Juniper Publishers: Celiac Disease and its Association with Infertility and Obstetric Complications in Women
JUNIPER PUBLISHERS- JOURNAL OF GYNECOLOGY AND WOMEN’S
HEALTH
Journal of Gynecology and Women’s Health-Juniper
Publishers
Authored by Taufner GH*
Abstract
Celiac disease is a multisystem resistant based issue
that is activated by the ingestion of gluten in hereditarily
defenseless people. The predominance of celiac disease has ascended in
late decades and is at present around 1% in most Western populaces. The
explanation behind this ascent is obscure, albeit natural elements
identified with the cleanliness speculation are suspected. The
pathophysiology of celiac disease includes both the natural and
versatile insusceptible reaction to dietary gluten. Clinical components
are various and incorporate gastrointestinal side effects, metabolic
bone disease, barrenness, and numerous different appearances. In spite
of the fact that a sans gluten eating regimen is powerful in many
patients, this eating routine can be troublesome and can restrain
personal satisfaction; thus, non-dietary treatments are at different
phases of improvement. This survey likewise covers non-celiac gluten
affectability. The pathophysiology of this clinical phenotype is
inadequately seen, however it is a reason for expanding enthusiasm for
sans gluten consumes less calories in the overall public. Throughout the
most recent decade when the commonness of the disease increments
quickly affirming the relationship between coeliac disease and a scope
of regenerative issue. Issues here are for the most part affirmed in
untreated ladies. Among the atypical side effects of coeliac disease
additionally incorporate fruitlessness, for example, deferred onset of
monthly cycle, early menopause, optional amenorrhea, barrenness and
pregnancy entanglements, for example, repetitive premature births,
intrauterine fetal development confinement, little hatchling for
gestational age, low birth weight and untimely birth. Celiac disease
maybe significant increases in spontaneous abortion, premature delivery,
and later age of menarche.
Keywords: Celiac disease; Pregnancy; Obstetric complications; Fetal growth restrictionIntroduction
Celiac disease (DC) is an autoimmune disease that
affects genetically predisposed individuals through the ingestion of
foods containing gluten proteins, the main compound of wheat, oats, rye,
barley and malt [1].
The disease is characterized by changes in the small intestine of the
carriers as the diminution of the intestinal villi and, consequently, of
the area of nutrient absorption [2].
The prevalence of the disease among countries and in
European or European ancestry populations varies from 0.3 to 1.0%, and
it is believed that much still remains undiagnosed [1,3,4].
In Brazil, official statistical data are unknown, however, it is
estimated that 300,000 Brazilians are carriers of the disease [1]. In Europe and the United States, prevalence ranges from 1: 100 to 1: 200 individuals respectively [5].
Numbers close to a study carried out in São Paulo (Brazil), in which it
demonstrated the prevalence of one celiac for each 214 inhabitants [6].
CD can present in a classic, non-classical or
asymptomatic way, with no or several signs and symptoms, which can often
be correlated with associated complications [7-10].
Despite the recent advances in the clarification of the association of
CD with several pathologies, its role in complications related to the
reproductive life of women is still little elucidated [11-15]. This article aims to review the association between CD, infertility and the main complications that occur during pregnancy.
Fundamental Concept
Celiac disease is a permanent intolerance to gluten,
characterized by total or subtotal atrophy of the proximal small
intestinal mucosa, resulting in malabsorption of food in genetically susceptible individuals [7-16].
It starts as an inflammation in the duodenum (duodenitis, infiltration
of cells of the immune system like the T lymphocytes). As gluten intake
is maintained, other mucosal changes occur, such as stretching of the
crypts and atrophy of the villi that line the duodenum, where the
absorptive process of many nutrients occurs. The celiac patient has an
abnormal immune response of the individual to peptides derived from
gliadin and glutenin. Sensitive CD4+T lymphocytes recognize multiple
gluten epitopes through presentation through the DQ2 and DQ8 molecules.
Activated lymphocyte clones proliferate and produce various
proinflammatory cytokines responsible for the stimulation of cytotoxic T
cells by promoting cell infiltrate and producing metalloproteinases
that damage the extracellular matrix [10].
Initially, MacDonald and colleagues, based on family
studies and using small intestinal biopsies, suggested that there was an
autosomal dominant inheritance for DC [17].
However, the pathophysiology of CD is much more complex because it
results from the interaction between environmental, genetic and
immunological factors [16].
CD is a multifactorial disease, therefore, of difficult genetic characterization [18].
The way out to uncover the basis of the disease and develop strategies
for detection, diagnosis and prevention is the identification of
susceptibility genes [19].
The celiac patient has a genetic defect that directly affects the major
histocompatibility complex (MHC), also known as the human leukocyte
antigen (HLA) system, located on the short arm of chromosome six. This
system is subdivided into three regions, called class I, II and III [20].
The class I region is composed mainly of the HLA-A, B, C loci and are
coding for molecules present in almost all nucleated cells; the class II
region is of great importance for the understanding of the genetic
bases of DC, encompassing the HLA-DR, PD and DQ loci, being HLA-DR and
DQ the most important when talking about gluten intolerance. This region
encodes surface molecules in macrophages, dendritic cells, monocytes,
B- and T-lymphocytes. The third and last region, class III, encodes
components of the complement system that is extremely important in
combating pathogens, and a range of enzymes Fernandes et al. [21]; Donadi [22]; Mackay et al. [23].
It was thought that two distinct unrelated loci were involved in the
etiology of CD, being a dominant inherited, this one linked to HLA-DR3,
and the other in a recessive, non-HLA-linked form [24].
The correlation of these two loci is the fruit of discussion to this
day. The association between DC and the HLA system is well established [25,26].
Among several complex autoimmune diseases, CD has a
strong association with HLA, and approximately 90-95% of celiac patients
are associated with HLA-DQ2 (alleles DQA1*0501 and DQB1*0201) and the
remainder with HLA-DQ8 (alleles DQA1*0301 and DQB1*0302). Although
important, in some cases, HLA-DQ2 and DQ8 molecules are not sufficient
to carry the phenotypic expression of CD. Therefore, because the disease
is of a polygenic nature, it is believed that there are mutations not
associated with HLA in patients with CD [27,28].
Symptoms and Diagnosis
There are three forms of clinical presentation of CD, classic, non classical or asymptomatic [9,10,16].
The classic form is characterized by the presence of chronic diarrhea,
usually accompanied by abdominal distension, weight loss, lack of
appetite, vomiting and iron deficiency anemia. In addition, patients may
present with decreased subcutaneous tissue, gluteal muscle atrophy, and
mood swings [29].
The nonclassical form is characterized by a mono or oligosymptomatic
framework, where the digestive manifestations are absent or; when
present, occupy a second plane. Celiac patients may present with
isolated manifestations, such as short stature, iron deficiency anemia
refractory to oral iron replacement, folate and vitamin B12 deficiency
anemia, osteoporosis, dental enamel hypoplasia, arthralgia or arthritis,
constipation refractory to treatment, pubertal delay, irregular
menstrual cycle, sterility, recurrent abortions, ataxia, epilepsy
(isolated or associated with cerebral calcification), peripheral
neuropathy, myopathy, psychiatric manifestations (depression, autism,
schizophrenia), recurrent aphthous ulcer. Elevation of liver enzymes
without apparent cause, adynamia, weight loss without apparent cause,
edema of abrupt onset after infection or surgery and non-ulcer dyspepsia
[29,30].
If not treated correctly, the classic and nonclassical form may have
severe evolution, known as celiac crisis. This potentially fatal
complication is characterized by the presence of diarrhea with severe
hypotonic dehydration, abdominal distension due to hypopotassemia and
severe malnutrition, in addition to other manifestations such as
hemorrhage and tetany [31].
The asymptomatic form is characterized by serological and histological
alterations of the DC-compatible small intestinal mucosa. This situation
can be verified especially among risk groups for CD, such as
first-degree relatives of celiac patients, and has been recognized more
frequently in the last two decades, after the development of the
serological markers for the disease [16,32-34].
Most DC cases have a difficult diagnosis to make.
Around 10% of the cases there is difficulty of diagnosis by discordant
findings between serology, clinical and histology [35].
The diagnosis of this disease is based on serological tests that detect
anti-endomysial antibodies (EMA), antigliadin (AGA) and
anti-transglutaminase (AtTG) [36].
A positive serological test suggests the diagnosis for CD, but the same
can only be confirmed through the distal duodenal biopsy, a gold
standard test, which shows a change in the histopathological
characteristics [37-39].
About duodenal biopsy, there is a need to perform a minimum of three to
confirm the diagnosis of the disease: the first one reveals atrophy of
the intestinal villi, the second one after treatment to demonstrate the
recovery of villi and crypts, and the third And last one that shows the
damages caused by the gluten intake [15,40].
Treatment
The only treatment available for celiac disease is the exclusion of gluten from the diet [16,41,42]
No food or medication containing wheat, rye, or barley gluten or its
derivatives in quantities over 20 parts per million (ppm) may be
ingested by a celiac patient [43].
After excluding it from the diet, approximately 70% of the patients
reported improvement of symptoms within two weeks after the start of the
gluten-free diet [44]. Many complications of the disease are preventable with a gluten-free diet [45,46].
With strict dietary adherence, the titer of antibodies specific for
celiac disease normalizes. Although the villous changes begin to improve
within months after the onset of a gluten-free diet, complete
histologic resolution may take years and may not be achieved in each
patient [47,48]. There is evidence that the lack of histological resolution may depend on the persistent consumption of gluten [49].
The safe limit of gluten intake varies from patient to patient and was
considered to be 10-100 mg/day, although a subsequent study indicated
that the upper limit should not exceed 50 mg/day [50].
General Complications
If a suitable diet is not introduced, celiac patients
may present with several types of malignant and non-malignant
complications that encompass several other organs and systems, and which
often do not demonstrate important postoperative symptoms. As
non-malignant complications, we highlight osteoporosis, infertility,
obstetric complications, pulmonary hemosiderosis, neurological and
psychiatric disorders, intestinal bleeding and intestinal ulcers, as
well as an infinity that has not yet been studied [15,51-54].
On the other hand, malignant complications, of a more severe nature,
can be highlighted in lymphoma in the small intestine (more frequent),
carcinoma of the esophagus and pharynx, as well as adenocarcinoma of the
small intestine that still has little etiopathogenesis [55-57].
In addition, CD is being correlated with several autoimmune diseases,
including type I diabetes, Down syndrome and Turner syndrome [58,59].
Obstetric complications
Infertility: There is controversy
regarding the possible association between CD and female reproductive
tract dysfunction. Several studies have suggested that before the
installation of a gluten-free diet, women with CD would have a higher
prevalence of infertility, recurrent abortions, restricted intrauterine
growth, and stillbirth [13,60,61].
The hypothesis of the association between celiac
disease and infertility was first reported in 1970, where Morris and
colleagues describe three patients with untreated celiac disease and
infertility who became pregnant after the onset of the gluten-free diet [62].
The high prevalence of celiac disease in infertile
women has been documented by several authors, and it is estimated that
the disease affects approximately 4 and 8% of women diagnosed with
infertility without apparent cause [63-66].
One of the first studies of the association with infertility consisted
of a study carried out with 74 women, carried out in 1982. It was
observed that patients with normal diet presented short reproductive
period, infertility, besides a higher incidence of spontaneous
abortions, unlike patients with diet gluten-free diet that presented
normal birth rates in addition to healthy childrenp [61].
A recent study using 170 Brazilian women and aimed at
the identification of celiac disease, identified in a subgroup of 29
infertile women the celiac seropositivity in three (10.3%) of the
patients with unexplained infertility Machado et al. [11].
In another similar study carried out in Brazil, with a group of 200
women with reports of difficulty in becoming pregnant, three patients
(1.5%) with positive serology for anti-transglutaminase antibody (tTG)
were identified, with a diagnosis of CD confirmed by endoscopic duodenal
biopsy and histopathological examination. In the control group with 400
women, there were no positive cases [51].
Despite numerous reports of association between
infertility and DC, one cannot confirm with absolute certainty that DC
is actually responsible for infertility. Tata and colleagues found
similar fertility rates among women with celiac disease and controls.
However, age-specific fertility rates varied, showing that celiac women
were more likely to have older children [67].
In a study of fertility in celiac women conducted in Sweden, 11,000
women of reproductive age and positive biopsy for celiac disease were
used. In this study, Zugna et al. [68]
showed that celiac disease was not associated with decreased fertility.
However, fertility was reduced in the two years prior to the diagnosis
(fertility risk ratio was 0.63 [95% CI: 0.57-0.70]), and this returned
to normal intervals after Diagnosis and treatment [68].
In contrast to most of the few publications to date
on infertility correlated with CD and as reported above, a study
conducted in the UK using 2,426,255 women as potential present in the
database of the UK health care system, observed that the rate of
infertility in clinically recorded celiac patients correlated with the
rate found in healthy people. However, infertility in celiac patients
was 41% higher than in healthy subjects when it ranked them by age 25-29
years [69].
Despite the impressive number of individuals studied, the study
presents the bias of studies whose data were collected in medical
records, which do not always express the truth. Given the great
importance of the association of infertility even without being
recurrent, it is essential to diagnose celiac disease in the population
with poor reproductive outcome because a simple therapeutic
intervention, such as a gluten-free diet, can result in conception and a
favorable outcome of pregnancy.
Pregnancy complications:
Malabsorption of nutrients caused by intestinal villi impairment in CD
can directly interfere with embryogenesis, altering the nutritional
status of the mother and the embryo to be developed.
This lack of control of maternal and fetal nutritional intake can lead
to several disorders related to embryo development, such as intrauterine
growth restriction (IUGR), recurrent spontaneous abortion (RSA),
stillbirth and congenital malformations [60,70-75].
Intrauterine growth restriction is a fetal pathology
defined by a birth weight of less than 10% based on a standard curve of
the general population [76].
The IUGR is a major complication of pregnancy and is responsible for a
5-20 fold increase in perinatal mortality and for considerable perinatal
morbidity. It can also have lifelong consequences ranging from delayed
neurodevelopment to an increased risk of developing hypertension, heart
disease, and diabetes [77,78].
This condition could be a consequence of extrinsic factors or intrinsic
growth retardation. When all causes are excluded it can be defined as
celiac intrauterine growth retardation.
The recurrent spontaneous abortion (RSA) is defined
as the presence of two or more miscarriages of unknown origin. It is
believed that in celiac patients there is an association with some
abnormalities in the vascular endometrium and an altered mechanism of
trophoblastic endometrial invasion and implantation [79].
An American study analyzed the prevalence of
undiagnosed celiac disease in patients with RSA, fetal death, IUGR and
infertility. Were analyzed 104 women with idiopathic RSA history, 104
women with a history of idiopathic fetal death, 150 women with
idiopathic IUGR, 230 women with unexplained infertility and 305 women
with a normal obstetric history. Founded 7 (6.7%) of 104 individuals in
the group with a history of recurrent abortions, 6 (5.7%) of 104 women
in the fetal death group, 13 (5.6%) of 230 women in the infertility
group, 14 (9.3%) of 150 women in the idiopathic intrauterine growth
restriction group, and 4 (1.3%) of 305 in the control group tested
positive for anti-tissue transglutaminase (tTG) IgA antibody. The
seroprevalence of the anti-endomysial IgA and tissue
anti-transglutaminase (tTG) IgA antibody was similar in all groups,
i.e., spontaneous recurrent abortion, stillbirths, infertility and
unexplained idiopathic intrauterine growth (P> 0.05) [52].
In another study in India, Sharma et al. evaluated
two groups of 45 Indian women, with and without IUGR, to analyze their
indecency in celiac patients, associating positive cases with the
presence of anti-transglutaminase antibodies (tTG). Two (4.4%) cases
from the group of women with IGR tested positive for tTG antibodies,
while none of the controls were positive [80].
In a study that aimed to evaluate the frequency of
celiac disease through the identification of anti-endomysial and
anti-transglutaminase antibodies (tTG) in women with recurrent abortion
and idiopathic intrauterine growth retardation, three groups were used:
44 patients with RSA, 39 with IUGR and 50 healthy. Patients in the first
and second groups had a significantly higher frequency of serologic
markers than controls. Three (8%) patients with IUGR and six (15%)
patients with IUGR had positive anti-endomysial and
anti-transglutaminase (tTG) serologic tests and none of the controls had
antibody positivity; of the 9 positive patients, 8 had confirmation of
jejunal biopsy tests. In another study by Moleski et al. [14] women with celiac disease had higher rates of spontaneous abortions than healthy women (50.6% vs 40.6%) [14].
Women with undiagnosed celiac disease were shown to have up to a
relative ninefold increased risk of recurrent miscarriage compared to
treated patients [60,71].
Other studies have demonstrated an association that is not as strong or statistically significant [67-81]
Studies observed that the abortion rate in women with celiac disease
was almost double that of controls, but this association was
statistically insignificant [81] and abortions were slightly more common in women with celiac disease (RR 1.31 [95% CI, 1.06-1.61]) [67].
Adopting an exempt diet can reduce the relative risk of miscarriage by about nine times [71]; this statement was proved by a positive pregnancy outcome when a gluten-free diet was adopted [82].
Pathophysiology of obstetric complications:
The mechanism underlying these disorders has not yet been fully
elucidated and some authors advocate malnutrition and consequent
deficiencies of zinc, iron and folate as a likely cause. However, it is
important to remember that infertility may occur in the absence of overt
malnutrition and may be the only symptom present in patients with
undiagnosed subclinical CD [64].
Some authors call attention to the evident correlation between the time
of exposure to gluten and the progressive increase of autoimmune
disorders [83].
The presence of autoimmunity in individuals with CD can vary between
extremes of 5.1% among children under two years and 34% in adults over
20 years of age [84].
These authors raise the possibility that the presence of specific
antibodies and T-cell mediated autoimmune response could be associated
with the outbreak of dysfunction of the female reproductive tract.
Celiac disease can lead to adverse pregnancy outcomes
through a number of mechanisms. The negative influence on nutritional
status due to malabsorption of mucosal inflammation has been postulated
as the probable pathogenesis for both reproductive and pregnancy
complications. Malnutrition has not been a consistent feature among
women with celiac disease and obstetric complications [71,81,85].
Gliadin may also induce an inflammatory reaction with the production of
associated cytokines that may adversely affect the fetus [72,86].
Recent research has shown that self maternal
antibodies bind to placental tissue transglutaminase and interfere with
the transfer of nutrients, alter the dynamics leading to cell apoptosis,
and damage secretory function placenta [87].
Studies further demonstrated impaired invasiveness, ability to migrate
and interact with reduced extracellular matrix, and altered apoptosis
when trophoblastic tissue was exposed to anti-tTG IgG [88]. These
data suggest a possible pathogenesis for early pregnancy loss and RSA
in untreated maternal celiac disease. Adherence to a gluten-free diet
has been shown to reduce circulating antibodies and the risk of fetal
growth restriction during pregnancy [72].
Conclusion
Despite the innumerable reports with different
positions on the association between celiac disease, infertility and
obstetric complications, it is still not possible to say with certainty
if there is the influence of CD in these complications that affect the
reproductive life of women, since the number of existing cases does not
currently a significant statistical value. However, one should not
exclude any hypothesis since there have been reports that with the
implementation of the treatment the obstetric and infertility related
problems presented considerable improvements.
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