Fertility, Pregnancy, and Systemic Lupus Erythematosus

Abstract

The desire for pregnancy in patients with systemic lupus erythematosus (SLE), which was previously considered a potentially lethal enemy for the mother and the product, today is part of the success of advances in the treatment and control of the disease. In this chapter, we will talk a little about the pathophysiology of the pregnancy of the patient with lupus, going through the relationship with the treatments received, and the way in which these can directly affect fertility and pregnancy. We will also briefly comment on the compromise of the product in the case of neonatal lupus, and if it really has to do indirectly or directly with the existence of SLE in the mother. We will address pregnancy-related complications along with biomarkers and clinical signs that could indicate inherent risks already widely known in the literature.

1. Introduction

Talking about lupus without talking about the reproductive probability of women is impossible. They go hand in hand, first because the disease is more common in patients of childbearing age, and because in the past pregnancy was an absolute contraindication. In current time a normal pregnancy we can achieve it as possible and also its activity since it plays an important role in the occurrence of relapses and therefore complications that generate morbidity and mortality in both mother and fetus. In this chapter, we are going to talk about a “deck” of possibilities of existing complications in the mother, also something about anti-inflammatory drugs and their use in pregnant patients and superficially direct effects of the disease on the product.

Currently, all processes related to reproductive health, such as contraception and stricter control of pregnancy, are more frequent for patients with good results in most cases, but without neglecting the fact that pregnancy continues to be associated with greater maternal morbidity and mortality and fetal. When reviewing the literature and in daily practice, we find that the persistence of activity in pregnancy has been directly related to estrogen levels. This “time bomb” triggers maternal, pregnancy-related, and fetal complications. In the case of the mothers, lupus outbreaks, with important compromises in target organs (brain, kidney, vascular, placenta, and lung). Obstetric complications (fetal loss, intrauterine growth retardation, and premature birth) and their incidence increase when it is related to anti-phospholipid antibody syndrome and in the newborn indirectly cases of neonatal lupus due to the transplacental passage of antiantibodies [anti-Sjogren’s syndrome A (SSA) or anti-Sjogren’s syndrome B (SSB)] [1]. Unquestionably, for a good outcome and development of these pregnancies, preconception counseling must be strictly followed, plus multidisciplinary management by a rheumatologist, gynecologist or perinatologist, nutritionist, and psychologist. The primary objective to achieve success in pregnancy and the reduction of complications is mainly that there is no lupus activity in at least 6 months, with an adequate prescription of medications that are safe in pregnancy, always taking into account clearly the patients and their risk factors, and mandatory regular follow-up [2].

2. Before the beginning

2.1 When you don’t know, it’s no!!

This point of the chapter is essential given that a large number, not to mention all, of the patients with systemic lupus erythematosus (SLE) are of childbearing age and previously aware of the hormonal effect on which the disease is active. It is very important that the type of treatment received by the patients is also taken into account since several medications have a teratogenic component [1].

2.1.1 There is desire we don’t know it’s

Patients with SLE should, as far as possible (and in an ideal world of course), receive clear, precise and, above all, timely advice on contraception, the effect of the medication on the product, and its suspension in the event of an unplanned pregnancy. And why not say it, the possible outcomes in the absence of strict control and clear communication in the relationship between the doctor and the patient, to reduce complications, answer questions, and clear up any doubts that arise at the time. This must always go hand in hand individually with each of the patients since each one of them is a “world apart.” Always taking into account the risk of each one not only due to the existing disease but also due to others that add up to further complicate the picture [3]. With this we can address, apart from SLE, chronic degenerative diseases together, such as high blood pressure, obesity, smoking, and in some other patients ask about existing family history of cancer that is hormone dependent. Together with SLE, the association with antiphospholipid antibody syndrome (APL) must be sought insistently, since this leads to an increased thrombotic risk.

The planning of the pregnancy by the multidisciplinary medical team and the patient increases the probability of a successful outcome and is a vital strategy to reduce perinatal morbidity and mortality complications, recognize them if they occur and make an “itinerary” with stations in which the patient knows how to deal with each of them always hand in hand with the medical team [4]. When preconception counseling begins, the main complications that could arise in pregnancy should be explained in detail, slowly and with the greatest simplicity, but without losing the meaning of the counseling.

2.1.2 Contraceptives: when you already know what you want but you cannot and you want to avoid it!

In the twenty-first century and despite advances in technology and communications, there are still problems with advising patients with SLE regarding contraception [4]. It is a vital part of the strategy to control the decrease in perinatal morbidity and mortality that women with SLE can access information on contraceptive methods and always according to the activity of the disease and the risk factors that each one of them has individually. Despite of that can increase in a prospective observational study of 86 patients, 59% had no advice regarding contraception despite using highly teratogenic drugs, 22% used contraceptives, and 53% only used barrier methods [5].

Looking at the existing literature and evidence, it could be said that we are slowly finding “clarity in a world of greys.” On the one hand, it was shown in a case–control study that there is a higher risk of developing disease activity in women aged 18–45 years who are using contraceptives based on combinations of estrogens or progestins with high doses of ethinylestradiol and that the time of starting the intake is recent [6]. On the other side of the coin, we find two randomized controlled trials that showed that the combination of estrogen and progestin or progestin alone does not increase the incidence of thrombotic events in patients as long as they have low or no disease activity and that there is no previous history of thrombosis and negative aPL titers [7]. On the contrary, in patients who are positive with high titers of antiphospholipid antibodies (whether or not they have antiphospholipid syndrome) added to risk factors for developing thrombotic events in which contraception with estrogen-based preparations (oral pill, vaginal ring, and patch transdermal) is contraindicated. In young women with a history of coronary thrombosis (myocardial infarction), cerebral thrombosis (ischemic stroke), and who have a positive lupus anticoagulant, the use of the combined pill increased the risk of thrombotic events at the arterial level [8].

However, in patients who are on strict anticoagulation and who generally have a low-risk antiphospholipid profile, progestogen alone (pill, depot subcutaneous injections) could be considered, provided there was no history or no high risk of thrombosis. Intrauterine devices (IUDs), such as the copper one, can be used in any patient with SLE relatively safely [1, 3]. The levonorgestrel-containing IUD could be used as long as the risks vs. benefits are weighed, and this by reviewing each patient individually. For emergency contraception, the progestogen combination is not contraindicated.

3. In the beginning

God blessed them and said to them, “Be fruitful and increase in number; fill the earth and subdue it.”

Genesis 1:28.

3.1 The delicate hormonal axis in women and the relationship with autoimmunity: when despite the intention something is not right!

Sex hormones are actors of great importance for the maintenance of the existing balance in the immune system. These hormones (estrogens and progesterone) and with them prolactin have many effects on cellular and humoral immunity and on various processes together. Clinical experience has shown that some changes in this delicate hormonal balance can contribute to a greater or lesser activity of SLE, such as the use of exogenous estrogens (oral contraceptives or postmenopausal hormone therapy), and hormonal changes where there is an increased secretion of endogenous estrogens such as those associated with pregnancy.

In reproductive pshysiology that leads to the successful implantation of the embryo, with the necessary protection against immune rejection due to being a semi-allograft and at the same time maintaining close control of the immune system and adequate response of the same during pregnancy and childbirth [9]. To achieve this goal, an arsenal of inflammatory mediators is needed, and for this reason, it is logical that many of the inflammatory or immune responses have the female sex steroids as protagonists: estrogen, progesterone, and prolactin (Figure 1).

Figure 1.

Expected effects of sex hormones on the immune response.

It has been found that there are estrogen receptors (α and β) that are essential for estrogen to act, and antibodies against these receptors, especially anti-Erα, have been detected in patients with SLE. These caused the induction of cell activation and apoptosis in lymphocytes and are closely related to the induction and maintenance of T-cell anergy and immune self-tolerance [10, 11].

One study analyzed the presence of specific antibodies against estrogens in patients with SLE. It was observed that in 45% of the patients studied these antibodies were found and induced cell activation and subsequent apoptosis in lymphocytes. There is a theory of the existence of an extracellular binding domain where these antibodies enter the cell and associate in some unknown way with the cell membrane, initiating the activation of the ERK/MAPK pathway when this is very important for selection, differentiation, and maturation of T cells and modulates their induction, their anergic quality, and self-tolerance. These antibodies could induce cell apoptosis and repeatedly alter cell-cycle control and modulation in T lymphocytes [12].

3.2 Pregnancy immunology: when the miracle has already taken place!

Progesterone is essential for the initiation and maintenance of pregnancy as it has important effects on the immune system [13]. These effects are coordinated by a progesterone-induced blocking factor (PIBF). This is encoded in a target gene located on chromosome 13 in humans. This protein has some isoforms, which act as cytokines, that exert their action on the metabolism of arachidonic acid, inhibit arachidonic acid by the direct action of phospholipase A2 and the subsequent decrease in prostaglandin and/or leukotriene synthesis.

Full-length PIBF (90 kDa) is anchored in the nucleus and is involved in cell-cycle regulation. The expression of PIBF seems to be crucial for the normal progression of pregnancy, which is why it is found in the lymphocytes of pregnant women as well as in other tissues inherent to pregnancy and has also been found to be related to the proliferation of cancer cells in tumors malignant [14]. The decreased production of this factor results in an alteration of the cell cycle with the consequent deregulated and uncontrolled invasion of the trophoblast, if it is the isoforms that are absent, it could result in the loss of local immunosuppression, necessary for maintenance and vitality of gestation.

NK (natural killer) cells tend to differentiate during pregnancy. While ordinarily, 90% of peripheral NK cells express a low density of CD56dim molecules and high levels of CD16; most decidual NK cells express a high density of CD56bright and not CD16. These secrete angiogenic factors and cytokines, and one of their functions is to control placentation in an orderly and adequate manner [15]. Peripheral CD56dim NK cells are cytotoxic, whereas CD56bright are not. The job of PIBF is to inhibit the release of perforins from activated peripheral NK cells and this, in turn, helps to maintain the low level of lytic activity of decidual NK cells.

It is understood that during pregnancy there is a predominantly Th2 immune response; however, there are certain moments of it where there is a change in response, for example at the time of implantation or at the time of childbirth.

Evidently, progesterone and PIBF alter cytokine homeostasis in favor of a Th2 response. And so, a nonhostile immune environment is promoted by the increase in IL-10 and regulatory T cells [16]. This response slowly changes and gradually reverses before the onset of labor. Progesterone reduces proinflammatory and cytotoxic T-cell responses by effectively modulating immune cell-mediated interactions and regulating differentiated memory cells. In a normal gestation process, PIBF in urine and serum increases until the 37th week of gestation, followed by a sharp decrease in labor. Whereas, in a pathological pregnancy, the levels of PIBF in urine do not increase. The onset of labor (both term and preterm) is predictable based on PIBF levels [17].

3.3 Immunology of pregnancy: the dance of the mother/fetus binomial

1. Recognition of fetal antigens: this recognition is carried out by Vγl cells (subset of γδT cells) that are found in greater proportion in the decidua.

2. Upregulation of progesterone receptors: these Vγl (CD56+) cells become activated and develop progesterone receptors.

3. Production and release of PIBF: when there is a conjunction between progesterone, CD56+, and 76+ cells, decidual NK cells together with a positive progesterone receptor carry out the synthesis of PIBF.

4. Pregnancy protection: this release of PIBF contributes to the success of the pregnancy through three actions: it induces an increase in “blocking” antibodies, Th-2 dominated cytoprotective immune response, and a reduction in NK cell activity. This will prevent the possibility of presenting inflammatory and thrombotic diseases in pregnancy (Figure 2) [18].

Figure 2.

Sequence of events in the immunology of pregnancy between the mother/fetus binomial.

We forget the very important role of the major histocompatibility complex (MHC) that protects the trophoblast from the destruction of the NK by inhibiting its lytic functions, as well as limits the cytotoxic activity of leukocytes, suppresses the production of cytokines of type proinflammatory, and also induces T cell apoptosis. [19]. Nonclassical MHC antigens also promote trophoblast proliferation and invasion. Altered expression of nonclassical MHC 501 antigens has been linked to recurrent pregnancy loss and preeclampsia. Placental expression of FAS ligand may also play a role in pregnancy success through the selective removal of antifetal T-cell clones.

3.4 Fetal Immune System

It begins at the moment of conception and continues until birth and later in infancy. In the first weeks of gestation, pluripotent stem cells form all the components of blood cells. In the sixth week, the thymus forms and lymphocyte differentiation begin. Subsequently, the first lymphocyte bud appears along with the plexuses. At the end of the first trimester of pregnancy, the fetus already has the ability to respond, although it decreases infections because there is already production of plasma cells and antibodies.

The trophoblast continues to develop as a barrier that is not entirely infallible but is effective in preventing the passage of cells with immunological capacity. Even thought maternal IgG action of placental Fc receptors passes a barrier levels are barely perceptible at the beginning of pregnancy; they have a slow increase in the second trimester and equal and reach maternal serum concentrations at 26 weeks of gestation reaching its maximum transfer in the last 4 weeks of gestation. Humoral immunity in the neonatal period depends exclusively on circulating immunoglobulins that have crossed the placenta. This is why potentially harmful maternal autoantibodies (anti-SSA, anti-SSB, and anticardiolipin) will pass into the fetal circulation and will have harmful potential just as maternal exposure to IgG-based pharmaceutical agents will also pass into the fetal circulation [20].

4. Pregnancy and lupus: when we have to face troubled waters!

Pregnancy in women with SLE, especially those with significant renal involvement (lupus nephritis), is associated with an increased risk of developing preeclampsia, fetal growth restriction, fetal loss, and preterm delivery. This risk remains latent, although lupus nephritis is inactive and rises considerably in cases where it is accompanied by proteinuria and/or high blood pressure. If there is already severe kidney damage, the possibility of pregnancy without problems is remote (Figure 3) [10].

Figure 3.

Consequences of pregnancy in patients with chronic kidney disease and SLE.

Lupus activity is a key predictor of pregnancy outcome. High levels of lupus activity before the start of pregnancy increased the risk of pregnancy loss and the risk of preterm delivery up to four times, the latter together with elevated anti-DNAdc (anti-double-stranded DNA antibodies) and low complement [21]. There are other biomarkers that can give clues about poor pregnancy outcomes in patients with SLE: Elevated ferritin as a marker of inflammation and low estradiol as a marker of poor placentation, are associated with preterm birth. In a meta-analysis where 362 patients with SLE were studied, their pregnancies showed an incidence of renal flare from 11% to 43%, acute kidney injury from 3% to 27%, and total loss of renal function in 11%. In another study, 113 pregnancies were evaluated in 81 women with preexisting biopsy with lupus nephritis (six women with class II, eight with class III, 48 with class IV, and 19 with class V). At the beginning of the pregnancy, 49% were in complete remission and 27% were in partial remission. Results included nine spontaneous abortions, one stillbirth, and five neonatal deaths. Thirty percent were premature births, and 33% were babies with low birth weight <2500 g. These outcomes were directly related to hypocomplementemia present at the time of conception and the use of aspirin during pregnancy [22].

Regarding kidney involvement, 33% had kidney flares (both during pregnancy and postpartum), 20 of these patients with reversible symptoms, and three with a progressive deterioration of glomerular filtration. One ended up on dialysis. These results were related to the maternal renal status prior to pregnancy.

In another study, they compared the results of pregnancy in patients with SLE who had already achieved clinical remission, taking into account the DORIS scale (definition of remission in SLE) and LLDAS (definition and initial validation of a lupus low disease activity state). A total of 49 patients were evaluated, when they were in modified clinical remission and 57 in modified LLDAS. In both groups, outcomes were similar: successful pregnancy, full-term births, fetal loss, miscarriage, small-for-gestational-age infants, low-birth-weight infants, maternal complications, and flares [23].

Pharmacological therapy is another point that must be taken into account due to the potential teratogenic effect of some medications. In general, the therapy used in pregnant women with SLE is safe (prednisolone, azathioprine, and hydroxychloroquine [HCQ]), and can even be continued without problems during lactation. However, in the case of women with lupus nephritis, many receive immunosuppressants such as mycophenolate mofetil (MMF), this drug has teratogenic potential (microtia and atresia of the external auditory canal, orofacial and cardiovascular malformations and digital hypoplasia), for which it should be discontinued before at least 6 weeks before conception in order not to have residual effects due to its enterohepatic circulation [24]. For these patients, the ideal would be to switch to azathioprine. In a study of 23 women with lupus nephritis with a low SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) had switched to azathioprine before conception, there were no flares in 18 pregnancies and only one case in the postpartum period after 17 live births. It was also found that as the dose of prednisolone or SLEDAI was required to be increased, the prognosis of pregnancy worsened [25].

4.1 Preeclampsia or lupus outbreak: “the great simulator”:

For several decades and until reactively recently, pregnancy in patients with SLE was discouraged due to the state of maximum activity with which it’s related and deleterious consequences. It was routinely considered an absolute contraindication in these women. At present, according to the evidence, we know that it is possible to have a pregnancy with excellent outcomes as long as certain conditions are met (stable SLE or low activity in the 6 months prior to conception, since patients with active disease at this time have the highest risk of an outbreak during pregnancy), and that this is of strict multidisciplinary management. The PROMISSE study (Predictors of Pregnancy Outcome in SLE and antiphospholipid syndrome) determined the degree of risk of exacerbation in women with stable SLE and found that 385 women with SLE (31% with renal involvement/nephritis), the mild or moderate outbreaks reached 15%, while severe ones were 5%. Quite the opposite with patients who became pregnant with the active disease even 6 months earlier, where relapses reached almost 60% [26].

In a prospective study where the outcomes in the pregnancies of 132 women with SLE were studied, there were outbreaks of SLE in 75 of the 132 pregnancies, mild in 84 cases, moderate in 11, and severe in 19. Before pregnancy, 36% had glomerulonephritis, 33% had joint manifestations, 37% had comp hematological disease, 13% had a skin disease, 6% had neuropsychiatric manifestations, and 1% had serositis. During the 6 months before conception, 48% had mild and/or stable clinical manifestations. Anti-dsDNA antibodies were positive in 56% and anti-ENA antibodies in 47%: anti-Ro/SSA: 32.5%, anti-La/SSB: 1.5%, anti-U1RNP: 4.5% and anti-Sm: 6.8%. In the multivariate analysis, the indisputable predictor of relapse of any severity was the number of relapses that the patients had before pregnancy. In each of the groups of outbreaks, according to their severity, there were several predictors that warned about it: mild was associated with hematological abnormalities before pregnancy, moderate was due to low C3 or C4, and severe was due to having involved with renal compromise, some type of glomerulonephritis, before or during conception. Protective factors it was observed the longer the duration of the disease there is more possibility. Joint involvement was predicted by anti-dsDNA positivity. Borella et al in made a study about pregnancy and SLE in which there were obtained 110 live births of 132 pregnancies. 81 were term babies and 29 were preterm. There were 22 losses: 14 miscarriages, seven stillbirths, and one volunteer. Fetal loss and small gestational age were associated with preeclampsia. Live births were obtained in 110 of the 132 pregnancies. Eighty-one were term babies and 29 were preterm. There were 22 losses: 14 miscarriages, seven stillbirths, and one volunteer. Fetal loss and small-for-gestational-age fetus were associated with hypertension at conception, miscarriage by a number of steroids taken in the last year before conception, stillbirth by a number of relapses in the last year before conception, premature birth and preeclampsia due to the coexistence of APS together with anti-dsDNA antibody levels before conception, and premature rupture of membranes due to a high ECLM (European Consensus Lupus Activity Measurement) score 6 months before conception. First births may be associated with a higher risk of exacerbation in SLE pregnancy compared to subsequent pregnancies, and the pattern of prior SLE involvement may be useful in predicting the course of SLE during pregnancy. Flare manifestations during a woman’s pregnancy tend to reflect prior organ involvement [22].

In Asian cohort, 153 patients of 240 pregnancies predominantly Malaysia, India and China there were 61.7% of the cases with complications, being the most common prematurity, miscarriage and presence. Use of HCQ with decrease in complications including preeclampsia, prematurity and intrauterine growth restriction ( IUGR) [27].

In a cohort in Trinidad, a cross-sectional analysis and analysis of negative outcomes in pregnancies of 122 Afro-Caribbean women with SLE and without SLE was performed. In women with more that one pregnancy the total number of pregnancies as similar in women with or without diagnosis of SLE. A lower proportion of women with SLE had ever been pregnant compared to women without SLE. In multivariate logistic regression analysis, SLE pregnancies were more than twice as likely to end in stillbirth. The odds of early miscarriage and second-trimester miscarriage were higher in pregnancies with SLE than in pregnancies without SLE. Ectopic pregnancy and preterm birth were higher in pregnancies conceived after diagnosis. Evidence of high levels of both IgM and IgG lupus anticoagulant was found among women who reported three or more miscarriages and elevated IgG in cases of ectopic pregnancy [28].

Pregnancy outcomes in SLE patients, the effect of flare, and treatment on pregnancy outcomes were examined in a study conducted in Saudi Arabia. Pregnancies in patients with SLE and active lupus nephritis, with anti-Ro/SSA antibodies, aPL, hypertension, Raynaud’s phenomenon, active disease at conception, and SLE exacerbations, were found to be at increased risk of adverse pregnancy outcomes [29] really without much difference with the other existing cohorts.

In Oman, a study found, apart from the complications already mentioned above where they do not differ from the rest, that pregnant patients with SLE and apart from antiphospholipid syndrome develop deep vein thrombosis and pulmonary embolism; therefore, it is a significant predictor of this type of complications (Tables 1–3) [30].

Prematurity

Fetal loss (miscarriage or intrauterine fetal death)

Intrauterine growth restriction

Small-for-gestational-age newborns

Preeclampsia

HELLP syndrome (eclampsia/hemolysis, elevated liver enzymes, low platelets)

Premature rupture of membranes.

Table 1.

Main complications in pregnancy in patients with SLE.

Disease activity at conception or 6–12 months before

Active nephritis during pregnancy or history of lupus nephritis

Severe organ involvement and end-stage damage to target organs

Table 2.

Factors directly proportional to SLE.

Lupus nephritis = preeclampsia. (Both become indistinguishable)

Premature labor: Directly proportional to its incidence with the activity of the disease Relationship with the use of treatment during pregnancy (especially glucocorticoids (prednisone 10 mg/day or higher).

Patients with antiphospholipid antibody syndrome (APS) or SLE with positive antiphospholipid (aPL) with a history of pregnancy morbidity and thrombosis, presence of lupus anticoagulant, and triple positivity for aPL antibodies.

Table 3.

Most common and/or expected adverse results.

According to the Hopkins Center for the management of pregnancy in lupus patients, there have always been three major doubts over time, and thanks to the existing evidence we can know at this time. First, if there really is a greater probability that there will be outbreaks during pregnancy and if so, which organs and/or systems will be most affected. Second, if there will be a renal compromise in these pregnancies and the third is if these patients really have a higher risk of presenting complications at the obstetric level. Today, we know that the answer is yes to everything. There is definitely a risk that outbreaks are more common during pregnancy, obtaining similar results in the different cohorts existing at the time, which include patients of all kinds of races, ethnicities, socioeconomic strata, associated comorbidities, etc. These factors are determining [31]. For example, in American studies, more than half of the patients are African–American. In this group of patients, the flare rate is much higher than in Caucasian patients and similar to Indian patients. Outbreaks in the renal and hematologic systems increase during pregnancy, whereas the involvement of the musculoskeletal system is less.

The differentiate lupus flare from preeclampsia, we have certain clinical predictors such as decreased complement serum levels, normal blood pressure and good response to prednisone, the latter use of intravenous to compare will worsen preeclampsia, howewer, it is necessary compare and analize the risk vs. benefity. Now there is the possibility of advising patients with lupus that despite having a lupus flare, their pregnancy can continue and at the same time decrease the activity of the disease as long as the rheumatologist, obstetrician, perinatologist, and other multidisciplinary team are pending the development and outcome of pregnancy. Because the arsenal of medications allowed in pregnancy is limited, in the acute management of a lupus flare that endangers the lives of patients, sometimes it is necessary to choose between fetal and maternal well-being. The beauty of this is that lupus activity can be controled with prednisone, HCQ and azathioprine. For moderate flare-ups, prednisone at 1 m/k is used, for urgent situations such as severe flare ups, pulses of intravenous methylprednisolone 1000 mg/day dose, for 3 days it’s effective.

One of the culprits in pregnant women is for lupus outbreaks apart from estrogens, is prolactin. This is associated with increased disease activity [32]. These patients also have a higher rate of complications in terms of morbidity, especially in relation to metabolic disorders (gestational diabetes and hyperglycemia), hypertensive disorders of pregnancy (including preeclampsia), and urinary tract infections. Greater complications during labor have also been shown, they have a higher risk of premature rupture of membranes and require cesarean sections in a greater proportion than healthy women [33]. In addition, women with SLE who develop anti-prolactin antibodies during their pregnancy are less likely to have both maternal and fetal complications compared to those who do not. For this reason, the administration of bromocriptine with the purpose of blocking prolactin is accepted as a way of preventing relapses during pregnancy and, in turn, obtaining a good result for both the mother and the product. It is administered even postpartum as it is related to less use of immunosuppressants and steroids [34].

5. The fetus and fetal complications: “pandora’s box”

The negative outcome of pregnancy in patients with SLE is always due to complications due to abortion, premature birth, and neonatal lupus. We know that this incidence has a multifactorial origin.

In the high-risk pregnancy controls of these women, certain protocols emanating from the existing guidelines and, of course, from the evidence must be adhered to, adjusting the frequency of fetal surveillance according to the maternal and/or fetal status [35]. Fetal surveillance is assessed based on biometry and Doppler ultrasound findings of the umbilical and uterine arteries at 20–24 weeks, since it is extremely valuable data for pregnancy disorders associated with the placenta, such as preeclampsia and IUGR, especially the distinction between early and late, since this will help us to adapt at the time of delivery and thus reduce perinatal morbidity and mortality. The mode (vaginal vs. cesarean section) and timing of delivery are influenced by maternal factors (hypertensive disorders and anticoagulation status) as well as fetal conditions during pregnancy [3].

Neonatal lupus syndrome compromises several organs, where skin involvement can be present at birth, or appear between 4 and 6 weeks of age in the form of erythematous, photosensitive, and ring-type lesions. As the first days of birth go by, the concentrations of maternal antibodies decrease, and with this, they are resolved without major problem. We can also find liver involvement that includes liver enzyme profile without clinical expression, mild hepatosplenomegaly, cholestasis and hepatitis, hematological with manifestations such as anemia, neutropenia, thrombocytopenia and, rarely, aplastic anemia. In a small cases, central nervous system involvement such as changes in white matter, calcification of basal ganglia, and hydrocephalia [36].

The case is different in cardiac compromise because despite being able to have evidence of a structurally healthy heart, the damage produced in the conduction system is usually irreversible. Fetal echocardiography is especially indicated in the context of the presence of maternal anti-Ro/SSA or anti-La/SSB antibodies due to the risk of congenital heart block (CHB), which reaches a rate of 16%. The suggestion accepted so far is to perform weekly fetal echocardiograms from week 16, with great reservations because it is still unknown if it is a truly cost-effective measure that is applicable to all women regardless of whether or not they are at risk of the fetal congenital block, in order to perform screening of these patients [37].

CHB is the most severe manifestation of neonatal lupus. Its pathophysiology is well-documented, where the transplacental passage of maternal antibodies (anti-Ro (Ro52) and Anti La) is related to direct damage to the fetal conduction system from approximately 18 to 25 weeks. The prevalence of CHB is 2% of cases in women with detected anti -Ro antibodies and 10-20% of cases with history of a child with previous pathology. Clinical findings are related to arrhythmias and conduction system abnormalities, such as complete atrioventricular blocks, fetal bradycardia and/or congestive heart failure, premature atrial contractions, pericardial effusion, or tricuspid regurgitation [38]. More than half of the children born with this pathology require the urgent insertion of a pacemaker since it is a life-threatening condition. The most accepted theory is that CHB originates from chronic inflammation of the fetal conduction tissue that mainly affects the atrioventricular node. Histology reports have found lymphocytic infiltrates, antibody and complement deposits, calcification, and fibrosis. It is believed that the presence of maternal antibodies goes hand in hand with autoimmune diseases, such as SLE and Sjogren’s syndrome, although it also occurs in women who do not apparently have any disease that explains this association in the fetus. The antigenic components of the antibodies have shown the existence of almost 100% of these directed to the RO-52 protein. Ro60 and anti-La antibodies are also related to CHB to a lesser extent. There are other antibodies that also participate, such as antibodies against muscarinic acethylcoline receptor of neonatal heart. Calreticulin has been indicated as an additional serological marker and is closely related to Sjogren’s syndrome [39].

Prenatal therapy with fluorinated steroids (FSs) is performed in cases of incomplete heart block, although evidence indicates that its use in many cases did not prevent the progression of the block and the subsequent need for the use of pacemakers (Figure 4).

Figure 4.

Response in degrees of blockade to therapy with FSs [40].

Therapy with FS can be started as long as both fetal (IUGR and oligohydramnios) and maternal side effects (infections, osteoporosis, osteonecrosis, and diabetes) vs. beneficial effects are taken into account. In a French cohort, it was determined that the use of FS was not associated with CHB regression or increased survival, despite evidence showing positive effects on cardiomyopathy, endocardial fibroelastosis, and hydrops fetalis [41].

In the European and American cohorts, no conclusion was found that could direct treatment. The prognosis after pacemaker placement in children is excellent. In another multicenter study, the combination with FS plus immunoglobulin and plasmapheresis was performed, where better results were obtained compared to those treated with corticosteroids alone. However, in another series, encouraging results were not obtained in relation to the efficacy of monotherapy with IVIG or plasmapheresis.

Regarding treatment, a survey was conducted by the organizing committee of the ninth International Conference on Reproduction, Pregnancy, and Rheumatic Diseases. For first grade is recommended start treatment with dexamethasone or hydroxychloroquine. For the second degree, dexamethasone was recommended. For third grade, starting dexamethasone or IVIg was recommended, although a percentage (27%) would no longer start treatment. Dr. Jill Buyon, who is an expert on the subject, recommends a treatment scheme according to the weeks of gestation together with the performance of the fetal echocardiogram (Figure 5) [42].

Figure 5.

Buyon scheme for the management of CHB.

Complications associated with neonatal antiphospholipid antibodies: the most frequent are prematurity and IUGR. These patients have a worse pregnancy outcome and neonatal outcome if they already have a history of thrombosis. Antiphospholipid thrombosis is unusual in the newborn or fetus despite the transplacental passage of antibodies.

6. Fertility and assisted reproduction techniques: “when you want to propitiate the miracle despite the risks.”

Although there is no evidence that the disease itself decreases fertility, what we do know is that high levels of activity and the use of certain medications can affect the fertility of patients. Cyclophosphamide (CYC), which is the most well-known example of drug, can cause everything from menstrual irregularities to even premature ovarian failure. This will depend on the age of the patients and the dose used and accumulated. When the manifestations of SLE are mild, consideration should be given to not using any treatment that could be gonadotoxic or should be weighed against the risk of ovarian dysfunction. Consider ovarian reserve measures, especially in young patients, if you have important risk factors for a probable alteration of fertility. Usually, the most extensively studied method for the prevention of ovarian failure in patients with SLE includes treatment with gonadotropin-releasing hormone analogs (GnRH-a). This should be administered 22 days before starting or continuing CYC and preferably before starting immunosuppressive treatment.

Embryo and oocyte cryopreservation are options for preserving fertility in patients who are stable enough to safely undergo ovarian hyperstimulation. They are generally safe for patients.

Ovarian hyperstimulation syndrome is a rare complication that results in severe capillary leak syndrome and this increases the risk of thrombosis and renal compromise, which in turn could trigger a flare in patients. However, assisted reproduction techniques have good results and many patients, the vast majority, have been treated prophylactically with anticoagulants. It is imperative to consider prophylactic anticoagulation in patients with high-risk antiphospholipid syndrome and is mandatory for those with confirmed antiphospholipid syndrome. The usual regimen [low-dose aspirin with low-molecular-weight heparin (LMWH)] should be recommended as antithrombotic treatment during pregnancy according to the individual risk profile of each patient.

Concomitant therapy with GnRH analogs, usually leuprolide, appears to decrease the risk of premature ovarian failure. Addressing fertility problems in these patients requires a multidisciplinary collaboration on the part of the perinatologist, obstetrician, rheumatologist, and pediatrician, and this union of powers will make the result favorable and successful [43].

7. Conclusions

• It is duty of physicians to instruct patients with SLE to receive clear, precise and above all timely advice and contraception.

• Pregnancy planning by the multidisciplinary medical team and the patient increases the probability of a successful outcome and is a vital strategy to reduce perinatal morbidity and mortality complications.

• The combination of estrogen and progestin or progestin-only preparations does not increase the incidence of thrombotic events in patients with low or no disease activity, no prior history of thrombosis, and negative aPL titers.

• Patients with contraindication for estrogen-based contraception: who have positivity with high titers of antiphospholipid antibodies (with or without antiphospholipid syndrome) and with risk factors for developing thrombotic events.

• Progesterone is essential for the initiation and maintenance of pregnancy.

• PIBF expression is crucial for normal pregnancy progression.

• Pregnancy in women with SLE, especially those with significant renal involvement (lupus nephritis), is associated with an increased risk of developing preeclampsia, fetal growth restriction, fetal loss, and preterm delivery regardless of activity level.

• CHB is the most severe manifestation of neonatal lupus.

• Prenatal FS therapy in cases of incomplete heart block in many cases did not prevent the progression of the block and subsequent need for pacemaker use.

Acknowledgments

I want to especially thank my patients who throughout these two years of being a rheumatologist have taught me important life lessons. Thanks to them we are here. Thanks to my teachers, especially doctors Carlos Abud, Enrique Cuevas, David Herrera, Ricardo Moreno, and doctor Eva Santillan from the Ignacio Morones Prieto Central Hospital. To my son and my husband. All my love and my affection.

Conflict of interest

The author has no conflict of interest for the realization of this chapter.

Nomenclature

SLE	systemic lupus erythematosus
SSA	anti-Sjogren’s syndrome A
SSB	anti-Sjogren’s syndrome B
APL	antiphospholipid antibody syndrome
IUD	intrauterine devices
ERK	extracellular signal-regulated kinases
MAPK	mitogen-activated protein kinase
PIBF	progesterone-induced blocking factor
NK	natural killer
MHC	major histocompatibility complex
DORIS	definition of remission in SLE
LLDAS	definition and initial validation of a lupus low disease activity state
MMF	mycophenolate mofetil
SLEDAI	systemic lupus erythematosus disease activity index
PROMISSE	predictors of pregnancy outcome in systemic lupus erythematosus
ANTI-ENA	extractable nuclear antigens
ANTI-U1RNP	ribonucleoprotein antibody
ECLM	European Consensus Lupus Activity Measurement
IUGR	intrauterine growth restriction
CHB	congenital heart block
FSs	fluorinated steroids
HCQ	hydroxychloroquine
CYC	cyclophosphamide
GnRH-a	gonadotropin-releasing hormone analogs
LMWH	low-molecular-weight heparin