Porphyrias are very rare and easily overlooked diseases in pregnancy. Among these eight known metabolic disorders, acute intermittent porphyria (AIP) is the most common and most severe type. An enzymatic alteration in the haem biosynthesis pathway causes liver overproduction of neurotoxic toxic metabolites, which cause attacks of acute neurovisceral symptoms, severe abdominal pain and/or skin lesions. Women with AIP can sometimes develop their first acute attack during pregnancy, and because the symptoms are unspecific, the diagnosis is difficult to obtain and often missed. However, prompt diagnosis of AIP during pregnancy is crucial as treatment can significantly improve the pregnancy outcome. The backbone of the therapy is food rich with carbohydrates, complemented by 20% glucose infusion and adequate pain control. We present a case of previously undiagnosed AIP in a 34-year primigravida, whose treatment was especially challenging due to co-existing gestational diabetes mellitus and problems with the central venous catheter.
Porphyrias are a group of eight metabolic disorders in which a specific enzymatic alteration in the haem biosynthesis pathway causes overproduction of toxic metabolites by the liver and subsequent neurotoxicity. Porphyric attacks are characterised by acute neurovisceral symptoms and/or skin lesions. They are triggered by endocrine changes (menstrual cycle, pregnancy); physical/emotional stress, fasting, smoking, alcohol, infections, or porphyrinogenic drugs , , . Pregnancy can sometimes precipitate the first acute attack and the diagnosis of the condition is often difficult due to its unspecific symptoms. We will describe obstetric challenges in managing a case of previously undiagnosed acute intermittent porphyria (AIP) in a 34-year-old primigravida with gestational diabetes mellitus (GDM).
A 34-year-old primigravida was admitted to our high-risk pregnancy ward, in the 24th week of gestation, with pain under the right side of the rib cage and a sensation of the baby pushing down. Initial blood and urine tests were normal. Analgesics did not help. She started complaining of skin pain on touch (dysesthesia) and migraines. Blood test results showed a haemoglobin drop from 108 g/L to 87 g/L. No obstetrical or surgical cause was found. Neuropathic pain that was unresponsive to a myriad of analgesics and unexplained haemoglobin drop led us to suspect AIP. The diagnosis was confirmed in the 27th week of gestation by testing 24-h urine sample for porphyrins. According to literature, we instituted food rich with carbohydrates, intravenous paracetamol and 20% glucose infusion. This treatment regime was difficult to maintain over a long-term period because carbohydrates and infusions adversely influenced GDM. There was an infection at the site of central venous catheter and we had difficulties keeping the catheters patent. Successful pain control was difficult to obtain. Haemoglobin levels fluctuated between 70 g/L and 100 g/L; there was no electrolyte imbalance. At 36 0/7 weeks of gestation, an elective caesarean section was performed because of the inability to control the patient’s pain. Surgery was uneventful. A healthy girl was born, 2740 g, 48 cm, Apgar score 9/9. After the surgery, the patient was in an intensive care unit (ICU) for 5 days. She was put on a carbohydrate rich diet with 20% glucose infusion. She was discharged on the 10th postoperative day and referred to the specialist for future management.
Abdominal pain in the second half of pregnancy is one of the most common complaints and can be due to pregnancy-caused (placental abruption, symphysis-pubis dysfunction, threatened premature labour, etc.), pregnancy-associated (urinary tract infections, adnexal torsion, etc.), or pregnancy-unrelated conditions (bladder/ureteral stones, acute appendicitis, pancreatitis, etc.) . Although AIP is the most common type of acute porphyrias , it is usually not a first-line differential diagnosis in the assessment of a pregnant woman with abdominal pain. However, it should be suspected in the absence of other causes, especially when dysesthesia and central nervous system (CNS) signs or symptoms are present. It is an autosomal-dominant disorder with an estimated incidence of around 1:75,000 and is 4 times more common in women , , . Because of the low penetrance of the gene, the attacks are infrequent; and because of non-specific symptoms, AIP is hard to diagnose , . Attacks occur most frequently in the 3rd decade and recur in less than 10% of the patients . They can be life-threatening and usually start with a prodromal phase with minor behavioural changes (anxiety, restlessness, insomnia), followed by an increased sympathetic activity (elevated heart rate, hypertension, sweating), severe abdominal pain (often epigastric and colicky in nature and lasts for several days), constipation, nausea and vomiting. Red or dark-coloured urine can be present. Dehydration and electrolyte imbalance can develop. Hyponatremia is present in 40% of the cases and can cause convulsions. Mental disturbance (anxiety, depression, disorientation, hallucination, paranoia, confusional states) occurs in 20%–30% of the patients . Skin lesions are typically absent . Attacks usually last 1–2 weeks. Neuropathy often develops when porphyrinogenic drugs are used during the attack. Diagnosis is made with the examination of urine for excess of porphobilinogen. Therapy consists of analgesics (preferably narcotics), antiemetics, maintenance of fluid balance, adequate intake of calories, carbohydrate rich food, infusion of glucose in 0.9% sodium chloride solution and antihypertensives , .
During pregnancy, the above mentioned treatment is complemented by careful pregnancy surveillance. Only drugs considered safe in pregnancy and in AIP may be used, as some medications that are commonly used in obstetrics (e.g. methergyn after delivery) can trigger an attack , , . For these reasons, we recommend a list of safe and unsafe medications in AIP to be added to the patient’s documentation as a reference during treatment. Patients experiencing severe attacks, especially those with severe neurologic symptoms, should be treated with haemin, which has proven to be safe and effective, with no adverse effects on the foetus or the mother , , .
Women with AIP sometimes develop their first acute attack during pregnancy and more than 50% of the women with AIP have an acute attack during pregnancy , , . There is very scarce data on the effect of the disorder on pregnancy outcomes. Most studies were performed on small series and have shown that acute porphyrias could be a risk factor for low birth weight, intrauterine growth retardation, premature delivery, spontaneous abortions and perinatal death. However, Tollanes et al. examined pregnancies of 200 women with porphyria between 1967 and 2006 and compared them to 11,00,391 controls. Their results showed an increased risk for perinatal death [odds ratio (OR) = 4.9] only for first-time mothers with active acute porphyria . Another retrospective analysis of 33 pregnancies in 15 women with acute porphyria also showed that these pregnancies were usually uneventful, but problems were more common if the disorder had not been previously diagnosed . Therefore, the prognosis for pregnancy in women with AIP is good if the diagnosis is already known and the disease is not active .
With this case, we would like to raise awareness of AIP, which can be first diagnosed in pregnancy. If undiagnosed, AIP can significantly affect the pregnancy outcome and cause foetal and maternal death. For successful perinatal outcome, early diagnosis is pivotal, followed by appropriate therapy, avoidance of triggering factors and pregnancy surveillance.
Conflict of interest: The authors declare no conflict of interest.
Material and Methods
Informed consent: Informed consent has been obtained from all individuals included in this study.
Ethical approval: The research related to human subject use has complied with all the relevant national regulations, and institutional policies, and is in accordance with the tenets of the Helsinki Declaration, and has been approved by the authors’ institutional review board or equivalent committee.
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