magnetic resonance techniques to diagnose the presence of specific metabolites or biomarkers for diagnosis of preeclampsia, gestational diabetes, preterm labor, and trisomy 21 [37].

With the appearance of the omics revolution, where through the analysis of metabolites and proteins of DNA and RNA in order to carry out diagnoses and treatments of different pathologies. These metabolomics search for low molecular weight cellular compounds such as carbohydrates, amino acids, peptides, nucleic acids, organic acids, vitamins, and lipids. They can be detected using nuclear magnetic resonance spectrometry methods in samples of blood, urine, amniotic fluid, tissue secretions, and placental tissue. These data are evaluated through computer programs where they are analyzed, studied to give their interpretation and use these data in prevention, evolution, treatment and prognosis.

These studies can be carried out at the prenatal level, during the control itself, and they can be carried out through a urine sample [38].

Diaz et al. [39] in urine samples from the 14th week of pregnancy, searched for metabolic signatures using nuclear magnetic resonance metabolomin, which revealed specific urinary metabolic signatures for malformations of the central nervous system, trisomy 21, preterm delivery, diabetes pregnancy, intrauterine growth restriction and preeclampsia, demonstrating the value of the urinalysis profile as a complementary method of diagnosis and early prediction of various disorders that occur during pregnancy [39].

Cantowine et al. [40] found urinary concentrations of Bisphenaol A and Phosphate, a metabolite which are man-made products for industrial use in a wide variety of products ranging from the lining of canned food containers, water bottles and pipes water supply, products that are released in an innocuous way to the general population throughout the world, the general population being exposed to them.

It has been shown that BFA can affect the proliferative process of trophoblast cells through an estrogen receptor with an effect of apoptosis of trophoblast cells through tumor necrosis factors which act on the placenta and therefore on the development of preeclampsia [40].

Taking into account that preeclampsia occurs more frequently in primiparous women, the use of Fit-1 tyrosine kinase has been proposed, which constitutes a promising biomarker for preeclampsia obtained from a urine sample. It is a growth factor antagonist and vasoconstrictor and sensitizes the endothelium to respond to stress and endothelial dysfunction. The study is performed with nuclear magnetic resonance spectrophotometry. The Fit-1 measures moderate to severe placental dysfunction, knowing that the development of preeclampsia occurs due to inadequate placentation with abnormal development of placental vessels at the time of trophoblastic invasion, creating high-resistance vessels instead of low-resistance ones. Resistance that occurs in normal pregnancies. For this reason, it is capable of measuring the development of preeclampsia [41].

Other metabolites and biomarkers developed from a urine sample include increased excretion of amino acids as a result of kidney damage from preeclampsia. Choline increases in these patients while glycine decreases at the same time [42].

3. Conclusions

The physiological modifications of the pregnancy through its adaptive changes, favor the development of the pregnancy, keep the expectant mother in balance to achieve its completion with the best results. However, in turn they can contribute to the appearance of pathologies caused by the lack of adaptation or poor adaptation to it, such as hypertensive disorders of pregnancy, gestational diabetes, or UTI, among others. In the effort to prevent, diagnose, treat and have an adequate prognosis, it is sought to be able to make simple and reliable diagnoses and the evaluation of uranalysis is one of the simplest methods that we have. The sample is easy to obtain and its analysis ranges from the use of reactive tapes to the diagnosis of glycosuria, proteinuria or a UTI. Urinary sediment and Ph allow us complementary diagnoses that make us suspect other pathologies such as pyelonephritis, gallbladder and renal lithiasis, facilitating their diagnosis. We must always clinically evaluate the patient according to the signs and symptoms they present in order to make the most assertive diagnosis possible. The presence of proteinuria should always make us suspect a hypertensive disorder of pregnancy, although its absence does not thus rule it out from the presence of renal pathologies or other systemic diseases present before pregnancy. The development of new techniques for evaluating a urine sample are the next stage in the diagnosis of pathologies through the metabolites excreted in the urine, which include the diagnosis of chromosomopathies, for which the urine test in pregnancy reaches every ever-greater importance.

Conflict of interest

“The authors declare no conflict of interest.”