*3.2.2 Pregnancy loss (PL)*

Pregnancy loss has decreased from 45% in the '60s to a 20–33% nowadays, but we can still talk about fewer than expected children in SLE due to recurrent miscarriage, fetal loss, stillbirth and increased perinatal death [1, 4, 10].

Main causes for pregnancy loss are increased complement activation and placental inflammation (C5a), secondary antiphospholipid syndrome (APS) with specific aPL antibodies, complete atrio-ventricular block (CHB) secondary to anti-Ro/SSA and La/SSB antibodies (diagnosis before gestational week 20 increases four times the intrauterine mortality rate), ventricular rate 50–59 bpm (with a five times higher mortality rate if under 50 pm) [1, 4, 10].


#### **Table 3.**

*Differences between preeclampsia and SLE activity.*

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


#### **Table 4***.*

*Differentiation of active lupus nephritis from preeclampsia (adapted [10]).*

Four main types of pregnancy loss predictors have been so far identified, as follows:


#### *3.2.3 Preterm birth (PTB)*

Preterm birth meaning pregnancy termination under 37 weeks of gestation is still reported in up to 40% of lupus pregnancies; even women with quiescent lupus prior to and during pregnancy have a higher rate of preterm delivery, with delayed development and lung immaturity, poor long-term outcomes and prolonged hospitalization (if PTB under 30 weeks) as main consequences [1, 2, 4–6, 9, 10].

*Spontaneous or lupus-related PTB* reflects hormonal dysfunction as well as clinical and subclinical inflammation: activation of maternal or fetal hypo-thalamus pituitary axis with cortisol and prostaglandin production, poor placental development with lower estradiol levels, inflammation with CK, prostaglandin and complement activation.

Conversely *induced PTB* mirrors high rates medical complications in women with lupus and may be related to disease activity, prior and current lupus nephritis, renal failure, maternal hypertension, lupus anticoagulant and corticosteroids use [1, 4, 6, 9, 10].

Several predictors of preterm birth in lupus pregnancy have already been reported, including:


#### *3.2.4 Intrauterine growth restriction (IUGR)*

Defined as a condition in which the fetus is smaller than expected for the number of weeks of pregnancy, the three different types of IUGR (*type I symmetric or primary,* 20–25% of cases*; type II asymmetric or secondary; type III or intermediate IUGR*) may depend on poor placentation and endothelial dysfunction, persistent inflammation (clinical, subclinical), high autoantibodies levels and medication (excess glucocorticoids have impact on placenta vascular resistance and fetal growth).

IUGR is significantly increased in SLE pregnancy (about 30%) and is typically associated with increased risk of perinatal morbidity and mortality as well as short and long-term neurological complications [1, 2, 4, 9, 10].

Predictors of IUGR include changes in cerebral brain blood perfusion (Doppler), increase in circulating mitochondrial DNA content, maternal hypertension, APS and active lupus [1, 2, 4, 10].

Interesting data are reported during the PROMISSE study - *Predictors of Pregnancy Outcome: Bio-Markers In antiphospholipid antibody Syndrome and Systemic Lupus Erythematosus*: up to 80% of lupus patients had a favorable pregnancy outcome. *Poor outcome predictors* recognized in PROMISE study are increase in lupus activity during pregnancy (SLEPDAI) ≥4 at baseline increase over baseline in SLEPDAI ≥3 at 20 or 32 weeks, high titer of aPL and high median uric acid levels at baseline, high prolactin levels related to disease activity and poor fetal outcome; SLE patients without anti-PRL antibodies had a significantly higher frequency of maternal and fetal complications, as premature deliveries or IUGR [1, 4, 5, 14–18].

#### *3.2.5 Neonatal lupus (NLE)*

Considered as fetal manifestation of passively acquired autoimmunity, neonatal lupus is caused by or associated with maternal anti-Ro/SSA (52 or 60KDa) and/or, rarely, anti-La/SSB (48KDa) positivity; around 10% cases present with skin rash, 20% with transient cytopenia, and up to one third with mild transient high levels of transaminases; all of these complications are usually short-lived and spontaneously resolves as the child's maternal antibodies disappear [1, 2, 4, 10]. More severe is the complete (third-degree) heart block (CBH) that occurs rarely, in about 2% of pregnancies of women with anti-Ro/La positivity who had never a prior infant with NLE; however, the rate increases up to 18% if a history of prior infant who had either cutaneous or cardiac NLE [1, 2, 4, 10].

The impact of autoantibodies on fetal health was analyzed in different cohorts, suggesting their role as predictors for NLE and CBH [1, 2, 4, 10]. High titers of antibodies carry on a specific risk for CBH. Regarded as a major and irreversible complication, CBH may associate with fatal outcome in one out of five cases (*in utero* or death first year of life), while more than half require a pacemaker [1, 4, 10].

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


#### **Table 5.**

*Contraindication for pregnancy in SLE.*

#### **3.3 Contraindications for pregnancy in SLE**

*Absolute pregnancy and relative contraindications in SLE* are listed above (**Table 5**) [1, 4, 9, 10].

#### **3.4 Predicting outcomes in lupus pregnancy**

Since SLE is highly associated with poor obstetric outcomes, predicting the risks is critical for optimizing pregnancy success [4, 10]. The risk of undesirable fetal outcomes estimation in the early first trimester of pregnancy by rheumatologists may guarantee a desirable pregnancy outcome [4, 10, 31].

An clinical decision support system has already been developed in SLE pregnant women based on the artificial neural network (multi-layer perceptron machinelearning algorithm, MPL) by Khadijeh and colab. (2017) helping physician to predict the pregnancy outcomes in women with SLE based on 16 different features (https://pubmed.ncbi.nlm.nih.gov/27919382/) [31].

Cumulative clinical, laboratory and serological parameters have been tested and classified as qualitative and quantitative factors [31].

Distribution of *qualitative features* predicting SLE-pregnancy outcomes and their influence on spontaneous abortion and live births focus on *flare-up* (yes/ no), *anemia and leukopenia before pregnancy* (positive/ negative), *APS* (positive/ negative), *anticardiolipin antibodies IgG in the first trimester of pregnancy* (positive/ negative), *anti-dsDNA in the first trimester of pregnancy* (positive/ negative), C*-reactive protein before pregnancy* (positive/ negative), *azathioprine before or in the first trimester* (use/ non-use) *and aspirin in the first trimester of pregnancy* (use/non-use) [31].

On the other hand, *quantitative features* predicting pregnancy outcome in SLE include *platelets count before and during pregnancy, hematuria during pregnancy, proteinuria before and during pregnancy, C3 complement level before and during pregnancy, and hydroxychloroquine dose before pregnancy* [31].

The use of the above-mentioned factors can help the rheumatologist to predict spontaneous abortion or live birth, allowing the optimal anti-rheumatic treatment [31].

#### **4. Guidelines for the management of pregnant lupus women**

Guidelines recommend addressing family planning in women with chronic rheumatic diseases focusing on medication, disease control and reproductive health outcomes [1–8].

**The preconception counseling** should address several aspects regarding fertility and pregnancy issue in women with SLE especially the impact of pregnancy on disease outcomes and vice-versa the impact of disease and SLE-related medication on maternal and fetal outcomes, factor that can influence the pregnancy course (e.g., maternal age, medication, previous pregnancies) and, finally, the attitude face to an unplanned pregnancy (**Table 6**).

Pregnancy may be responsible for exacerbation of SLE clinical activity and, in turn, active disease may challenge pregnancy course [4]. Since the outcomes of SLE pregnancies and the complication rates are linked to diseases activity, achievement of remission or stable disease is recommended before pregnancy to reduce maternal-fetal problems [1, 4, 10].

Adequate **preconception assessment** should be advanced including a complete obstetric-gynecological history, comorbidities, contraindications and risks of pregnancies based on individual evaluation of clinical SLE activity at the time of conception, antibody panel and medication (**Table 7**).

Apart from this plan before pregnancy, another check list including **risk factors for maternal and fetal complications in SLE pregnancy** should be included in patient's file and updated during pregnancy according to individual data (**Table 8**).

Women with SLE require additional care and will qualify as high-risk pregnancies; they should be informed about specific risks such as IUGR, pregnancy loss, preterm birth and neonatal lupus [4, 10]. High risk lupus pregnancy factors comprise active lupus, medication that can cause birth defects and untreated antiphospholipid syndrome.

Gestational planning and the follow-up should be performed by a multidisciplinary team including at least an experienced in high-risk pregnancy obstetrician and treating rheumatologist with broad experience in planning and control pregnancy in SLE; accurate obstetric visits as well as strict control of the underlying lupus are essential, but the schedule of follow-ups will depend on both obstetric evaluation and disease activity [1, 4–6, 10].

Thus, we can identify at least three situations [4]:


**Check-ups visits** include preplanned evaluation tests [4]:


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

#### **Preconception issue**

**Impact of SLE on fertility Impact of SLE on pregnancy Impact of pregnancy on SLE Planning the pregnancy:** disease activity prior conception, drug modification prior to conception, calendar for visits, pre-pregnancy tests **Measures required during pregnancy and breastfeeding Risks in newborn**: risks to develop maternal disease, sequelae related to medication used during pregnancy, special care **Unforeseen management of pregnancy**

#### **Table 6.**

*Preconception counseling in SLE women (adapted [4]).*

#### **Preconception steps**

	- Fertility issues
	- Data about previous pregnancies: parity, term delivery, type of delivery (vaginal/ caesarian section), abortions, fetal loss
	- Complications: preeclampsia, HELLP, hypertension, thrombosis
	- IUGR, low birth weight
	- Hypertension, diabetes
	- Activity scores (SLEDAI, SLAM, LAI), damage scores (SLICC/ ACR)
	- Last flare (time, duration, medication)
	- Remission/ sustained remission; low disease activity/ high disease activity; stable disease
	- Glucocorticoids, antimalarials, immunosuppressives, biological agents during the last 6–12 months
	- Contraindicated drugs in pregnancy and time to last administration
	- Adapt medication according to disease activity
	- Complication in previous pregnancies
	- Age, disease activity, medication, serology
	- Standard analysis
	- SLE-related: complement, ANA, anti-dsDNA, aPL (lupus anticoagulant, anti-β2 glycoprotein, anticardiolipin), anti-Ro/ La

#### **Conclude on risks, complications, follow-up**


#### **Table 7.**

*Algorithm for pregnancy planning in SLE women (adapted [4]).*

#### **Risk factors**

	- Preeclampsia/ severe preeclampsia
	- HELLP syndrome
	- Thrombosis 6 months prior to pregnancy
	- Creatinine >2.8 mg/dL
	- Age > 40
	- Family or personal history of preeclampsia
	- Multiple pregnancies
	- Nulliparity
	- Diabetes
	- Obesity or hypertension before pregnancy
	- Active SLE
	- History of lupus nephritis class III or IV
	- aPL positivity

5. SLE

	- history of abortion, neonatal deaths, premature delivery, low birth weights infants
	- avoid pregnancy in severe pulmonary hypertension or thrombosis within the last 6 months

#### **Table 8.**

*Check list: risk factors for maternal and fetal complication in SLE pregnancy (adapted [4]).*

Disease activity should be assessed using indexes adapted for the use during pregnancy (e.g. SLEPDAI), as gravidity may influence certain variables used in the evaluation of activity scores.

Two main recommendations are on the so-called "To do list" for pregnant SLE-women [1–4]:


All the above-mentioned specialists play specific roles in managing the disease and may result in decreased hospital stay and/or serious morbidity and mortality. This can be also largely attributed to the excellent work of midwifes and interdisciplinary approach on Public Health. Doctors and midwifes collaborate with researches in creating a research group of professionals in order to monitor and evaluate the safety of women giving birth [1–3].

These demonstrated that midwifes support is indispensable for the wellbeing of childbearing women and their infants before and after delivery.

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