**2. Healthy pregnancy** *vs***. lupus pregnancy**

It is critical to mention that pregnancy represents a unique clinical situation, physiologically characterized by a well-documented Th2-cell polarization at both systemic and maternal-fetal interfaces, developed on a background of depressed cellular-mediated immunity, changes in Th1/Th2 cytokine profile, and placental synthesis of complement inhibitors [4, 9, 10]. Also, progressively increased levels of sex hormones - estrogens, progesterone, prolactin, as well as and glucocorticoids are commonly reported during pregnancy [1, 4, 9, 10]. Complex immunological and hormonal adaptive mechanisms are activated to allow the tolerance of fetus classically considered as an immunogenic allograft [4, 9].

A closer look to the pathogenic pathways of autoimmune rheumatic conditions emphasizes specific genetic susceptibility and aberrant immune response driving definite behavior during pregnancy [4, 10]. Rheumatic diseases respond differently to pregnancy, as immune system adjustments may positively or negatively interrelate with underlying autoimmune disease: spontaneous improvement occurs in some of them, while persistent activity or severe flares are seen in others, such as systemic lupus erythematosus [1, 4, 10].

Despite significant progress in understanding and treating autoimmune rheumatic conditions, pregnancy in such patients remains a challenge due to complex interplay between pregnancy, disease activity and medication; the main debate focuses on the paradigm "flare without medication" *vs*. "safe drug in pregnancy", emerging the unmet needs for pregnant rheumatic patients [1, 4, 6, 9, 10].

Furthermore, it is widely recognized that the management of reproductive issues in patients with rheumatic diseases commonly differs from general population, requiring a cross-over team with rheumatologists, specialists in the fields of obstetrics-gynecology and maternal-fetal medicine, and, in special cases, reproductive endocrinology and infertility [1–4, 10]. Patients should be counseled about contraception, pregnancy and lactation; additionally, pregnancy in IMRDs needs to be planned and risks assessed in mother and child [1–4, 10, 11]. High-risk pregnancies require careful monitoring and tailored therapy to secure maternal health and positive pregnancy outcomes [4, 10].

Systemic lupus erythematosus is a multi-system autoimmune disease of still unknown etiology, defined by a wide spectrum of organ involvement occurring on a background of fatigue, fever, joint pain and weight changes, and a chronic evolution with exacerbations alternating with quiescent disease [1, 4, 6, 8]. It develops predominantly in women of their reproductive age, making pregnancy a major concern in routine practice; lupus women have higher risk for infertility, miscarriages, and other pregnancy complications due to disease activity, renal involvement, medications (e.g. cyclophosphamide), and presence of certain autoantibodies (anti- Ro/SSA, anti-La/SSB, antiphospholipid antibodies) [4, 10, 12].

The outcomes of lupus pregnancies have dramatically improved over the last decade thanks to advance understanding of disease and its effects in the body, pregnancy planning, multidisciplinary management and close monitoring [1–6]. However, there are clear differences between pregnancy in general population and lupus pregnancy. While a healthy pregnancy is widely defined by specific immunological and hormonal changes, underlying lupus pregnancy is characterized by higher serum pro-inflammatory cytokines, lesser Th2 polarization, lower estrogen and progesterone levels, lower number of T-Reg defective cells, blockade of complement inhibitors by anti-phospholipid antibodies (aPL), increased placental complement component deposition, aberrant activation and, finally, local inflammation. In another words, we talk about an altered physiological response, leading to significant pregnancy morbidity in lupus patients [1–4, 10].

Furthermore, the physiological modulation of the immune system by pregnancy and related hormonal changes may interact with disease activity in autoimmune rheumatic disorders and drive complications (e.g. disease flares); on the other hand, lupus may have a significant impact on pregnancy outcomes [1, 2, 4, 10]. Disease activity, severity of organ damage, antibody profile and drug treatment may promote maternal (e.g. preeclampsia) and fetal complications (pregnancy loss, intra-uterine growth retardation, preterm birth, even neonatal lupus) [1, 4, 9, 10].

Pregnancy in lupus is still considered at increased risk for adverse pregnancy outcomes (APOs) [1–10]. Pregnant SLE-women can develop in 19–57% cases severe obstetric complications including spontaneous abortion (SA), preeclampsia (PE), intrauterine growth restriction (IUGR), small for gestational age (SGA), preterm birth, fetal death in utero and neonatal death. APOs particularly develop if significantly longer disease duration and higher disease activity 6 preconceptual months, during pregnancy and 6 months postpartum period [1, 4, 9, 10, 12, 13]; furthermore, active SLE at the time of conception is a strong predictor of APOs and current recommendations consider disease quiescence for 6 months prior to conception [1, 4, 10, 12, 13].

A detailed look to one of the most important multiethnic cohort of lupus patients in the PROMISSE (*Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus*) prospective study revealed APOs in 19% of pregnancies, with fetal and neonatal death in 4% and 1%, respectively, preterm delivery in 9%, and small-for-gestationalage neonate in 10% suggesting how important is to accurately identify, counsel, and manage lupus patients in order to optimize their pregnancy outcomes [1, 14–17].

#### **3. Biomarkers in lupus pregnancy**

A *biomarker* is an indicator of normal biological processes, pathogenic processes or responses to an intervention [16]. Besides their triple diagnostic, prognostic and therapeutic value, biomarkers have major implications in personalized medicine [1, 2, 4, 16].

Specific biomarkers and novel serum or urine biomarkers may represent the best choice to classify stage and treat patients with SLE; an extended list includes complement level, specific antibodies level, CXCL10, Galectin 9, SIGLEC-1, IL-1 family, BAFF family, lymphocyte populations as serum biomarkers, as well as urine biomarkers [16].

In an attempt to identify biomarkers in lupus pregnancy, pivotal studies suggested that active disease, prior nephritis, use of antihypertensive medications, antiphospholipid antibodies (aPL), hypocomplementemia and anti-double stranded DNA (anti-dsDNA) antibodies are highly associated with APOs [1, 4, 9, 10].

We will further focus on different APOs in lupus, emphasizing the role of biomarkers in stratifying risks and, eventually, driving a more personalized approach in lupus pregnancy.

#### **3.1 Impact of pregnancy on SLE**

#### *3.1.1 Lupus flares associated with pregnancy*

It is well known that 40 to 60% of women with SLE will experience a flare during pregnancy or the first post-partum year; moreover, disease can exacerbate *Challenges in the Delivery Room: Integrated Analysis of Biomarkers Predicting Complications… DOI: http://dx.doi.org/10.5772/intechopen.96099*

at any time during pregnancy and postpartum period, without any clear pattern [1, 2, 4–6, 8]. Commonly utilized instruments to asses disease activity in non-pregnant lupus patients have been specifically adapted and validated for the use in pregnant women [5, 6, 8, 18–20]; *SLE Disease Activity Index in Pregnancy* (SLEPDAI), *modified-SLE Activity Measure for Pregnancy* (m-SLAM) and *Lupus Activity Index in Pregnancy* (LAI-P) and are able to detect changes in disease activity in pregnancy, to monitor and to diagnose flares of maternal disease during gravidity, without mistaking signs and symptoms physiologically associated with pregnancy [1, 4, 5, 8, 18, 21].

According to their severity, lupus flares may be classified as *mild flares* (involving skin and joints), with no major impact on pregnancy outcomes, and *severe flares* (in which kidney features, significant hematologic, serositis and severe arthritis may develop) with poor pregnancy outcomes [1, 2, 5, 6, 8].

Most of lupus exacerbations during pregnancy and postpartum period had mucocutaneous, renal and hematological involvement; additionally, postpartum 6-month period appears to have the highest risk for disease exacerbation and up to 50% of flares in postpartum are severe according to a recent analysis [1, 4–8, 10, 13].

SLE flares critically depend on disease activity 6 to 12 months prior to the conception suggesting that pregnancy outcomes are optimal when disease is in complete clinical remission for 6–12 months before conception; besides, there is a 2 to 4 times risk of flare if active lupus before pregnancy, and a SLEDAI≥4 points 6 months before pregnancy and lupus nephritis are main predictors of adverse maternal outcomes [1, 4–8].

Several factors should be considered for risk stratification in SLE women in preconception [1, 4–10] (**Table 1**).

Biomarkers predicting lupus flare in pregnancy may be classified in three main categories, as follows [1, 4–8, 10]:


Although it is widely recognized that low C3 and C4 levels are associated with active SLE, it seems that low complement occurring during SLE pregnancy may predict APOs [1, 4, 6–8, 22]. Recent data confirm that low C4 at preconception predict flares during pregnancy and suggest that complement evaluation during pregnancy is suitable to detect the high-risk patients that require a more vigilant SLE monitoring and management [23]. Surprisingly, the same study failed to demonstrate any statistical correlation between lupus flare and anti-dsDNA positivity, disease activity (SLEDAI at preconception visit and SLEPDAI during pregnancy), antiphospholipid antibodies positivity as well as clinical SLE manifestations [1, 4–8, 18, 24].


#### **Table 1.**

*Risk stratification of SLE in preconception period.*


#### **Table 2.**

*Differences between lupus flare and physiological pregnancy changes.*

On the other hand, many authors reported that disease activity during pregnancy increases the risk of APO, while patients with sustained low lupus disease activity scores have significantly lower APO rates [8, 13, 18].

Recognizing a lupus flare can be difficult given that normal changes related to pregnancy can mimic lupus activity [1, 4, 10]. Main clinical and lab assessment in lupus flare and normal pregnancy are summarized in table above (**Table 2**).

Serological biomarkers are suitable for monitoring lupus activity, but serological activity that develops during pregnancy, especially in the context of clinical activity, may be associated with increased risk for pregnancy loss, intrauterine growth restriction and preterm birth [1, 4–10].

Finally, the so-called *'critical' clinical and serological lupus phenotypes* define patients at increased risk for pregnancy complications; such phenotypes require a special monitoring during pregnancy and encompass for past or present history of lupus nephritis, anti-Ro/SSA and/or La/SSB positivity and aPL positivity or SLE associated with APS [1, 4–10].

#### *3.1.2 Lupus nephritis and pregnancy*

It is basically recognized that renal activity may be associated with APOs, requiring a strict follow-up based on urine protein excretion, urine sediment analysis (haematuria, urinary casts) as well as serum creatinine level and glomerular

*Challenges in the Delivery Room: Integrated Analysis of Biomarkers Predicting Complications… DOI: http://dx.doi.org/10.5772/intechopen.96099*

filtration rate [1, 2, 4–9]. Moreover, urinary levels of CXCL10, and CXCL16 are highly increased in lupus nephritis, TCD4 cells may be an indicator of all treatment response and CCL2 sensitive indicator of renal flare [16].

Recommendations for the approach of pregnancy in the context of lupus nephritis have been released by *European League Against Rheumatism* (EULAR) in 2017. Severe renal flares during pregnancy not responding to drugs with an acceptable safety profile (azathioprine, antimalarials) warrant for a complex, multidisciplinary management, with potential early termination of pregnancy and/or use of embryotoxic drugs if required. [4, 6–8, 25–28].

Several practical points should be emphasized as follows:


#### **3.2 Impact of SLE on pregnancy**

#### *3.2.1 Pre-eclampsia (PE)*

Considered as a syndrome unique to pregnancy, preeclampsia remains a significant maternal complication in lupus pregnancy [1, 4–10] and a challenge in clinical practice. Key parameters that allow us to distinguish between PE and SLE activity are listed below (**Table 3**) [1, 4–8, 10, 22, 29]. Interestingly, serologic biomarkers can also distinguish between SLE flare (decreased serum C3 and C4 levels associated with increased anti-dsDNA concentrations) and pre-eclampsia. [4, 7, 8, 22, 24].

*Mild PE* refers to the new onset of hypertension (≥140/90 mmHg) associated with proteinuria (≥300 mg/24 h urine specimen) after 20 weeks of gestation in a previously normotensive women, while *severe PE* account for new onset proteinuric hypertension and at least one of the following: thrombocytopenia (less than 100.000 platelets/mm3 ), symptoms of central nervous system dysfunction, proteinuria ≥5 g/24 h and oliguria, liver involvement (serum transaminase at least twice normal), severe blood pressure elevation (≥160/110 mmHg). It is undoubtedly associated with high risk for stroke, preterm birth, death and eclampsia [1, 4, 10].

Furthermore, preeclampsia should also be differentiated by active lupus nephritis and there are several clinical and lab parameters that help to correctly assess the patient and recognize the renal involvement or pregnancy complication (**Table 4**) [1, 4, 10].

Finally, biomarkers predicting preeclampsia in lupus are already documented, as follows [4, 8, 22, 29, 30]:

• *SLE-specific factors -* active lupus nephritis (especially class III or IV), renal failure at the time of conception, sustained use of prednisone (≥ 20 mg/day during pregnancy), thrombocytopenia, active SLE at conception, low C4, anti-RNP positivity, presence of aPL antibodies; and

• *Maternal factors -* age ≥ 40 years, previous personal or family history of preeclampsia, pre-existing hypertension or diabetes, multiple pregnancies, obesity, low pro-angiogenic factors (VEGF, PIGF1), high anti-angiogenic factors (sFlt-1, soluble endoglin), increased vascular resistance in uterine artery with deficient spiral artery remodeling.

The use of vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and FMS–like tyrosine kinase-1(sFlt-1) are useful for the differential diagnosis between nephritis and preeclampsia [1, 4, 10].

Asymptomatic aPL-positive patients (without any pregnancy complications or history of thrombosis) are not generally treated with prophylactic therapy to prevent pregnancy loss. However, presence of aPL regardless of clinical history is considered a risk factor for development of preeclampsia [4, 5, 8, 10, 22, 29].

Although the outcomes of lupus pregnancy have dramatically improved, *pregnancy loss, preterm birth, low birth weight and cesarean section* are still reported in such patient population [1, 4, 9, 10].
