**7.1 Lupus flare**

*Lupus - Need to Know*

(BILAG2004-P)*.*

should be applied [20].

judgment and laboratory parameters.

**6. Disease activity assessment during pregnancy**

proteinuria, increase of ESR and complement levels).

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

As mentioned above, a strict assessment and control of disease activity before and throughout pregnancy is fundamental. Physiological changes in pregnancy may mimic a lupus flare (e.g. constitutional symptoms, non-inflammatory joint pain, skin rash, alopecia), as well as, laboratory changes (e.g. anemia, thrombocytopenia,

In order to reduce confounding features from physiological pregnancy and SLE exacerbations, three scores were modified in order to adapt to these changes: the SLE-Pregnancy Disease Activity Index (SLEPDAI), the LAI (Lupus Activity Index) in Pregnancy (LAI-P), and the modified SLAM (Systemic Lupus Activity Measure) (m-SLAM). Two other pregnancy-adapted scores have been introduced more recently, the modified-European consensus lupus activity measurement (m-ECLAM) and the British Isles Lupus Assessment Group-2004 for pregnancy

In all the above-mentioned indices, modifications were made to address influential items: some were eliminated (e.g. ESR, asthenia) and others were adapted to physiological pregnancy changes (e.g. proteinuria levels), emphasizing the need to differentiate those changes from pregnancy comorbidities (e.g. PE/E). The scoring of each index is calculated in the same way as the original version, except for the LAI-P, in which the weighted score given to each item has been modified. Although many attempts have been made to have a reliable tool, the clinical judgment of an experienced physician remains the gold standard in the management of pregnant women with SLE. As recently recommended, these women should be frequently monitored (every 2 to 8 weeks). During each visit, prostaglandin A (PGA) in conjunction with at least one of the activity tools and pregnancy-specific SLE activity indices (such as SLEPDAI, LAI-P, BILAG 2004- P)

**7. Maternal and fetal complications during lupus pregnancy**

Maternal and fetal complications are more frequent in lupus pregnancy than in healthy ones. So, even if new treatment strategies have been incorporated in guidelines for managing this complex situation, SLE is still a severe risk factor for

As discussed, SLE pregnancy is related to an increased risk of miscarriage, stillbirth, neonatal death, premature delivery and FGR [33, 34]. Cesarean section due to pregnancy complications is also more prevalent in lupus patients. A large nationwide study revealed that maternal mortality rate in SLE patients reaches 325/100,000 live births, meaning more than 20-fold higher than in non-SLE population [35]. The risk for other maternal complications includes thrombosis, hypertension, infection, thrombocytopenia, and transfusion, being each 3- to 7-fold

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pregnancy.

During lupus pregnancies, there is an increased risk of maternal and fetal morbidity and mortality, but a stable disease prior to conception can act as predictor of a good outcome [38]. The onset of new symptoms or signs as arthritis, discoid or subacute cutaneous lupus lesions, oral ulcers, vasculitis, polyserositis, lymphadenopathy, positive direct Coombs, myocarditis, pneumonitis, proteinuria, leucopenia, thrombocytopenia, complement consumption or raised anti-DNA antibody expression must arise the suspicion about an ongoing lupus flare [12, 38].

During a healthy pregnancy, complement levels are usually raised, as it acts as acute phase reactant [31]. So, normal or lower range of complement suggests serum consumption due inflammatory process [38]. The coexistence of hypocomplementemia and high SLE activity usually predicts a poor pregnancy outcome. Proteinuria and leukopenia are also associated to a worse prognosis [31, 38].

Recently, the PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus) study revealed that up to 20.8% lupus pregnancies experience mild to moderate flares but only 6.25% have severe ones [39]. Patients at risk were the ones with younger age, low C4 and higher physician global assessment at baseline as independent risk factors for having at least one flare during pregnancy. This study is remarkable and unique in that it has a multicenter, multiethnic and multiracial sample included. Hence, non-white race was also identified as a risk factor for lupus flare. According to the authors, there were no medications associated with flare, including hydroxychloroquine, in contrast to other studies.

SLE patients with central nervous system (CNS) involvement during pregnancy have higher risk for maternal and fetal complications and poor prognosis [40]. Preterm birth incidence can be 60% higher than in other lupus pregnancies and extreme prematurity can reach 40% of the newborns. CNS lupus pregnancies have higher risk for complications, whether neurological symptoms are present or not.

In contrast, in cutaneous lupus erythematosus the pregnancy outcomes are comparable to those of healthy populations [41].

As mentioned on Section 5.1, lupus patients can also have APS. Although rare, catastrophic APS (CAPS) can occur in up to 1% of patients and mortality reaches 50% [31].

#### **7.2 Pre-eclampsia and lupus nephritis**

Lupus nephritis (LN) is severe and independent risk factor for both maternal and fetal outcomes. It is related to preterm birth, hypertension and pre-eclampsia [42]. Pre-eclampsia have an increased risk in SLE pregnancy and can appear in up to 25% of SLE patients [31, 33]. Active LN at the time of conception has been pointed as the major risk factor for pre-eclampsia in SLE pregnancies [43]. LN activates in 4–30% of patients; those who had previous recurrence of LN are at a higher risk 20–30% [44].

The definition of pre-eclampsia by the International Society for the Study of Hypertension in Pregnancy Society (ISSHP) has recently been considered as being more sensitive than the definition made by the American College of Obstetricians and Gynecologists [45]. Pre-eclampsia is defined by the ISSHP as gestational hypertension, accompanied by at least one of the following conditions, at/or after 20 weeks' of gestation:

	- a.Acute kidney injury (creatinine greater than 1 mg/dL)
	- b.Liver involvement (alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 40 IU/L)
	- c.Neurologic complications (eclampsia, altered mental status, blindness, stroke, clonus, severe headaches, persistent visual scotoma)
	- d.Hematological complications (thrombocytopenia less than 150000/μL, disseminated intravascular coagulation, hemolysis)

Therefore, after 20 weeks of gestation, the distinction between a lupus flare and pre-eclampsia can represent a diagnostic dilemma, since both can have similar characteristics – increased proteinuria, hypertension, thrombocytopenia, kidney dysfunction and generalized symptoms [31]. A thorough clinical history and biochemical investigation are always required. In a normal pregnancy, the complement is expected to be normal or high, since it acts as an acute phase reactant. If a normal or decreased range is detected, immune complexes are probably being formed and a lupus flare is ongoing. An increase of anti-DNA antibody levels is also related to lupus activity [31]. The onset of unexpected significant proteinuria should raise suspicion, especially if it occurs in the first trimester or part of the second trimester. In these cases, a proper clinical and laboratory approach is mandatory. In discordant results, renal biopsy can be considered. However, if aPL are present, the risk of thromboembolism should prompt to anticoagulation treatment, which would, in turn, raise the risk of major bleeding after biopsy. Other procoagulant factor include pregnancy itself, nephropathy, and SLE activity, so the need to a biopsy must be carefully outweighed [31].

If a patient develops only pre-eclampsia, it is not expected to find hematuria, urinary casts, complement consumption or increased anti-DNA antibodies [31]. On the other hand, LN can also induce pre-eclampsia, so, once again, the distinction of these two entities can be problematic. The correct diagnosis must be accurate, as the treatment approach will be totally different: in pre-eclampsia, the delivery should be anticipated; in LN, immunosuppressive treatment should be immediately started.

HELLP (Hemolysis with elevated liver enzymes and thrombocytopenia) syndrome is the worst manifestation of pre-eclampsia [22]. It is usually associated with aPL, but evidence has shown that it consists of a complementopathy, either due to an inherited defect in a complement regulatory protein or an acquired autoantibody [47]. *In vitro* experiments, using serum from HELLP patients in modified Ham test,

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**Table 2.**

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

hemolytic uremic syndrome.

increase during pregnancy.

**lupus pregnancy**

more prevalent in these newborns.

disclosed activation of the alternative pathway of complement cascade (C5b-9). This dysregulation of complement system would be similar to that occurring in

Although pre-eclampsia and LN exhibit different clinical manifestations, clear discrimination in the set of a new-onset SLE during pregnancy can be challenging – see **Table 2**. Soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PIGF) ratio can be useful in discriminating these two entities: women with SLE and APS who develop pre-eclampsia have a significantly higher sFlt-1/PIGF ratio compared with women with SLE and APS, but without pre-eclampsia [31, 48]. These variances

**7.3 Impact on fetal development and monitoring of fetal development during** 

As mentioned above, fetal risks of lupus pregnancy include pregnancy loss, preterm birth, premature rupture of membranes and FGR. Preterm birth is more frequent than pregnancy loss, and even if its relation to pre-eclampsia and disease activity is established, a causative factor may not be identified [22]. Other fetal complications associated with SLE include infants small for gestational age and infants with low birth weight [33]. Neonatal intensive care unit admissions are also

Zhan Z et al., in a retrospective study identified that the best method to monitor adverse pregnancy complications during third trimester of pregnancy is by doing an umbilical artery Doppler. Nevertheless, the umbilical artery Doppler can be initiated in the second trimester in monitoring for neonatal heart block for possible earlier intervetion [49]. The use of hydroxychloroquine (HCQ ) is associated with

**Clinical measure Preeclampsia Lupus nephritis**

Creatinine Normal to raised Normal to raised

Urine active sediment Rare Common

Uric acid Raised Normal

Lupus activity No Yes

*sFlt-1 – soluble fms-like tyrosine kinase; PIGF – placental growth factor.*

*Differentiation of preeclampsia from lupus nephritis flare in pregnancy.*

Complement products Normal-low Rising titres Anti-DNA Absent or unchanged Normal to increased

24 hour Urine calcium <195 mg/day >195 mg/day Thrombocytopenia Yes (HELLP) 20% of SLE

Liver function test May be elevated (HELLP) Usually normal Kidney biopsy Glomeruloendotheliosis SLE nephritis sFlt-1/PIG ratio Higher Normal Response to steroids No Yes

*Abbreviations: HELLP - hemolysis, elevated liver enzymes, low platelets; SLE – systemic lupus erythematosus;* 

Hypertension After 20 weeks gestation Any time during pregnancy

Onset of proteinuria Abrupt, after 20 weeks Abrupt or gradual, anytime

C3 and C4 Usually normal Usually low or decreasing

Other organ involvement Occasionally CNS or HELLP Evidence of active nonrenal SLE

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

*Lupus - Need to Know*

20 weeks' of gestation:

2.Other maternal organ dysfunction, such as:

ferase (AST) greater than 40 IU/L)

must be carefully outweighed [31].

a.Acute kidney injury (creatinine greater than 1 mg/dL)

disseminated intravascular coagulation, hemolysis)

1.Proteinuria

The definition of pre-eclampsia by the International Society for the Study of Hypertension in Pregnancy Society (ISSHP) has recently been considered as being more sensitive than the definition made by the American College of Obstetricians and Gynecologists [45]. Pre-eclampsia is defined by the ISSHP as gestational hypertension, accompanied by at least one of the following conditions, at/or after

b.Liver involvement (alanine aminotransferase (ALT) or aspartate aminotrans-

c.Neurologic complications (eclampsia, altered mental status, blindness,

d.Hematological complications (thrombocytopenia less than 150000/μL,

3.Uteroplacental dysfunction – including fetal growth restriction, abnormal

Therefore, after 20 weeks of gestation, the distinction between a lupus flare and pre-eclampsia can represent a diagnostic dilemma, since both can have similar characteristics – increased proteinuria, hypertension, thrombocytopenia, kidney dysfunction and generalized symptoms [31]. A thorough clinical history and biochemical investigation are always required. In a normal pregnancy, the complement is expected to be normal or high, since it acts as an acute phase reactant. If a normal or decreased range is detected, immune complexes are probably being formed and a lupus flare is ongoing. An increase of anti-DNA antibody levels is also related to lupus activity [31]. The onset of unexpected significant proteinuria should raise suspicion, especially if it occurs in the first trimester or part of the second trimester. In these cases, a proper clinical and laboratory approach is mandatory. In discordant results, renal biopsy can be considered. However, if aPL are present, the risk of thromboembolism should prompt to anticoagulation treatment, which would, in turn, raise the risk of major bleeding after biopsy. Other procoagulant factor include pregnancy itself, nephropathy, and SLE activity, so the need to a biopsy

If a patient develops only pre-eclampsia, it is not expected to find hematuria, urinary casts, complement consumption or increased anti-DNA antibodies [31]. On the other hand, LN can also induce pre-eclampsia, so, once again, the distinction of these two entities can be problematic. The correct diagnosis must be accurate, as the treatment approach will be totally different: in pre-eclampsia, the delivery should be anticipated; in LN, immunosuppressive treatment should be immediately

HELLP (Hemolysis with elevated liver enzymes and thrombocytopenia) syndrome is the worst manifestation of pre-eclampsia [22]. It is usually associated with aPL, but evidence has shown that it consists of a complementopathy, either due to an inherited defect in a complement regulatory protein or an acquired autoantibody [47]. *In vitro* experiments, using serum from HELLP patients in modified Ham test,

stroke, clonus, severe headaches, persistent visual scotoma)

umbilical artery Doppler wave form analysis or stillbirth [46].

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started.

disclosed activation of the alternative pathway of complement cascade (C5b-9). This dysregulation of complement system would be similar to that occurring in hemolytic uremic syndrome.

Although pre-eclampsia and LN exhibit different clinical manifestations, clear discrimination in the set of a new-onset SLE during pregnancy can be challenging – see **Table 2**. Soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PIGF) ratio can be useful in discriminating these two entities: women with SLE and APS who develop pre-eclampsia have a significantly higher sFlt-1/PIGF ratio compared with women with SLE and APS, but without pre-eclampsia [31, 48]. These variances increase during pregnancy.
