Cecilia Nalli1 , Alessandro Iodice2 , Rossella Reggia1 , Laura Andreoli1 , Andrea Lojacono3 , Mario Motta4 , Antonella Meini5 , Elisa Fazzi2 and Angela Tincani1
(1)
Rheumatology and Clinical Immunology, Department of Clinical and Experimental Sciences, Spedali Civili and University of Brescia, Piazzale Spedali Civili 1, Brescia, 25133, Italy
(2)
Unit of Child and Adolescent Neuropsychiatry, Department of Clinical and Experimental Sciences, Spedali Civili and University of Brescia, Piazzale Spedali Civili 1, Brescia, 25133, Italy
(3)
Obstetrics and Gynecology, Department of Clinical and Experimental Sciences, Spedali Civili and University of Brescia, Piazzale Spedali Civili 1, Brescia, 25133, Italy
(4)
Neonatology and NICU, Spedali Civili and University of Brescia, Piazzale Spedali Civili 1, Brescia, 25133, Italy
(5)
Unit of Pediatric Immunology and Rheumatology, Pediatric Clinic, Spedali Civili and University of Brescia, Piazzale Spedali Civili 1, Brescia, 25133, Italy
Cecilia Nalli
Email: cecilianalli@libero.it
Alessandro Iodice
Email: alle.iodice@gmail.com
Rossella Reggia
Email: rossyr85@alice.it
Laura Andreoli
Email: box.lauraandreoli@libero.it
Andrea Lojacono
Email: alojacono2005@libero.it
Mario Motta
Email: Ivmott@tin.it
Antonella Meini
Email: antonella.meini@yahoo.it
Elisa Fazzi
Email: elisa.fazzi@gmail.com
Angela Tincani (Corresponding author)
Email: tincani@bresciareumatologia.it
Introduction
Rheumatic diseases often affect women during their childbearing years. For a long time, pregnancy was not recommended in women affected by most of the rheumatic diseases, because it was reported that the disease could become more aggressive during pregnancy, putting both the mother and the fetus at high risk. However, in the last 20 years the diagnosis and management of these diseases has greatly improved and the approach to pregnancy along with it: now, affected women are no longer discouraged from bearing children, as long as the disease can be sufficiently controlled during pregnancy.
Therefore, it is more important than ever that clinicians caring for women with rheumatic disorders introduce and discuss pregnancy and related issues with their patients. In order to both increase maternal compliance with a treatment plan and manage difficult cases, a multidisciplinary team (rheumatologists/internists, obstetricians, and neonatologists) should ideally care for patients throughout gestation. Recent data strongly support the validity of such a multidisciplinary team to ameliorate pregnancy outcome in women with rheumatic diseases [1].
Some important issues must be initially addressed with a patient suffering from a rheumatic disease who wishes to become pregnant:
· Impact of pregnancy on disease activity
· Impact of disease on gestational outcome
· Drug compatibility with pregnancy
· Presence of factors such as autoantibodies and disease severity that may interfere with pregnancy outcome.
Moreover, women with rheumatic diseases may be concerned that medication and/or disease activity could somehow influence the physical and mental development of the child. With this in mind, the short- and long-term outcome of the offspring of the pregnancies in women with rheumatic disorders becomes one of the most important issues in this field.
Pregnancy and Rheumatic Diseases
In order to fully understand the potential long-term impact of a mother’s rheumatic disease on her offspring, it is important to first understand the potential interactions between pregnancy and autoimmune disease, and the resulting immediate fetal and neonatal issues. These topics are discussed in detail in earlier chapters, a brief summary follows.
Pregnancy affects the course of various rheumatic diseases differently. As an example, systemic sclerosis (SSc) tends to remain stable during gestation [1] as does ankylosing spondylitis (AS). In the latter case, however, it is not so simple to evaluate disease activity, since pregnancy itself physiologically alters inflammatory indices and often causes low back pain. Well-defined data are available for rheumatoid arthritis (RA), a disease that shows a spontaneous amelioration during pregnancy in nearly 80 % of the cases [2, 3]. Still unclear is the course of systemic vasculitides during pregnancy: profound transformation of the immune and endocrine systems favoring Th-2 cytokine polarization [4–6] may explain the improvement of primarily Th1-mediated vasculitides (mainly Takayasu arteritis and Behçet disease) and the worsening of Th2-driven ones, such as granulomatosis with polyangiitis (Wegener’s granulomatosis) or eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome).
The literature is controversial regarding change in systemic lupus erythematosus (SLE) activity during pregnancy: while some authors report an increased risk for lupus flare, others reach the opposite conclusion, finding flare rates to be unchanged as compared to nonpregnant SLE patients [7]. It has been estimated that risk of SLE flare during pregnancy ranges from 7 to 33 %.
Influence of Maternal Disease on Children’s Outcome
Over the last 20 years, much effort has been directed towards improvement of pregnancy management, permitting women with rheumatic diseases to have safe and successful pregnancies. More recently, attention has shifted to whether rheumatic diseases and/or medication used for the management of these disorders impacts the subsequent development of children exposed to these factors in utero.
The frequency of preterm birth is high even in the general obstetric population, at rates of 12–13 % in the USA and 5–9 % in Europe; in addition, incidence of preterm birth is increasing [8]. One of the most frequent problems related to maternal SLE and certain other rheumatic diseases is preterm birth (birth before 37 weeks of gestation): this affects 23–28 % of SLE pregnancies [9]. Risk factors for preterm delivery include clinical and serological activity of the disease, high prednisone dose, hypertension [5], and thyroid dysfunction [10]. Preterm birth is mainly due to the preterm premature rupture of membranes (PPROM), but, in a number of cases, it is medically induced to protect the health of the mother and/or of the baby (due to onset of fetal distress or pre-eclampsia) [11]. Babies born before 28 weeks of gestation merit particular attention, because they are at highest risk for neonatal death, medical complications, and neurodevelopmental problems, most importantly cognitive impairment [12]. Low birth weight newborns (<2,500 g) and SGA (small for gestational age) neonates are also reported in SLE pregnancies, ranging from 6 to 35 % [11, 13], and likely to be related to placental dysfunction.
Data from the study of preterm delivery in normal women can (to some extent) be extrapolated to SLE and other rheumatic disease patients. Importantly, prematurity is a critical prognostic factor for perinatal complications such as hypoxic-ischemic brain injury or intracranial hemorrhage that can lead to long-term neurodevelopmental disabilities, especially in infants born with a very low birth weight (VLBL) [14]. Cognitive deficits without major motor deficits are by far the dominant neurodevelopmental sequelae in infants with VLBW. Moreover, an increased prevalence of cognitive impairment, poorer educational achievement, and specific language difficulties has been repeatedly observed among school-age children after extremely preterm birth, as compared with those born at full term [15, 16].
The rate of survival in very premature infants has gradually increased because of progress in therapy and quality of care, but this achievement has raised issues about the increasing rates of neurological disabilities and cognitive dysfunction [17]. In this group, various brain lesions can occur, including periventricular leukomalacia (PVL), a distinctive form of cerebral white matter injury that accounts for most of the subsequent motor abnormalities, cognitive defects, and visual impairment, and is caused by hypoxic-ischemic events.
Germinal matrix-intraventricular hemorrhage is the most common variety of neonatal intracranial hemorrhage, and its incidence is directly related to the degree of prematurity. Long-term outcome, including incidence of major neurological sequelae, depends primarily on the degree of associated parenchymal injury [14]. Recently, Volpe coined the term “encephalopathy of prematurity” in order to describe a complex amalgam of primary destructive disease (PVL accompanied by neuronal/axonal disease) and secondary maturational and trophic disturbances [18]. Encephalopathy of prematurity is clinically associated with a high occurrence of cognitive, behavioral, attentional, or socialization deficits in this population even without any major motor deficits (e.g. cerebral palsy) [19].
The spectrum of visual problems in preterm infants is extremely broad; it may include both peripheral problems (strabismus, refraction disorders, and retinopathies) and problems of central origin. Cerebral visual impairment is among the most common sequelae of a preterm birth and usually arises from hypoxic-ischemic injury to watershed areas of the brain [20]. Cerebral visual impairment includes all visual dysfunctions “caused by damage to, or malfunctioning of, the retrogeniculate visual pathways (optic radiation, occipital lobe and associative visual areas) in the absence of visual system abnormalities” or of any major ocular disease [21, 22]. Recently Fazzi et al. suggest a widespread involvement of higher visual processing systems, involving both the ventral and dorsal streams, in preterm children with PVL. These children displayed an uneven neuropsychological profile, with deficits in visual object recognition, visual imagery, visual–spatial skills, and visual memory, and sparing of visual associative abilities, non-verbal intelligence, and face and letter recognition [23, 24].
In women with rheumatic diseases, in particular SLE, fetal complications and prematurity may be related to the presence of aPL, which are autoantibodies that are hallmarks of and are known to be associated with thrombosis and pregnancy loss [25]. Rare cases of thrombosis related to maternal transplacental passage of aPL have been described in neonates born to mothers with APS: between 1987 and 2002 only 13 neonatal thromboses possibly related to acquired aPL were reported [25]. In 2003, a large prospective European study was initiated with the aim to assess the outcome of the offspring of mothers with APS. During a 5-year follow-up, it was shown that one-third of infants passively acquire maternal antibodies, which are subsequently cleared during the first 6 months of life and usually become undetectable by the first year of life [26]; however, no cases of neonatal thrombosis were reported in 134 children born to mothers with aPL during pregnancy [27, 28].
It is relatively common to find healthy children who are positive for aPL, mainly anti-beta 2 glycoprotein I (b2GPI). Our group studied 57 healthy children aged 1-year and positive for IgG anti-b2GPI who were born to 56 mothers with systemic autoimmune disease attending our multidisciplinary pregnancy clinic [14 SLE, 11 undifferentiated connective tissue disease, 10 primary Sjögren’s syndrome, 7 primary APS, 4 mixed connective tissue disease, 2 rheumatoid arthritis, 5 asymptomatic aPL carriers, 3 anti-nuclear antibody (ANA) carriers]. Only 25 % of these mothers were found to be aPL positive during pregnancy. All children were free of thrombotic events. The detection of anti-b2GPI in early childhood suggests a de novo production of antibodies, related not to the maternal background, but rather to environmental factors (vaccines, infections or beta 2-glycoprotein I in food) acting on the children’s immune systems. Beta 2-glycoprotein I, the main target of aPL, is a protein composed of five different domains [29]. Recent literature suggests antibodies directed against different domains of b2GPI may have different biological effects. aPL found in healthy children carry preferential specificity for domain 4/5 of b2GPI, while patients with APS mainly have antibodies directed to domain 1. The two types of antibodies likely carry different pathogenic potential: antibodies versus domain 1 seem to cluster in patients with systemic autoimmune conditions, including APS, and to be more specific for thrombotic events, while antibodies specific for domain 4/5 have been identified in subjects with no history of thrombosis or systemic autoimmune disease [29].
To test the hypothesis that the presence of anti-b2GPI IgG in these children was not related to maternal autoimmune background we evaluated anti-b2GPI in 100 children (from 3 months to 7 years of life) who were admitted to the hospital for elective surgical procedures and whose families were free of autoimmune diseases. Antibody levels showed different titers to be associated with different age ranges. In particular, pre-school children displayed IgG anti-b2GPI in 48 % of cases; yet, no cases of thrombosis were found. These data support the hypothesis that anti-b2GPI in children are the result of environmental triggers such as viral infections and vaccines.
Neonatal lupus is a passively acquired autoimmune disease mediated by maternal anti-Ro/SSA and anti-La/SSB antibodies, which can cross the placenta and harm the fetus. The less severe form of neonatal lupus includes typical cutaneous manifestations, usually transient, such as annular or elliptical rash of the face, scalp, trunk, or extremities. Rash usually appears 6 weeks after delivery and disappears without any sequelae by the age of 6–8 months. Anti Ro/SSA antibodies can also damage fetal cardiac conduction tissue resulting in conduction abnormalities, termed first-, second-, or third-degree (complete) congenital heart block (CHB). Due to important bradycardia, children born with complete CHB usually require early implantation of a pacemaker. Studies evaluating the long-term outcome of these children note no negative effects on neurodevelopment and suggest a normal quality of life.
Few data are available regarding fetal morbidity in RA pregnancies: outcomes in women with well-controlled RA are comparable to those in the general population. However, women affected by RA (or other inflammatory arthritis) who experience a higher level of disease activity during the third trimester and/or are taking a moderate to high amount of glucocorticoids are at risk for SGA babies and for preterm delivery [30, 31], with all the associated potential for subsequent neurodevelopmental sequeli. A recent study found a high rate of preterm birth in these pregnancies, but no association between this complication and disease activity at conception or during pregnancy was noticed [32]. According to the few available case reports, ankylosing spondylitis has no significant effects on pregnancy outcome [33, 34].
Systemic vasculitides are uncommon diseases and few cases of pregnancies are reported in literature. The most frequent fetal complications due to maternal disease are low weight at birth and IUGR, and, less often, preterm delivery and fetal loss [35]. The incidence of fetal complications seems to be higher in mothers with more severe disease and with a higher number of damaged vessels. In children of mothers with ANCA-associated vasculitides, two cases of microscopic polyangiitis-like syndrome were described in the newborns, potentially due to the passage of maternal ANCA through the placenta. In one case, the syndrome was characterized by purpuric rash that spontaneously disappeared within 3 days; the other case developed pulmonary hemorrhage and kidney involvement successfully treated with high-dose steroid therapy and exchange transfusion. It has been suggested that maternal treatment with immunosuppressive therapy may prevent the onset of this syndrome in the child [36–38]. Several cases of transient neonatal Behçet’s disease have reported, probably due to diffusion of lesional lymphocytes in the placenta, but more data are needed [39]. Generally, the outcome of pregnancy from systemic vasculitides seems to be favorable in the majority of cases if pregnancy is planned during a remission period of the disease.
Thyroid autoimmunity is often part of the picture of systemic autoimmune diseases. The transplacental passage of maternal anti-thyroid antibodies can influence fetal clinical outcome. Transplacental passage of thyroid stimulating immunoglobulin can result in thyrotoxicosis in the fetus after 20 weeks gestation, when the fetal thyroid can respond to the stimulus. Both fetal hypo- and hyperthyroidism may occur, especially during the first trimester of gestation. Maternal hypothyroidism is associated with impaired fetal neurological development and delayed mental and motor development [40] (Table 15.1).
Table 15.1
Potential effects of transplacental passage of maternal antibodies during pregnancy (modified from Parke) [41]
|
Maternal antibody |
Fetal outcome |
|
Anti-Ro/SSA, anti-La/SSB |
Neonatal lupus: transient cutaneous rash, congenital heart block (various degrees), asymptomatic elevation of liver enzymes, cytopenia |
|
Antiphospholipid antibodies |
Fetal wastage, placental insufficiency, prematurity and preterm birth, fetal/neonatal clinical thrombotic events (rare) |
|
Thyroid antibodies |
Hypothyroidism, hyperthyroidism |
Influence of Maternal Therapy on Pregnancy Outcome
The management of rheumatic diseases often requires immunosuppressive therapy during pregnancy. Drugs can cross the placental barrier and enter into the fetal circulation. Obviously, it is desirable to minimize fetal exposure and to avoid known teratogens and mutagens. As a result, pregnancy should be planned for a period of remission in which no drugs (or drugs compatible with pregnancy) are used. It is advisable for these women to consult with a multidisciplinary management team in which different experts (rheumatologist, obstetric expert, neonatologist, psychologist, and neuropsychiatrist) cooperate to handle and integrate the patients’ needs. While a full discussion on medication use during pregnancy is discussed elsewhere, below we will highlight some of the important documented effects of specific agents on childhood development.
Several studies have investigated the effects of antenatal steroids on adverse neonatal neurologic short- and long-term outcomes with conflicting results. Spinillo et al. described an increased risk of leukomalacia and neurodevelopmental abnormalities in preterm babies (born between 24 and 34 weeks gestation) exposed to multiple doses of dexamethasone (DEX); in the same population, betametasone may be safer [42]. Lee et al. studied neurodevelopmental outcome in a large population of extremely low birth weight infants exposed prenatally to DEX, betamethasone, or no steroid (control group). Prenatal betamethasone exposure was associated with reduced risks of hearing impairment and neurodevelopmental impairment when compared with no prenatal steroid exposure, whereas prenatal dexamethasone was associated with a less favorable outcome [43]. In 2004 a group of 13 children exposed to DEX antenatally (cumulative dosage range 20–260 mg) were tested with different scales according to their age. All of them were found to have a normal intelligence quotient (IQ > 90) [44]; these results need to be confirmed with a larger series.
A large 2003 case–control study evaluated 133 pregnancies in patients taking hydroxychloroquine (HCQ) throughout pregnancy: no significant differences were found either in pregnancy or in neonatal outcome. Follow-up data of these children were collected at a mean age of 26 months: no visual, hearing, growth or developmental abnormalities were reported by pediatricians. In addition, no conduction abnormalities were reported [45]. Motta et al. found no ocular or neurodevelopmental abnormalities in 40 infants at 1, 3, 6, and 12 months of life born to mothers who were taking HCQ (200 mg/daily) during pregnancy and lactation [46]. Considering that HCQ may accumulate in the retina of patients taking this drug, this rare collateral effect was evaluated in children born to mothers taking HCQ during pregnancy. The ophthalmologic evaluation in several studies did not show retinal abnormalities [47, 48].
Available data on newly introduced drugs are sparse and limited because, for ethical reasons, it is not possible to include pregnant patients in randomized clinical trials. However, experience with pregnancies inadvertently exposed to biological drugs is slowly accumulating. Biological manufacturers recommend stopping these medications during pregnancy and lactation and both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) do not consider biologic therapies to be safe during pregnancy or lactation [49–51]. Anti-tumor necrosis factor (anti-TNF) agents and anakinra are classified as pregnancy FDA category B, while rituximab, abatacept, and tocilizumab are pregnancy FDA category C. These drugs are transported through the placenta and reach important levels in exposed newborns. As an example, the concentration of infliximab in cord blood is about 160 % that found in maternal blood because the antibodies containing the Fc component of IgG1 are actively transported through the placenta. Other biological agents show less transplacental passage: 4–7 % with etanercept and 3.9 % with certolizumab [52]. No data were found concerning use of tocilizumab and golimumab during gestation; abatacept and anakinra experiences are very limited (2 and 10 pregnancies, respectively) [52]. On the contrary, a significant number of pregnancies exposed to infliximab, etanercept, and adalimumab are reported in the literature. Even though the available data are too limited to claim safety of these drugs during gestation, the existing evidence suggests that the overall risk of anti-TNF agents is relatively low. It is often difficult to understand whether fetal complications (preterm births, IUGR, small for gestation age babies) are due to the effect of biological drugs or to maternal disease activity.
Some reassuring data are available on the effects of immunosuppressive drugs on the developing fetal immune system. Airò et al. studied 17 babies born with complete CHB who were treated in utero with high-dose DEX therapy, and characterized the production, function and survival of T lymphocytes. They observed that T-cell compartments in these children did not show any relevant abnormality and were comparable to those of age-matched controls [53]. The same authors studied a child born to a woman affected by an overlap syndrome of systemic lupus erythematosus/polymyositis (PM), who presented with active myositis at the beginning of pregnancy. Therapy with cyclosporin, corticosteroids, hydroxychloroquine, and high-dose intravenous immunoglobulin induced a progressive remission of clinical and laboratory signs of myositis. Although the child was born premature (33 weeks) and small for gestational age, he had normal growth and did not show any clinical signs of immune deficiency. Lymphocyte phenotype and function studies, as well as response to vaccination, were also normal [54].
Cimaz et al. also performed immune function evaluations in both humoral and cellular compartments in 14 children of patients with autoimmune disorders taking immunosuppressants including cyclosporin during pregnancy. Overall, in utero exposure did not significantly influence the children’s immune systems. Complete blood count, immunoglobulin (Ig) serum levels, IgG subclasses, and lymphocyte subpopulations were determined at about 1 year of age and no alterations compared to controls were found. All children responded satisfactorily to hepatitis B vaccination [55].
Limited data are available on long-term follow-up of children exposed in utero to immunosuppressants, in particular, for neurological outcome; further studies are warranted to improve the current state of knowledge.
Neurodevelopmental Outcome
Behavioral and neuropsychological outcome in children born to patients with rheumatic disease is a matter of great interest. In fact, a number of heterogeneous factors may interact to influence the neuropsychological development of these children.
As stated above, IgG maternal antibodies can cross the placenta after week 12 of gestation and potentially act on the developing fetus. Maternal aPL could potentially react directly with fetal cerebral tissue (during the fetal period the blood–brain barrier is still incomplete) and continue their pathogenic effect during the early life of the child through microthrombosis and inflammatory reactions leading to further disruption of the blood–brain barrier. The in vitro demonstration of binding of aPL to neuronal cell-surface antigens supports a possible direct action of autoantibodies on the neurons of these children. These perspectives are supported by several in vivo animal models [56]. A number of studies support a relationship between aPL positivity and neurological manifestations such as migraine, epilepsy, and movement disorders in positive patients [57], but there are no data suggesting an increased risk of development of these disorders in the offspring of aPL-positive patients.
In toddlers and children born to mothers with aPL positivity, intelligence levels have been found to be normal: it may be concluded that aPL exposure during fetal life does not impair global intelligence capacity [58–60]. However, language delay and learning disabilities (LD) have been described in children of mothers with APS with a higher rate than that of the age-matched peers. The transplacental passage of maternal aPL as well as other well-known risk factors (prematurity, genetic and environmental factors) could contribute to the occurrence of LD in this population [59].
Several studies have been performed on mothers with SLE to evaluate their children’s long-term outcome. Maternal SLE does not appear to impair intelligence levels independent of its association with prematurity; however, it may increase the occurrence of LD (and particularly dyslexia) in male children [50, 60, 61].
Lahita first investigated the prevalence of learning disabilities in the children of parents with SLE. Forty-five percent of the 55 male children of mothers with SLE had an LD, whereas none of the 13 children of fathers with SLE were affected. Furthermore, if the finding of LD was significantly attributable to the stress of having a parent with chronic disease, then LD should have been found in the female children also [61]. Over 90 % of the learning disabilities were diagnosed as dyslexia, however Lahita’s definition of dyslexia in the offspring of patients with SLE—discrepancy between verbal and performance IQ—does not correspond to the current DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, fourth edition text revision) definition of dyslexia which is reading achievement substantially below that expected, given the person’s age, measured intelligence, and age-appropriate education [59]. McAllister et al. also proposed an association between maternal immunoreactivity, as represented by women with SLE, and adverse child developmental outcome, particularly in male children (hyperactivity, attention deficit, and reading difficulties) and considered the role of prematurity, but with a different methodological weakness: the authors only asked to report the presence or absence of each developmental problem [62].
Subsequent studies performed by direct examination of the children rather than by interviewing the parents or reviewing school records have confirmed a high incidence of LD in offspring of women with SLE [58]. In one study, LD were related to presence of maternal aPL and, in the other case, to maternal anti-Ro/SSA and anti-La/SSB antibodies and disease activity during pregnancy. The latter study, by Ross et al., compared children of SLE mothers to gestational-age-matched controls to eliminate the confounding effect of prematurity on diagnosis of neurodevelopmental problems [60].
Urowitz et al. confirmed the previous findings reporting an increased rate of neurocognitive abnormalities in the offspring of mothers with SLE. Analyses of the neuropsychological domains revealed impairment in learning, memory, and behavior in 57 SLE children (with age range of 2–26 years) compared with matched controls. It was difficult to differentiate the impact of prematurity or fetal distress from that of maternal disease in this study however since neurocognitive abnormalities were seen more frequently in small for gestational age or low weight at birth offspring [63]. Multiple studies confirm that prematurity is an independent risk factor for neurodevelopmental disabilities, especially in very low birth weight infants; consequently, the majority of neonatal complications of children born to mothers with rheumatic diseases could be a direct consequence of prematurity.
The sequelae of encephalopathy of prematurity include a high occurrence of cognitive, sensorial, behavioral, attentional, or socialization deficits even without major motor deficits (e.g. cerebral palsy) [14–19]. However, it is important to note that a number of the cited studies on children of mothers with SLE did focus on the relationship between premature birth and LD occurrence and failed to show a statistically significant relationship. In fact, LD were also described in term birth babies, supporting the hypothesis of a multifactorial origin of the neurodevelopment abnormalities occurring in children of patients with SLE [58–61].
Interestingly, a recent study analyzed the relation between azathioprine (AZA) therapy during pregnancy and developmental delays in offspring. Authors evaluated 60 children born to mothers with SLE who were exposed to AZA in utero: 15 (25 %) required neuropsychiatric evaluation, in most cases for a speech delay. AZA was significantly and independently associated with increased special educational requirements even after controlling for confounders (including pregnancy duration, SGA, and maternal aPL positivity) [64].
In addition to effects of autoantibodies, prematurity, and medication, another factor to be considered is the potential influence of the mother’s chronic illness on psychological and behavioral aspects of her children. Several studies have focused on the impact of chronic illness on quality of life and consequent psychological health and function [65–68]. Chronic disease may have an adverse impact on patients’ quality of life as well as on relationships with other family members, including the offspring. Patients with chronic disease may feel insecure about their future and may be fearful of becoming parents. Those with musculoskeletal limitations in particular may doubt their ability to care for their children. For a woman, pregnancy and the upbringing of the newborn may generate distress and fear and the related emotional and physical distress may impact the development of the child [69]. It is reasonable to expect that different rheumatic diseases impact the pregnancy experience differently: for example, mothers with systemic sclerosis report difficulty with parenting, which can be related to the severity of the symptoms [70]. In fact, disabilities related to maternal disease prior to conceiving are an important prognostic factor, since lower levels of body pain are associated with a better quality of life. There is often a discrepancy between chronic inflammatory arthritis and other rheumatic diseases during pregnancy: in general, most women with RA experience an improvement in their clinical condition, On the contrary, patients with connective tissue diseases, for example SLE, usually undergo more rigorous monitoring and follow-up during pregnancy due to the risk of a flare. Differences in expectations and intensity of monitoring may affect stress levels for these women.
RA may become a significant limitation after delivery when the disease often flares. The mother may suffer due to physical pain as well as the difficulty of attending to the family: this poor parental ability may also influence the children’s outcome. Chronic disease causes anxiety and worry in the entire family. Affected mothers may experience a conflict between accepting the illness and denying their symptoms so that they might appear healthy to the other family members. Generally, the presence of a chronic disease in the mother and the attendant emotional distress can interfere with parenthood and baby holding [68].
Furthermore, maternal distress and depression during the pregnancy itself may impact pregnancy and neonatal outcome: these emotions produce a characteristic hormonal response with increased cortisol levels and decreased dopamine and serotonin levels. This hormonal environment may promote premature delivery of low birth weight babies. A similar effect may be seen with corticosteroid treatment in mothers with rheumatic diseases [69].
Only one study has addressed the presence of fathers with immunologic disorders as a risk factor. No statistical significance was found but the authors suggested, based on trends in the data, that daughters born to these fathers seem to have more hyperactivity disorders and sons to have more reading problems. These findings seem to support a genetic role for an association between immunoreactivity and developmental problems (rather than a strictly gestational role) but no additional studies are currently available on the paternal role [71].
Ideally, clinical follow-up of newborns of mothers with rheumatic diseases would include a neuropsychiatry expert’s intervention to evaluate the child’s development and identify any neurodevelopmental problems at an early stage. The first year of life represents a critical period for psychomotor development. The consultant could help the parents to recognize their own and their child’s competences. During this period we underline the importance of baby holding and care in order to achieve a “good enough” relationship between mother and child. By helping the child to have a harmonious development, one achieves a positive feedback on parental perception of their own competences and consequently reduces parental anxieties [72].
To the best of our knowledge, no studies are available on the very long-term outcome of this pediatric population, i.e. adolescence and youth. Information on the recurrence of maternal or paternal autoimmune diseases in the long-term follow-up of children is lacking. The previously cited papers focusing on the neurological development do not mention any associated diseases in the children. Nevertheless, common experience of pediatricians is that children born to mothers with rheumatic disease do not generally show a significantly increased risk of developing the autoimmune disease of their parents. In addition, offspring have uncomplicated growth [25, 45, 53, 73] and are usually healthy with a normal intelligence level. Some children may experience LD or behavioral problems. The limited statistical power of the current literature does not permit us to distinguish whether the increased rate of cognitive impairment is primarily related to the maternal autoimmune disease or to prematurity: it is likely that both factors play some role.
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