**5. Pregnancy: physiological changes versus SLE activity**

It is crucial to differentiate physiological changes that occur during a normal pregnancy versus pathological conditions, since both situations can have clinical and/or laboratory changes.

In a healthy pregnancy, many clinical manifestations can overlap those of an active SLE – see **Table 1**. Sex hormone levels vary throughout pregnancy, which affect the immune system and can lead to a SLE flare [28]. The hormonal system has receptors for cytokines, immune cells, and lymphatic tissues. In a pregnancy with SLE, the serum levels of gonadotropins and sex steroids differ from the healthy individuals; as there is a decrease of estradiol, cortisol, testosterone, dehydroepiandrosterone and progesterone. Estrogen stimulates, by itself, the maturation of peripheral immune cells, especially Treg cells, that will further promote the immune system tolerance or suppression. In a healthy pregnancy, as explained in point 2.2.1, Treg cells numbers can increase, providing a higher level of fetal tolerance [15, 28]. However, in SLE pregnancy, a reduced number and function of Treg cells has been detected, which can lead to a worse outcome.

It is also known that pregnancy stimulates an increase in blood volume, involving an increase in plasma volume, raising both red-blood cell and white-blood cell volumes [29]. The discrepancy between plasma volume expansion and red-blood cell augmentation will provoke a hemodilution and cause the so-called, "physiological anemia of pregnancy" (normal hemoglobin of >11 g/dL and hematocrit >33% in the 1st and 3rd trimester). This may be caused by an increase in sodium retention, mediated by mineralocorticoid stimulation, that will lead to fluid retention and, subsequently, vasodilatation. During labor, blood volume will increase even further, due to uterine contractions, squeezing blood out of the intervillous space into the main circulation. So, after delivery, retraction of uterus and interruption of placental circulation will raise about 500 mL of blood, acting like an auto-transfusion.


**89**

*Systemic Lupus Erythematosus Pregnancy DOI: http://dx.doi.org/10.5772/intechopen.99008*

bleeding during labor [29].

another increased risk of thrombosis.

blood pressure are elevated.

Levels of clotting factors, fibrinogen, platelet production, aggregation and destruction will also be elevated, causing a hypercoagulable state [29]. Endogenous anticoagulants, such as protein S, are also diminished and there is an acquired resistance to activated protein C. Fibrinolysis is also impaired due to placental production of plasminogen activator inhibitor. Overall, these imbalances will also promote a prothrombotic and procoagulant status. This process of enhanced coagulation and increased blood volume guarantees important functions: supplying an increase uterus, a placenta and a growing fetus, and protecting the mother from a massive

Following delivery, blood volume will then be restored to its normal levels about 8 weeks' post-partum. Moreover, it is known that the increase in blood volume leads to an increase in glomerular filtration, which in turn will stress the renal function [28]. This aggravation will be more pronounced in patients with underlying kidney disease. In a healthy pregnancy, glomerular filtration rate can increase up to 50% and creatinine clearance by 30%. Tubular reabsorption of sodium is then enhanced, but glucose and amino acids may not be absorbed in the same proportion, leading to glycosuria and aminoaciduria in healthy pregnancies [29]. Renal failure before pregnancy, as it may occur un SLE, is related to poor fetal outcome and early delivery [28]. When serum creatinine is higher than 140 mmol/L, there's a 50% chance of miscarriage; this probability raises up to 80% when creatinine is over 400 mmol/L. Nephrotic syndrome will further worsen the prognosis, as it relates to

Cardiac output will increase, reaching a plateau at 28–32 weeks' gestation [29]. Stroke volume will increase ejection fraction and maternal heart rate is also accelerated [30]. However, the distended uterus compresses aortocaval circulation, reducing cardiac filling while in supine position. Filling pressure will not change, due to myocardial remodeling that occurs during pregnancy. Peripheral and systemic vascular resistance is reduced, due to vasodilation. Altogether, these changes will contribute for blood pressure stabilization in a healthy pregnancy. This equilibrium will be imbalanced in nephrotic syndrome and PE situations, as cardiac output and

The enlarged gravid uterus displaces the heart to the left and upward, so the electrocardiogram may present sinus tachycardia, benign dysrhythmias, depressed ST segments or flattened T waves, left axis deviation and left ventricular hypertrophy [29]. Diaphragm will also be displaced, progressively decreasing functional residual capacity (FRC), expiratory reserve volume and residual volume. Tidal volume and inspiratory reserve volume will increase, so that vital capacity will remain unchanged. Reduction of FRC combined with an increase of oxygen consumption

Heartburn progressively increases, as the uterus displaces and disrupts the lower esophageal sphincter, intensified by progesterone induced relaxation [29]. Although gastric pressure increases, gastric emptying is normal. Obstipation is frequent, due to an increased intestinal transit time. Liver enzymes are normal, but placental production of alkaline phosphatases can increase up to 2–4-fold of its normal range.

can provoke a rapid development of maternal hypoxemia during apnea.

Gallstone formation can be induced by impaired emptying of gallbladder.

accurate clinical history and examination is hence always mandatory.

Neuropsychiatric symptoms represent a clinical challenge, as they can result from the pregnancy itself or postpartum period, but also from preeclampsia, eclampsia, or even electrolyte imbalance, infection, renal failure, and drug toxicity [31]. For example, headaches can result from hormonal and postural changes, insomnia, anxiety, preeclampsia, but can also be a symptom of neurolupus [32]. An

Laboratory tests may reveal different values from the normal range that are considered acceptable in pregnancy, which makes them less reliable. Pregnant women

#### **Table 1.**

*Overlapping features of pregnancy and systemic lupus erythematosus (SLE).*

#### *Systemic Lupus Erythematosus Pregnancy DOI: http://dx.doi.org/10.5772/intechopen.99008*

*Lupus - Need to Know*

and/or laboratory changes.

**5. Pregnancy: physiological changes versus SLE activity**

cells has been detected, which can lead to a worse outcome.

raise about 500 mL of blood, acting like an auto-transfusion.

Hyperpigmentation

Palmar erythema Friable mucous membranes

Clinical Features Facial flush

*Abbreviation: ESR - erythrocyte sedimentation rate.*

*Overlapping features of pregnancy and systemic lupus erythematosus (SLE).*

It is crucial to differentiate physiological changes that occur during a normal pregnancy versus pathological conditions, since both situations can have clinical

In a healthy pregnancy, many clinical manifestations can overlap those of an active SLE – see **Table 1**. Sex hormone levels vary throughout pregnancy, which affect the immune system and can lead to a SLE flare [28]. The hormonal system has receptors for cytokines, immune cells, and lymphatic tissues. In a pregnancy with SLE, the serum levels of gonadotropins and sex steroids differ from the healthy individuals; as there is a decrease of estradiol, cortisol, testosterone, dehydroepiandrosterone and progesterone. Estrogen stimulates, by itself, the maturation of peripheral immune cells, especially Treg cells, that will further promote the immune system tolerance or suppression. In a healthy pregnancy, as explained in point 2.2.1, Treg cells numbers can increase, providing a higher level of fetal tolerance [15, 28]. However, in SLE pregnancy, a reduced number and function of Treg

It is also known that pregnancy stimulates an increase in blood volume, involving an increase in plasma volume, raising both red-blood cell and white-blood cell volumes [29]. The discrepancy between plasma volume expansion and red-blood cell augmentation will provoke a hemodilution and cause the so-called, "physiological anemia of pregnancy" (normal hemoglobin of >11 g/dL and hematocrit >33% in the 1st and 3rd trimester). This may be caused by an increase in sodium retention, mediated by mineralocorticoid stimulation, that will lead to fluid retention and, subsequently, vasodilatation. During labor, blood volume will increase even further, due to uterine contractions, squeezing blood out of the intervillous space into the main circulation. So, after delivery, retraction of uterus and interruption of placental circulation will

**Pregnancy changes SLE activity**

Fatigue Fatigue

Mild resting dyspnea Pleuritis

Laboratory features Mild anemia Immune hemolytic anemia

Arthralgia Inflammatory arthritis

Mild peripheral edema Moderate to severe edema

Mild thrombocytopenia Thrombocytopenia

Mild ⇧ ESR ⇧ inflammatory marker levels Physiologic proteinuria Proteinuria >300 mg/day

Photosensitivity Vespertilio

Oral or nasal ulcers

Lethargy

Pericarditis

Leukopenia Lymphopenia

Active urinary sediment

**88**

**Table 1.**

Levels of clotting factors, fibrinogen, platelet production, aggregation and destruction will also be elevated, causing a hypercoagulable state [29]. Endogenous anticoagulants, such as protein S, are also diminished and there is an acquired resistance to activated protein C. Fibrinolysis is also impaired due to placental production of plasminogen activator inhibitor. Overall, these imbalances will also promote a prothrombotic and procoagulant status. This process of enhanced coagulation and increased blood volume guarantees important functions: supplying an increase uterus, a placenta and a growing fetus, and protecting the mother from a massive bleeding during labor [29].

Following delivery, blood volume will then be restored to its normal levels about 8 weeks' post-partum. Moreover, it is known that the increase in blood volume leads to an increase in glomerular filtration, which in turn will stress the renal function [28]. This aggravation will be more pronounced in patients with underlying kidney disease. In a healthy pregnancy, glomerular filtration rate can increase up to 50% and creatinine clearance by 30%. Tubular reabsorption of sodium is then enhanced, but glucose and amino acids may not be absorbed in the same proportion, leading to glycosuria and aminoaciduria in healthy pregnancies [29]. Renal failure before pregnancy, as it may occur un SLE, is related to poor fetal outcome and early delivery [28]. When serum creatinine is higher than 140 mmol/L, there's a 50% chance of miscarriage; this probability raises up to 80% when creatinine is over 400 mmol/L. Nephrotic syndrome will further worsen the prognosis, as it relates to another increased risk of thrombosis.

Cardiac output will increase, reaching a plateau at 28–32 weeks' gestation [29]. Stroke volume will increase ejection fraction and maternal heart rate is also accelerated [30]. However, the distended uterus compresses aortocaval circulation, reducing cardiac filling while in supine position. Filling pressure will not change, due to myocardial remodeling that occurs during pregnancy. Peripheral and systemic vascular resistance is reduced, due to vasodilation. Altogether, these changes will contribute for blood pressure stabilization in a healthy pregnancy. This equilibrium will be imbalanced in nephrotic syndrome and PE situations, as cardiac output and blood pressure are elevated.

The enlarged gravid uterus displaces the heart to the left and upward, so the electrocardiogram may present sinus tachycardia, benign dysrhythmias, depressed ST segments or flattened T waves, left axis deviation and left ventricular hypertrophy [29]. Diaphragm will also be displaced, progressively decreasing functional residual capacity (FRC), expiratory reserve volume and residual volume. Tidal volume and inspiratory reserve volume will increase, so that vital capacity will remain unchanged. Reduction of FRC combined with an increase of oxygen consumption can provoke a rapid development of maternal hypoxemia during apnea.

Heartburn progressively increases, as the uterus displaces and disrupts the lower esophageal sphincter, intensified by progesterone induced relaxation [29]. Although gastric pressure increases, gastric emptying is normal. Obstipation is frequent, due to an increased intestinal transit time. Liver enzymes are normal, but placental production of alkaline phosphatases can increase up to 2–4-fold of its normal range. Gallstone formation can be induced by impaired emptying of gallbladder.

Neuropsychiatric symptoms represent a clinical challenge, as they can result from the pregnancy itself or postpartum period, but also from preeclampsia, eclampsia, or even electrolyte imbalance, infection, renal failure, and drug toxicity [31]. For example, headaches can result from hormonal and postural changes, insomnia, anxiety, preeclampsia, but can also be a symptom of neurolupus [32]. An accurate clinical history and examination is hence always mandatory.

Laboratory tests may reveal different values from the normal range that are considered acceptable in pregnancy, which makes them less reliable. Pregnant women

frequently present mild anemia and thrombocytopenia, elevated erythrocyte sedimentation rate, proteinuria (up to 300 mg/day) and increased levels of complement [31]. So, it is essential that a proper evaluation of disease activity is done. Also, complement levels can be falsely increased, so it will not serve as a strong biomarker. On the other hand, anti-DNA antibodies can still be related to disease activity. The scales of pregnancy SLE, as mentioned above, SLEPDAI, LAI-P, and BILAG2004-Pregnancy index, can also be a useful tool, combined with clinical judgment and laboratory parameters.
