A Series of Pregnancies in Women with Inherited Metabolic Disease
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A series of pregnancies in women with inherited metabolic disease: case reports (supplemental material)
Janneke G Langendonk1, Jonathan CP Roos2, Lindsay Angus1, Monique Williams1, François PJ Karstens1, Johannes BC de Klerk1, Charlé Maritz2, Tawfeg Ben-Omran3, Catherine Williamson4, Robin H Lachmann2, Elaine Murphy2
1Centre for Lysosomal and Metabolic diseases, Departments of Internal Medicine and Pediatrics, Erasmus MC, Rotterdam, The Netherlands
2Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, United Kingdom
3Clinical and Metabolic Genetics, Weill Cornell Medical College, Department of Pediatrics, Hamad Medical Corporation, P.O.BOX. 3050, Doha-Qatar
4Maternal and Foetal Disease Group, Institute of Reproductive and Developmental Biology, Dept. of Surgery and Cancer, Imperial College London, Du Cane Rd., London W12 0NN, United Kingdom
Corresponding Author:
Dr Elaine Murphy, MRCP(Ire), FRCPath Consultant Inherited Metabolic Disease Charles Dent Metabolic Unit Internal Mailbox 92 National Hospital for Neurology and Neurosurgery 8-11 Queen Square London WC1N 3BG United Kingdom
Tel: 0044 207 829 8778 Fax: 0044 207 209 2146 [email protected]
WORD COUNT TEXT: 3970
KEYWORDS: Pregnancy; inherited metabolic disease; homocystinuria; propionic acidemia, phenylketonuria; methylmalonic acidemia; glutaric academia; ornithine transcarbamylase deficiency; 3-hydroxy-3-methylglutaric(HMG)-CoA lyase deficiency Introduction In this case series we report twelve pregnancies, in nine women with inherited metabolic disease illustrating how specific pregnancy, labour and delivery issues were managed and the outcome for the mother and child in each case.
A 24 year old woman with methylmalonic acidemia A 24 year old woman presented to the outpatient clinic at 6 weeks’ gestation with a planned pregnancy. She had been diagnosed with methylmalonic acidemia (MMA, OMIM 251000) at 14 years, having presented with anorexia, poor growth (height and weight < third percentile) and polyneuropathy. Urinary methylmalonic acid excretion at diagnosis was elevated at 227µmol/mmol creatinine (normally not detectable) and fibroblast propionic acid incorporation was 5% (69dpm/µg protein) of normal. Molecular diagnosis was not performed. Despite long periods of non- compliance, prior to pregnancy she was well apart from occasional anorexia and episodes of cramps in her calf muscles. She had only had one hospital admission for management of fever and myalgia aged 16 years. Her neuropathy gradually resolved and she had normal intelligence. Her final height and weight were 1.53m and 43.6kg respectively (BMI 19kg/m2). Renal function was normal, with serum creatinine 50µmol/l. In her previous obstetric history she had a termination of pregnancy at 10 weeks and a spontaneous abortion at 5 weeks gestation.
Treatment Preconception spot urinary MMA level was 758µmol/mmol creatinine. Serum vitamin B12 was 101pmol/L (RR: 146-637) and free carnitine was 18µmol/L (RR: 22-54). Preconception treatment consisted of a protein restricted diet (45g/day) with oral vitamin B12 1mg daily, carnitine 330mg twice daily and iron supplementation 200mg twice daily. During pregnancy, folic acid 0.5mg, calcium 500mg twice daily, potassium 600mg twice daily, and vitamin D 400IU twice daily were added. Protein intake was increased to 60g/day at 33 weeks of gestation. Urinary MMA excretion increased during pregnancy and ranged between 1700-3886µmol/mmol creatinine. Plasma amino acid levels measured in the first trimester were within normal limits.
Pregnancy course The pregnancy was uneventful, except for two episodes of headache, nausea, muscle cramps, anorexia, and mild hyperammonemia (49µmol/l). Symptoms resolved and ammonia normalized following an increase of oral vitamin B12 to 1mg twice daily. Carnitine supplementation was increased to 1.4g twice daily to maintain carnitine levels within the normal range. There were no concerns regarding foetal growth on ultrasound.
Labour and delivery management At 38 weeks’ gestation she had a spontaneous vaginal delivery of a female infant. During labour caloric intake was ensured with intravenous glucose (10% at 2 litres per day). There were no complications during delivery.
Outcome The baby girl weighed 2850g with Apgar scores of 8 and 9, at 1 and 5 minutes respectively. On postpartum day two, mother and baby were discharged home, both well. Five years later, mother and child are healthy and the child is growing and developing normal.
A 19 year woman with methylmalonic acidemia A 19 year old woman with non-B12 responsive methylmalonic acidemia presented at her regular out- patient review at 12 weeks gestation, following an unplanned pregnancy. She had known learning difficulties with a full scale IQ of 55. She was initially diagnosed at the age of 6 months when she presented with acute encephalopathy and a history of failure to thrive. During early childhood she had multiple hospital admissions with metabolic decompensation but had been well since mid childhood with no further hospitilisation. Fibroblast propionic acid incorporation was 10% of normal, with reduced holomutase activity and reduced adenosyl-cobalamin. Molecular diagnosis was not performed.
At this presentation, at 12 weeks pregnant, she had low total carnitine (13µmol/L (RR:26-62)) and free carnitine (5µmol/L (RR:22-50)) levels as well as being vitamin B12 deficient (157pg/ml (RR:191-663)) with secondary hyperhomocysteinemia (total homocysteine 65μmol/L (RR:5-15)). Plasma MMA was elevated at 120µmol/L (RR: <0.29) and urinary MMA excretion was also elevated (2240µmol/mmol creatinine (RR:0-30)). Renal function was normal.
Treatment She followed a self-imposed low protein diet (estimated natural protein intake 35g/day) but was not taking her regular prescribed multivitamins and carnitine supplements, as, despite reassurance, she felt these might harm her baby. She was advised to restart carnitine 3g daily in three divided doses, multivitamins and regular additional intramuscular vitamin B12 supplementation. She remained poorly compliant with these throughout pregnancy, but did receive 4-6 weekly intramuscular B12 (1mg) whenever she attended a hospital appointment. She continued on her own self–imposed protein restricted diet which was of poor quality with minimal meat, fish, dairy products, fruit and vegetables. She was also poorly compliant with additional prescribed essential amino acid supplements.
Pregnancy course By the third trimester total (13µmol/L (RR:26-62)) and free carnitine (8µmol/L (RR:22-50)) levels remained low although serum B12 levels (626pg/ml (RR:191-663)) improved and the hyperhomocysteinemia (total homocysteine 10μmol/L, RR:5-15) resolved following some B12 supplementation. Plasma MMA levels fell with treatment and as pregnancy progressed (37µmol/L in the third trimester (RR: <0.29)). Ammonia levels remained normal and she was clinically well throughout pregnancy with no metabolic decompensation. Renal function remained normal throughout (creatinine 66umol/L and eGFR >90mL/mim/1.73m2 in the third trimester). A foetal ultrasound at 32 weeks showed poor intra-uterine growth.
Labour and delivery An early caesarean section at 35 weeks was planned for intra-uterine growth restriction. The patient was given intravenous dextrose (10% at 2ml/kg/hr) and carnitine starting four hours pre-operatively until normal eating resumed post-partum. She was also prescribed additional oral glucose polymer (200ml of a 25% glucose solution four hourly post-partum for 48 hours) but was poorly compliant with this. There were no complications during labour or the post-partum period.
Outcome The baby girl was of low birth weight, weighing 1530g with Apgar scores of 9 and 9, at 1 and 5 minutes respectively. She required nutritional support in a special care baby unit for three weeks post- partum, but was otherwise well. The baby, now 1 year of age, is currently being brought up by her mother and aunt, with support from social services. There are currently no concerns regarding the baby’s growth or development. The mother developed new-onset probable myoclonic seizures several months post-partum and is currently under investigation for these.
A 25 year old woman with homocystinuria A 25 year old woman was referred for the first time to the adult metabolic clinic at 14 weeks gestation, following an unplanned pregnancy. A diagnosis of classical homocystinuria (OMIM 236200) was made aged 4 years in Poland, when she presented with developmental delay and bilateral lens subluxation. During childhood she had been treated with a protein restricted diet, vitamin B12, vitamin B6 and folate supplementation. She was apparently discharged from medical care at 18 years of age, with no further treatment. At this presentation her total homocysteine was 284µmol/L (RR:5-12), free homocystine 51µmol/L (normally not detected), methionine 35µmol/L (RR:13-40), and serum vitamin B12 135pg/mL (RR:191-663). Her serum folate was within the normal range (6.3ng/mL (RR:2.3- 17.6)) as she had already been started on folate 5mg daily by the referring doctor.
Treatment At initial presentation she was receiving no treatment and was following a normal diet. She was immediately commenced on hydroxocobalamin 1mg IM weekly, pyridoxine 300mg daily, folic acid 5mg daily, betaine 2g three times daily, and low molecular weight heparin sc daily (as anti-thrombotic prophylaxis). No alterations were made to her diet.
Pregnancy course Within five days of commencing treatment total homocysteine fell to 41µmol/L (RR:5-12) and free homocysteine was undetectable, indicating that she had pyridoxine-responsive homocystinuria. Unfortunately, an 18 week ultrasound scan showed multiple foetal anomalies including talipes, micrognathia and an abnormal cardiac axis.
Outcome The patient opted for a termination of pregnancy. She attended the outpatient clinic only once post- partum, and had again stopped all medications. She was advised to restart pyridoxine, folic acid and vitamin B12 supplementation. She has now returned to Poland and no further follow-up is known.
A 26 year old woman with propionic acidemia A 26 year old woman with propionic acidemia (OMIM 606054)(PA) presented pregnant. The diagnosis of proprionic acidemia had been made biochemically as part of a sibling screen directly after birth, as her older brother had previously been diagnosed. Measured propionyl-CoA carboxylase (PCC) activity in fibroblasts was 0.11 nmol/min/mg (9% of controls). Previously she had two episodes of metabolic decompensation leading to coma (complicated with hyperammonemia and metabolic acidosis). She had otherwise been asymptomatic. She was of average intelligence, and worked in the administration department of an insurance company. Preconception, there were no signs of leucopenia, thrombocytopenia, or cardiomyopathy.
Treatment Her protein intake was 75g per day (1.1g/kg body weight). Preconception medication included folic acid 5mg daily and carnitine 1g twice daily. During pregnancy carnitine was increased to 1g three times daily. Her protein intake was variable and often less than 70g per day, although she had been advised to increase this towards the third trimester. There was no metabolic decompensation.
Pregnancy course In the first trimester, pregnancy was complicated by placenta praevia with cramps and a short period of vaginal bleeding.
Labour and delivery management At 40+1 weeks of gestation she gave birth to a baby girl. During labour she was given intravenous glucose (10% at 2 litres per day). Directly post-partum she had a 2L haemorrhage, due to an atonic uterus. Protein intake was decreased to 36g per day (0.5g/kg body weight). Glucose infusion was continued until day 6, as her appetite and food intake were poor. There was no evidence of metabolic decompensation.
Outcome The baby girl was healthy, weighing 4410 gram, with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively. The child has normal growth and development at 9 months old. The mother has been admitted twice for vomiting related to psychosocial stress (divorce). Metabolic decompensation was prevented with glucose infusions.
A 21 year old woman with glutaric acidemia type 1 A 21 year old woman with glutaric acidemia type 1 (OMIM 231670)(GA1) was re-referred to the adult metabolic clinic at 26 weeks gestation after a history of non-attendance at out-patient follow-up. She had a background of epilepsy and was known to have some learning difficulties with a verbal IQ of 76 and a performance IQ of 93. At presentation her total carnitine (7µmol/L (RR:26-62)) and free carnitine (4µmol/L (RR:22-50)) levels were low. She was also vitamin B12 (112pg/ml (RR:191-663)) and iron deficient.
Treatment She was prescribed carnitine 3g daily, riboflavin 400mg daily, iron and vitamin B12 supplementation. She remained on a normal diet.
Pregnancy course There were no epileptic fits or episodes of metabolic decompensation during pregnancy and no concerns regarding foetal growth.
Labour and delivery She had a short (45 minute) uncomplicated delivery of a baby boy. There were no peri-partum complications. No additional treatment was given during labour.
Outcome The baby boy was healthy, weighing 3017g. He was breast fed without difficulty. The boy (now aged 2 years) is well and is being brought up by his mother with the support of his grandmother.
An 18 year old woman with glutaric acidemia type 1 A year 18 old woman was re-referred to the adult metabolic clinic at 26 weeks gestation after a history of non-attendance at out-patient follow-up. At presentation her total carnitine (5µmol/L (RR:26-62)) and free carnitine (3µmol/L (RR:22-50)) levels were low. She was also vitamin B12 (162pg/ml (RR:191-663)) deficient and had iron deficiency anaemia (Hb 9.9g/dL, ferritin 7µg/L (RR:13-150)).
Treatment She was prescribed carnitine 3g daily, riboflavin 400mg daily, iron and vitamin B12 supplementation. She remained poorly compliant with these throughout pregnancy. She continued on a self–imposed protein restricted diet of poor quality – with minimal meat, fish, dairy products, fruit and vegetables. She refused additional amino acid supplementation.
Pregnancy course She had multiple attendances at the accident & emergency department during the first 5 months of pregnancy with nausea and vomiting. She was also treated for a urinary tract infection and vaginal candida, but did not require hospitalisation.
Labour and delivery Despite a detailed labour plan in place at a specialist centre she instead presented to her local district hospital at 38 weeks gestation with sepsis secondary to a urinary tract infection. She was then transferred to a specialist centre for induction of labour and management of sepsis. Following induction of labour she had a vaginal delivery of a baby boy. She had epidural anaesthesia, without complications, during labour. During labour she was treated with intravenous dextrose (10% at 2ml/kg/hr), antibiotics and carnitine until normal eating resumed post-partum.
Outcome The baby boy was healthy, weighing 4030 gram, with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively. Urine organic acids levels were normal. The patient discharged herself and her son on day 1 post-partum against medical advice. She was followed up at home by district health services and no problems have been reported with mother or child. The child is being brought up by his mother, with the support of his grandmother.
A 24 year old woman with symptomatic ornithine transcarbamylase (OTC) deficiency A 24 year old woman with OTC deficiency (R141Q mutation in the OTC gene)(OMIM 311250) presented to the outpatient clinic with an unplanned pregnancy at six weeks of gestation. Her original presentation was at 2 years of age with a hyperammonemic coma. Diagnosis was confirmed with raised urinary orotic acid (119 µmol/l (RR:not detectable)) and reduced OTC activity in a liver biopsy (0µmol/min/g (RR:9.0-12.0µmol/l/g)). With therapy she recovered and developed normally. Her full scale IQ aged 4 years was 90. At the age of 23 years she was also diagnosed with combined antithrombin III and protein S deficiency following a deep venous thrombosis.
Treatment Her therapy consisted of strict natural protein restriction (20-23g/day, including 8g of an essential amino acid mixture), sodium benzoate 6g daily, citrulline 5g daily, calcium 500mg daily, folic acid 1mg daily, and vitamin B6 100mg daily. During pregnancy low molecular weight heparin was given as anti- thrombotic prophylaxis.
Pregnancy course Chorionic villus sampling in the first trimester of pregnancy showed a normal foetal karyotype 46,XX and no OTC gene mutations. Her total daily protein intake was increased to 42g/day towards the end of pregnancy, including 5g and later 17g/day essential amino acid supplement. Pregnancy was complicated in the first trimester with periods of hyperammonemia (117-129µmol/L) with nausea and drowsiness. Precipitants for hyperammonemia included a respiratory tract infection, a once daily medication schedule, and food cravings with hence a non-prescribed increase in protein intake. The amino acid supplement was difficult to tolerate due to sensitivity to the smell and taste. Medications and amino acid supplements were changed from once daily to frequently divided doses. Citrulline was gradually increased to 12g/day. After 4 months gestation, glutamine and ammonia normalized to levels around 600µmol/L and 25µmol/L respectively.
Labour and delivery management At 37 weeks gestation the patient had a spontaneous uncomplicated vaginal delivery. No specific treatment was given during labour. Several hours before delivery she developed mild hyperammonemia (60µmol/l (RR:< 40)) but was clinically well throughout labour and the immediate post-partum period. Three days post-partum ammonia increased further to 130µmol/l and glutamine to >1000µmol/l. Caloric intake was maintained, sodium benzoate was increased to 12g/day, and citrulline to 13.5g/day. Amino acid supplement was decreased to 14g and natural protein to 16g daily. At day 11 post-partum her ammonia suddenly increased to 279µmol/L with associated agitation. Natural protein intake was stopped and phenylbutyrate 12g daily given in six divided doses intravenously. Within 6 hours the patient clinically improved and ammonia fell to 82µmol/L.
Outcome The baby girl was healthy weighing 2830g, with Apgar scores of 9 and 10, at 1 and 5 minutes respectively. She was breast fed by her mother without difficulty. On post-partum day nineteen mother and daughter were discharged home well. At 27-years old, during a second pregnancy, chorionic villus sampling detected an affected male fetus and the pregnancy was terminated. Twelve years later, mother and daughter are healthy and the daughter is growing and developing normal.
A 22 year old woman with 3-hydroxy-3-methylglutaric(HMG)-CoA lyase deficiency Pregnancy 1 A 22 year old lady of Pakistani origin presented to the obstetric services at 7 weeks gestation with a four day history of nausea and vomiting. She had a neonatal diagnosis of 3-hydroxy-3-methylglutaryl- (HMG)-CoA lyase deficiency (OMIM 246450)(HMG-CoA lyase deficiency). She was not taking any medications or other treatment and had not attended for medical follow-up with the metabolic services for several years. Her parents were first cousins and she had two siblings, a twin brother and an older sister, who were also affected. Two other siblings were unaffected.
Pregnancy course On admission, she was afebrile and normotensive. Arterial blood gases revealed compensated metabolic acidosis: pH 7.39, PaCO2 3.39kPa, HCO3 12mmol/L, base excess -8.1mmol/l. Renal function and full blood count were normal. Blood glucose was also normal at 5.1mmol/L.
Treatment She was treated with 5% dextrose intravenously, intravenous carnitine 100mg/kg in four divided doses and an anti-emetic. She recovered well and was discharged home within 48 hours. Over the next 6 weeks she had 3 further admissions with similar episodes of compensated/partially compensated metabolic acidosis. In view of these, as well as her persistent nausea and vomiting she was commenced on a reducing course of oral prednisolone. Her nausea settled and she had no further problems during pregnancy. She was advised to take 60g of uncooked cornstarch daily before bed. There were no concerns regarding foetal growth.
Labour and delivery management Following induction of labour at 40 weeks gestation she gave birth to a baby girl. During labour she was maintained on a 10% dextrose infusion (0.2g/kg/hour). Her blood glucose remained between 6-
10mmol/L at all times. Lactate was 1.15-1.44mmol/L and HCO3 between 18-21mmol/L.
Outcome The baby girl was healthy, weighing 3218g. There were no maternal post-partum complications. Following discharge, the mother did not attend for further follow-up with the metabolic services.
Pregnancy 2 The same patient re-presented 2 years later, now aged 24 years and again pregnant at 9 weeks’ gestation. She was seen in an obstetric medical outpatient clinic where she reported experiencing mild intermittent anorexia, nausea and vomiting for the previous three weeks.
No abnormalities were found on examination and she was normoglycemic. She was receiving no treatment except for carnitine 1g twice daily which she was taking only sporadically. She was advised to check her blood glucose daily and to take prochlorperazine 5mg twice daily, folic acid 400μcg daily, cyclizine 50mg three times daily, thiamine 50mg daily and carnitine 1g twice daily and to return for review after 1 week or earlier if symptoms worsened.
Pregnancy course Three days later, while moving house over a bank holiday weekend, she developed severe anorexia, nausea and vomiting. She attended the Accident and Emergency department in the evening where unfortunately her past medical records were unavailable. She had not brought her disease information sheet with her and was not wearing a MedicAlert® bracelet as previously advised. Neither she nor her family knew the name of her condition although they did report that she had problems with ‘low sugars’ in a previous pregnancy. Unfortunately therefore, it was not recognised by staff that she had an underlying metabolic condition and was at high risk of metabolic acidosis. She had difficult intravenous access and was admitted to the ward without commencing intravenous glucose or other fluids.
The following morning she was reviewed but the medical team remained unaware of her underlying metabolic condition. Peripheral venous access was not possible and it was felt at the time that central venous access was not warranted. The patient continued to vomit despite anti-emetic treatment.
Later that day the medical team were asked to review her as blood glucose levels were felt to be low (3.6-3.8mmol/L) despite her being encouraged to take oral glucose-rich drinks. At the time Glasgow Coma Scale (GCS) was 14/15, blood pressure 115/64mmHg with a pulse of 94bpm. Urine output was 50mls/hour. The patient was thought to be drowsy and somewhat uncooperative with assessment. Oral intake was encouraged and the ward nurses were asked to monitor regular hourly blood glucose levels.
Several hours later the patient became short of breath and tachypnoeic. Arterial blood gases showed a pH of 7.08, PaCO2 1.06kPa and BE of -26.8mmol/L. Blood glucose was 5.6 mmol/L. A pulmonary embolus was suspected and anticoagulation commenced. A central line was placed and intravenous rehydration with normal saline commenced. Repeat arterial blood gases showed worsening metabolic acidosis with a pH of 7.03, PaCO2 2.23kPa, PaO2 7.27kPa, BE -24.5mmol/L. Repeat blood glucose level was low, 2.7mmol/L, with elevated lactate, 13.02mmol/L. Several hours later she remained acidotic (pH 7.07) and hypoglycaemic (blood glucose 2.3mmol/L) and was transferred to the intensive care unit. Her medical notes were located and the diagnosis of HMG-CoA lyase deficiency recognised. She was commenced on 10% dextrose intravenously with sliding scale insulin if required, hydrocortisone 50mg three times daily, carnitine and bicarbonate. Nutritional support was also started with an additional 1,600kcal and vitamin supplementation. Within 12 hours her pH had increased to 7.38, base excess improved to -13.4mmol/L and blood glucose returned to the normal range.
She developed a coagulopathy and had a spontaneous abortion several hours later. GCS deteriorated (3/15), she became hyperammonemic (ammonia 195μmol/L) and required intubation and hemofiltration. During her stay in ITU she progressively developed cerebral oedema, sepsis and pulmonary oedema with increasing ventilatory requirements and inotropic support. On day 18 she had a cardiac arrest and CPR was unfortunately unsuccessful.
A 20 year old woman with 3-hydroxy-3-methylglutaric(HMG)-CoA lyase deficiency A 20 year old lady from Qatar with polycystic ovarian syndrome (PCOS) was referred to our obstetric services for consideration of assisted conception. She had a neonatal diagnosis of 3-hydroxy-3- methylglutaryl-CoA lyase deficiency. During childhood she had several mild episodes of decompensation which had responded well to intravenous dextrose, carnitine and bicarbonate, which led to mild cognitive impairment. She was taking carnitine 1g three times daily orally and avoided red meat in her diet.
A year previously she had conceived following a 3 month course of clomiphene, prescribed elsewhere. During that pregnancy, she presented at 8 weeks’ gestation to another hospital with nausea and vomiting. Blood sugar was normal at 5.3mmol/L, but bicarbonate was low at 16 mmol/L. She was treated with intravenous sodium bicarbonate and carnitine, responded well and was sent home 4 days later in a stable condition.
Two days later, she again presented to hospital with nausea and vomiting. Treatment was as before with the addition of an antiemetic (metoclopramide) and pyridoxine. Her symptoms initially resolved and she was kept in for observation. However by 10 weeks gestation and because of persistent nausea and vomiting with poor intake, and she no longer responded to intravenous antiemetics. She had a reduction in consciousness (GCS 5/15) and respiratory distress (respiratory rate 42/min). In addition she became hyperammonaemic (ammonia 370 mmol/L) with a lactic acidosis; pH 7.29, HCO3 4.7 mmol/L, and lactate 11.84 mmol/L. She was treated with intravenous dextrose, sodium bicarbonate, carnitine, L-arginine, sodium benzoate, inotropic support and broad-spectrum antibiotic cover. She required ventilation and continuous haemodialysis for persistent hyperammonaemia. Two days later she had a spontaneous abortion. She then gradually recovered and was discharged well other than with a residual unilateral foot drop.
Outcome Following discussion with the patient and her husband we declined to prescribe clomiphene as we felt the increased risk of a multiple pregnancy, during which vomiting might be more common, was unacceptable given her previous severe decompensation despite appropriate treatment. Furthermore, given the history we felt that the use of metformin, which has been associated with lactic acidosis, was not appropriate for the management of her PCOS. The patient has not returned for any further follow-up appointments.
Pregnancy 2 The same patient re-presented 3 years later to her local hospital, now aged 24 years and again pregnant at 6 weeks’ gestation. She was electively admitted to the obstetric unit and, although well, decided to have a termination of pregnancy two days later. There were no complications.
More recently she has been diagnosed with type 2 diabetes mellitus and hypercholesterolemia and has commenced oral hypoglycemic medication. This has further complicated her course of management in particular during periods of metabolic decompensation.