Pregnancy and coeliac disease

Abstract

Coeliac disease (CD) is a small bowel disorder known for its intestinal manifestations like diarrhoea and weight loss. Less known are the extraintestinal manifestations of CD like haematological abnormalities but also altered female reproduction and pregnancy outcomes. Especially, undiagnosed CD may lead to adverse reproductive outcomes such as intrauterine growth restriction, stillbirth and preterm birth. In diagnosed and treated CD, adverse pregnancy outcomes might be prevented.

Background

Coeliac disease (CD) is a chronic small intestinal immune-mediated enteropathy with many forms of presentation. It is a disease that is induced by exposure to dietary gluten, and a strict gluten-free diet is currently the only treatment.¹ CD has a worldwide prevalence estimated at 1%, of whom 0.2% are clinically diagnosed. Of the clinically diagnosed population, women account for approximately 60%–70%.² The majority of people with CD is not diagnosed because they do not present with typical complaints. This can be a problem in fertile women as undiagnosed CD may be associated with fertility problems and adverse fetal outcome.^{3 4}

Case presentation

A 37-year-old woman (gravida 3, para 2, mater 1) presented at our outward patient clinic for prenatal counselling due to her obstetric history.

In 2014, she delivered a son of 3110 g after an uncomplicated full-term pregnancy. In 2016, the pregnancy was complicated by an intrauterine fetal death (IUFD) at 27 weeks and 4 days gestation. Additional diagnostic workup showed no abnormalities besides a maternal thrombocytosis (507×10⁹/L (normal 150–400)). The MRI, fetal X-ray and cytogenetics were normal. Pathological examination of the placenta showed 10%–30% infarction and increased parenchymal maturation, and the IUFD was attributed to placental insufficiency.

In 2017, this patient was pregnant again and was advised to start acetylsalicylic acid 80 mg a day from gestational week 12 to week 36. She presented a few times with vaginal blood loss in the first trimester, and after the second episode of vaginal bleeding, the acetylsalicylic acid was discontinued. With abdominal sonography, a retroplacental haematoma was seen. Vaginal swabs showed no bacterial abnormalities. Laboratory evaluation revealed the following: haemoglobin (Hb) 97 g/L (115–152), mean corpuscular volume 77 fL (83–100), leucocytes 9.6×10⁹/L (4–10), thrombocytes 530×10⁹/L, iron 4.7 µmol/L (10–30) and ferritin 10 µg/L (10–100). At 15 weeks and 4 days gestation, our patient had a spontaneous abortion.

After excluding primary thrombocytosis (normal bone marrow biopsy and negative testing for mutations in Janus kinase 2, calreticulin and myeloproliferative leukaemia protein and absence of bcr-abl), a secondary thrombocytosis due to iron deficiency was considered. A diagnostic workup to uncover the cause of the iron deficiency unveiled a very high level of IgA against tissue transglutaminase (anti-tTG) of >128 U/mL (normal <7.0 U/mL) and histological examination of a duodenal biopsy showed the presence of intraepithelial lymphocytosis, crypt-hypertrophy and severe villous atrophy (classified as Marsh 3B according to the widely applied modified Marsh classification of histological findings in CD) confirming the diagnosis of CD. The patient had otherwise no symptoms.

Outcome and follow-up

The patient was treated with a strict gluten-free diet. Serum iron and ferritin levels, as well as Hb and thrombocyte count, normalised and there was a gradual decline and normalisation of the anti-tTG level. A subsequent pregnancy was uneventful with the birth of a healthy son.

Discussion

CD has a multifactorial pathophysiology with genetic and environmental factors.^{1 3} It is a small bowel disorder characterised by an immune response to gliadin in individuals with a genetic predisposition.⁴ The classical signs and symptoms of CD are weight loss and chronic diarrhoea, occurring in only less than 30% of the patients.¹ So, most patients have only minor symptoms or are asymptomatic.^{5 6}

The gastrointestinal symptoms are non-specific. Next to diarrhoea, CD may manifest itself by bloating, alternating bowel habits, constipation and gastro-oesophageal reflux disease.¹

Among the extraintestinal manifestations of CD, there are a variety of haematological abnormalities. Anaemia, the most frequent one, is thought to develop secondary to deficiency of iron, folic acid, vitamin B₁₂ and other micronutrients. In patients with CD, the prevalence of anaemia of any origin was around 20%. Besides anaemia, CD may also be associated with thrombocytosis or thrombocytopenia, with thrombocytosis being more common. Thrombocytosis may be seen in up to 60% of patients with CD. The pathophysiology remains unclear, but a few explanations have been proposed, such as secondary to iron-deficiency anaemia, functional hyposplenism or cross-reaction between erythropoietin and thrombopoietin receptors.⁷

In our case, evaluation of the thrombocytosis revealed an iron deficiency which subsequently led to the diagnosis of CD. After iron substitution and a gluten-free diet, anti-tTG levels decreased in our patient with normalisation of the haematological parameters. She had never experienced other signs or symptoms of CD.

In women, CD may influence reproduction and pregnancy outcomes, and women with unexplained infertility or recurrent miscarriage have a significantly higher risk of CD than the general population.^{1 6 8} Multiple studies revealed a higher risk of preterm birth, intrauterine growth restriction, small for gestational age (OR 8.5, 95% CI 1.85 to 38.97), low birth weight, stillbirth and spontaneous abortions in women who were diagnosed with CD after giving birth (undiagnosed CD). Notably, women with diagnosed CD and who are using a gluten-free diet during pregnancy had no higher risk on adverse fetal outcomes compared with women without CD.4 6 8 9 It has to be stated that the association between CD and reproductive outcomes is not confirmed by several other studies.^{2 5 10}

In the placenta, tissue transglutaminase is expressed in the outer surface of the syncytiotrophoblast microvillous membrane and is accessible to circulating maternal antibodies. These anti-tTG antibodies might affect trophoblast survival by reducing the proliferation rate and promoting apoptosis, leading to developmental or functional impairment of the placenta.¹¹ One prospective cohort study found that levels of anti-tTG are inversely associated with fetal growth.¹²

Women with diagnosed CD should be offered preconception counselling. In pregnancy, the advice would be to do multidisciplinary follow-ups by a gynaecologist and an internist. A gluten-free diet should be advised and the anti-tTG levels should be monitored. Moreover, there should be regular growth ultrasounds because of a higher risk of intrauterine growth restriction.

In conclusion, undiagnosed CD may lead to adverse reproductive outcomes such as intrauterine growth restriction, stillbirth and preterm birth. Women with intrauterine fetal demise or repeated miscarriages should be asked for complaints of CD and accordingly tested for. Further research is required to determine whether asymptomatic women with previous adverse pregnancy outcomes should be screened for CD, and whether proper dietary measures in diagnosed CD indeed improve the pregnancy outcomes.

Patient’s perspective.

Though obviously traumatised from my pregnancy losses, I was determined to not accept what happened as a mere “medical mystery”. After several discussions and a collaborative relationship between my stellar haematologist and gynaecologist, I underwent a bone marrow biopsy, several rounds of blood tests and an endoscopy. When I was diagnosed with coeliac disease, I was initially shocked (I am asymptomatic) but relieved that I could trace the losses back to an autoimmune disorder. Whilst it is a lifelong condition, coeliac disease is manageable through proper diet. After incorporating the necessary dietary changes, I had an uncomplicated pregnancy and delivered a healthy baby boy who is a symbol of my doctors and my determination to get to the root cause of my tragic loss.

Learning points.

• The majority of people with coeliac disease (CD) is undiagnosed due to atypical symptoms.

• Anaemia or thrombocytosis can be a sign of CD.

• Undiagnosed or untreated CD may have a higher risk of adverse reproductive outcomes.