Abstract
Falling insulin requirements during pregnancy in women with diabetes mellitus in pregnancy raise concerns regarding placental insufficiency and adverse pregnancy outcome. A case of a rapid fall in insulin requirements in a woman with type 2 diabetes mellitus, obesity, hypertension and chronic kidney disease at 23 weeks’ gestation with high titres of insulin antibodies is presented. The possibility of exogenous insulin autoimmune syndrome as a cause for hypoglycaemia and reduction in insulin requirements is discussed.
Keywords
Case
A 39-year-old woman of Pacific Islander ethnicity in her second ongoing pregnancy, was transferred from another hospital at 24 weeks’ gestation because of a one-week history of increasing dyspnoea, orthopnoea and peripheral oedema, visual deterioration, and repeated hypoglycaemic episodes requiring cessation of exogenous insulin. The woman's medical history was significant for obesity (preconception body mass index 39 kg/m2), type 2 diabetes mellitus diagnosed at the age of 29 years complicated by non-proliferative diabetic retinopathy, stage G3aA3 chronic kidney disease with nephrotic-range proteinuria and hypertension. Her previous pregnancy five years earlier had been complicated by preeclampsia at term.
The woman conceived while taking sitagliptin and metformin, with a first trimester HbA1c of 10.9% (93 mmol/L). She had not been taking antihypertensive medication. The woman was referred to the obstetric medicine service at her local hospital at 9 weeks’ gestation and commenced on methyldopa and a basal bolus regimen of insulin (aspart and glargine insulin). Worsening hypertension at 20 weeks’ gestation prompted addition of labetalol and nifedipine slow release. The woman presented with abdominal pain at 22 week's gestation and underwent laparoscopic appendectomy. Intravenous ferrous carboxymaltose 1000 mg was administered postoperatively. At 23 weeks’ gestation total daily insulin dose was 136 units (Figure 1). The woman then abruptly developed repeated episodes of hypoglycaemia resulting in rapid down titration and subsequent cessation of insulin, and symptoms of dyspnoea, orthopnoea, peripheral oedema and blurred vision. Hypoglycaemic episodes resolved with insulin cessation and the woman's capillary glucose levels remained between 4 and 7 mmol/L for the next four weeks.
Total daily dose of insulin and insulin antibody titres plotted against gestation.
Medications on interhospital transfer were methyldopa 1500 mg/day, labetalol 900 mg/day, slow release nifedipine 120 mg/day and enoxaparin 80 mg/day. Examination revealed oxygen saturation of 97% breathing room air, pulse 80 min regular, blood pressure 160/100 mm Hg, jugular venous pressure was not elevated, dual heart sounds, bilateral pleural effusions and peripheral oedema. Ophthalmological review found grade 4 hypertensive retinopathy with cystic macular oedema, disc swelling, multilayer retinal infarcts and haemorrhages. Laboratory investigations in early pregnancy, and at transfer of care at 24 weeks’ gestation are shown in Table 1. There was no evidence of haemolysis. Echocardiography revealed a moderate-severely dilated left ventricle with ejection fraction (LVEF) 55%, mildly increased left ventricular wall thickness, normal right ventricular systolic function and moderate pulmonary hypertension, likely postcapillary, with estimated right ventricular systolic pressure 50 mm Hg. Polysomnography showed no evidence of sleep disordered breathing, and there was no evidence of pulmonary emboli on computerised pulmonary angiography. Plasma metanephrines, aldosterone: renin ratio and renal artery Doppler ultrasound were normal.
Laboratory investigations in first trimester, and at 24 weeks’ and 33 weeks’ gestation.
The woman was managed with a fluid restriction, intravenous frusemide, and darbepoetin was commenced for treatment of anaemia, with resolution of dyspnoea and signs of fluid overload, and improvement in blood pressure, hypertensive retinopathy and anaemia.
The cause of the sudden reduction in insulin requirement was unclear. Fetal ultrasound revealed estimated fetal weight on the 45th centile, abdominal circumference on the 75th centile, mildly increased amniotic fluid, and normal fetal biometry and umbilical artery pulse indices for gestational age. Serum cortisol was 451 nmol/L (> 300), insulin-like growth factor I was 7.5 nmol/L (7–25) and prothrombin time was normal. The woman denied intake of any alcohol or complementary or herbal therapies. The minor deterioration in renal function was thought to be unlikely to account for the development of hypoglycaemia. Capillary glucose levels subsequently rose from 27 weeks’ gestation and insulin therapy was resumed with aspart and glargine insulins. At 29 weeks’ gestation the result for insulin antibodies measured at 24 weeks’ gestation became available, revealing an insulin antibody titre of more than 50 U/mL (0–0.5), with low levels of immunoreactive / free insulin recovered from plasma following precipitation with polyethylene glycol, consistent with the presence of insulin in bound complexes. Unfortunately, inadequate sample was available for the laboratory to perform serial dilutions and determine the absolute value. This raised the possibility of exogenous insulin autoimmune syndrome (EIAS). C-peptide and insulin levels had not been measured at hospital transfer. Given the absence of recurrent hypoglycaemia despite resumption of insulins aspart and glargine this regimen was continued. Insulin antibody titres were repeated at 29 weeks’ gestation and postpartum, demonstrating progressive fall in titre (Figure 1).
Deteriorating maternal renal function and new left ventricular dysfunction (LVEF 45%) prompted elective caesarean section at 33 weeks’ gestation, delivering a healthy female birthweight 1770 g. Initial neonatal venous glucose was 1.5 mmol/L requiring intravenous 10% dextrose for 36 h. Placental weight was 295 g (25th–50th centile for gestational age) and histology showed appropriate maturation of the placental disc without infarcts or intervillous thrombi. Postpartum the woman's capillary glucose levels were satisfactory on diet alone.
Discussion
In women with preconception diabetes mellitus, insulin requirements usually fall between 6- and 16-weeks’ gestation, then rise progressively until 36 weeks’ gestation, before declining towards term. Approximately 15–30% of women have a fall in insulin requirements (FIR) of at least 15% in third trimester.1–3 An unexpected significant FIR raises concerns regarding placental insufficiency. The significance of FIR is however unclear, and there are no guidelines to inform management when insulin requirements drop.4,5 While some studies have associated FIR with adverse pregnancy outcomes including polyhydramnios, neonatal respiratory distress and requirement for neonatal intensive care admission, 3 small for gestational age infants, 6 and preeclampsia, 7 other studies have not found an association between FIR and adverse pregnancy outcomes.4,8,9 Falling insulin requirements in women with preconception diabetes were not associated with changes in placental flow or fetal growth restriction. 10 Potential causes of marked FIR that warrant consideration in pregnancy are listed in Table 2.
Potential causes of reduction in insulin requirements in pregnancy.
* Type 2 diabetes mellitus and gestational diabetes mellitus.
In most patients with severe CKD total daily insulin dose needs to be reduced, albeit with a high degree of variability, thus management needs to be individualised. 11 Individuals with T2DM and stage V chronic kidney disease typically require approximately 50% less insulin than their daily insulin requirement prior to developing renal failure.12–14 Factors include reduced insulin clearance by the kidneys and peripheral tissues, reduced renal gluconeogenesis, reduced food intake, changes in insulin secretion, but also factors increasing insulin resistance including metabolic acidosis, uraemic toxins, low vitamin D and inflammatory state.
Insulin antibodies may occur following exposure to subcutaneous and inhaled insulin. 15 The risk of this appears to be particularly high with the use of insulin pumps. Insulin antibodies are common and not always pathological, with prevalence in patients with diabetes mellitus treated with insulin as high as 78%. 16 Most studies have not shown a relationship between insulin dose and the development of insulin antibodies. 17 While animal insulins have higher immunogenicity, human insulin and human insulin analogues have been documented to result in high levels of insulin antibodies, particularly in Asian populations. Insulin glargine and insulin aspart may be more antigenic than other insulin analogues. 18 EIAS refers to the development of insulin antibodies following exposure to exogenous insulin associated with clinical events. 15 IgG antibodies predominate, although IgM, IgA and IgE have also been described. EIAS is associated with fluctuations in blood glucose. Binding of insulin to antibodies may result in reduced insulin action and early postprandial hyperglycaemia. Insulin antibodies may also act as an insulin carrier having a reservoir-like effect, thus prolonging insulin action. This may result in the release of large amounts of insulin with dissociation of insulin from insulin antibodies, the free insulin resulting in unexpected hypoglycaemia 2–6 h after eating, as well as nocturnally and with fasting. 19 Hypoglycaemia particularly occurs where insulin antibody levels are high. A review of symptoms in 122 patients with EIAS (97.5% of Asian heritage) found hypoglycaemia in 87%, recurrent episodes of symptomatic hypoglycaemia in 36%, nocturnal hypoglycaemia with daytime hyperglycaemia in 21% and recurrent hypoglycaemia following cessation of insulin in 64%. 20 Skin reactions with rash, pruritus, redness and swelling occurred simultaneously with onset of hypoglycaemia in 13%. 20 EIAS has been predominantly described with insulin therapy of type 2 diabetes mellitus (91% of cases), though has been described with type 1 diabetes mellitus (5.5%), latent autoimmune diabetes (2.7%) and type 3c diabetes.19–22 Mean duration of exposure to insulin prior to diagnosis of EIAS was 24 months (range 2 days to 78 months). 20 EIAS was associated with plasma insulin levels of > 1000 U/ml in 41% of individuals and > 100 U/ml in 95% of affected individuals, with low levels of C-peptide relative to glycaemia in type 2 diabetes.19,20
Insulin antibody levels gradually fall within one month of insulin withdrawal, becoming negative after a median period of six months, though may take 1–2 years to completely resolve.20,23 Treatments for EIAS have included alternative insulin preparations, GLP-1 receptor agonists, oral hypoglycaemics, acarbose, glucocorticoids, rituximab, mycophenolate and plasmapheresis.
An unrelated condition, insulin autoimmune syndrome (IAS), or Hirata's disease, has been described in individuals naïve to exogenous insulin with hyperinsulinaemic hypoglycaemia, markedly elevated serum insulin and elevated insulin autoantibodies. 24 The disorder predominantly occurs in individuals of Japanese (44%) and Chinese (42%) ethnicity, and represents the third most common cause of hypoglycaemia in the Japanese non-diabetic population. Approximately 33% of IAS cases coexist with other autoimmune diseases, particularly Graves’ disease. Approximately 50% of IAS cases have previously been exposed to drugs containing sulphydryl groups, including methimazole/carbimazole, alpha-lipoic acid, tiopronin, clopidogrel (metabolites) and captopril, although more than 35 medications as well as sulphydryl-containing health products have been implicated. 24 Management options include drug withdrawal, dietary changes, glucocorticoid therapy, other immunosuppressives and plasma exchange.
It is not clear whether insulin antibodies, which can undergo placental transfer to the neonate, have a direct impact on neonatal morbidity, including hypoglycaemia and respiratory distress syndrome, as studies have shown variable results. 17
An atypical feature in this case was that aspart and glargine insulins were able to be reintroduced in the woman without recurrence of hypoglycaemia and insulin antibody titres continuing to fall.
Pacific Islander and East Asian individuals share distinct human leucocyte antigen allele frequencies likely related to the Ancient Lapita expansion. This may be the cause of the common susceptibility to genetic muscle disorders such as thyrotoxic and hypokalaemic periodic paralysis. 25
Conclusion
The significance of falling insulin requirements in pregnancy is unclear, though warrants increased surveillance for signs of placental insufficiency. Other rare causes of decreased insulin requirements warrant consideration where there is marked sudden reduction in insulin requirements in the setting of recurrent hypoglycaemia.
Footnotes
Ethical approval
Ethical approval was waived by Mater Health Human Research and Ethics Committee.
Informed consent
Written informed consent was provided by the patient for publication of this article.
Author contributions
AM: writing – original draft, writing – review and editing.
VR: writing – review and editing.
JH: writing – review and editing.
All authors approved the final manuscript for submission.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Guarantor
Adam Morton.