Endogenous hyperinsulinemic hypoglycemia is a rare condition characterized by hypoglycemic episodes caused by autonomous insulin secretion without the presence of an insulinoma.

The histological finding is Langerhans’ cell hyperplasia with nesidioblastosis (neo-formation of these cells from the ductal epithelium of the pancreas) (1, 2). The older nomenclature (nesidioblastosis) originates from this histological description (3).

While the congenital form of hyperinsulinemic hypoglycemia is a common cause of persistent hypoglycemia in neonates—termed “persistent hyperinsulinemic hypoglycemia of infancy”—it is uncommon in adolescence or even in adulthood (4). In specific forms, the severity of the disease reduces with age (5).

Focal and diffuse forms of the disease are known, requiring distinct therapeutic approaches. Genetic background is still not fully understood. Specific genetic mutations leading to some of these forms are published. The recessive mutations of the paternal allele of ATP-sensitive K-channel subunit genes (ABCC8 and KCNJ11) have a relatively high specificity (90%) and sensitivity (97%) for focal forms of the disease (6).

As a non-invasive method, ¹⁸F-DOPA-PET-CT is the best known way to differentiate between focal and diffuse manifestations of endogenous hyperinsulinemic hypoglycemia (7).

The first-line therapy should be diazoxide. In some cases, short-acting somatostatin analog octreotide was also effective, but the available data are very limited (8, 9).

Focal forms may be treated surgically. In diffuse forms, partial or near-total pancreatectomy could be considered. In mild cases, dietary modifications could be enough to avoid hypoglycemic episodes (10).

The problem arises in women of childbearing age. There are no available data about the effect of diazoxide on human intrauterine development, but some animal research results showed that it passes through the placenta (11). Experimental results in animals suggest that it might cause teratogenic malformations like skeletal and cardiac anomalies and degeneration of pancreatic beta cells (11). When given to neonates and infants, diazoxide is also shown to cause reversible pulmonary hypertension according to some post-marketing reports (11). The United States Food and Drug Administration (U.S. FDA) ranked earlier diazoxide in pregnancy risk category “C”, which means that adverse effects were observed during animal reproduction studies, but there are no adequate human data (11).

We present a case of a pregnancy in a patient with hyperinsulinemic hypoglycemia.

The patient had recurrent hypoglycemic episodes since 4 months of age, and diazoxide treatment was introduced (with a daily dose built up to 3 × 3 of 25-mg tablets, which equals 225 mg). Further diagnostic examinations supported the diagnosis of endogenous hyperinsulinemic hypoglycemia.

To exclude focal forms, abdominal ultrasound, CT scan, and a gold standard imaging technique ¹⁸F-DOPA-PET-CT (7) were performed. None of these showed signs of a focal disease or insulinoma.

Genetic testing gave negative results regarding ABCC8, GCK, HNF1A, HNF1B, INS, and KCNJ11 gene mutations.

Her family history was negative.

Ammonia levels were consequently normal, so hyperinsulinemia/hyperammonemia syndrome could also be excluded ( Table 1 ).

During infancy, the patient was not exposed to any provoking factors like drugs and viral infections, which made insulin autoimmune syndrome (IAS) unlikely. Insulin autoantibody measurement at the clinic was not available at the time of diagnosis, and predisposing HLA status was not yet known (12).

At the age of 13 years, the patient went underwent spinal fusion surgery because of scoliosis.

At the age of 23 years, malignant melanoma was surgically removed from her right knee region. Further treatment was not needed.

The patient had her first pregnancy at the age of 26, which had to be terminated on the 13th week predominantly because of life-threatening, uncontrollable maternal hypoglycemic events.

At the age of 29, the patient attended the clinic because of a positive pregnancy test. At the time of clinical admission, the patient was 9 weeks pregnant. When the patient had a positive pregnancy test at home, she decided to lower the dose of diazoxide from 9 tablets (225 mg) daily to only 2 tablets (50 mg). Her blood glucose levels started to get lower, so she compensated with nutritional changes by having a carbohydrate-rich meal every 1–2 h. Hypoglycemic episodes still occurred, so she applied to our clinic for further treatment options.

Basic anthropometric data of our female patient were the following at admission: weight 66 kg, height 163 cm, and body mass index (BMI) 24.8 kg/m².

Blood samples were taken at the time of admission, and as previously found, severe hypoglycemia with measurable insulin level and C-peptide level was present ( Table 2 ).

We corrected hypoglycemia with intravenous glucose infusions, and for further clinical observation, we hospitalized the patient until a decision is made about the pregnancy. Blood glucose level was checked every 1–1.5 h by self-check blood glucometer, and if the patient had symptoms or low values, laboratory testing was done. The patient had to eat carbohydrates every 1 or 2 h to avoid hypoglycemia.

β-Human chorionic gonadotropins (β-hCG) measurement supported the pregnancy (166,946 U/L). Gynecological examination, including transvaginal sonography, confirmed the intrauterine pregnancy and established the gestational age.

Genetic consultation was organized to evaluate potential harm to the fetus. The patient was informed about the risks and possible complications of her condition and the available data about octreotide treatment during pregnancy, and she decided to keep the pregnancy.

We reported a normal pregnancy outcome with the short-acting somatostatin analog octreotide in a patient with endogenous hyperinsulinemic hypoglycemia. In our experience, diazoxide therapy was replaceable with somatostatin analog octreotide.

Earlier, these patients were advised against pregnancy because of high hypoglycemic risk and because there were no sufficient data about the ideal management of the condition during pregnancy. Our case shows the possibility for selected patients with endogenous hyperinsulinemic hypoglycemia for childbearing.

The clinical data about somatostatin analog in pregnancy are still very limited in the literature. Animal experiments did not reveal any teratogenic effects of the drug (14). Geilswijk et al. however reported a case where restricted fetal growth was observed in an infant whose mother was treated with octreotide because of hyperinsulinemic hypoglycemia (15). On the contrary, Boulanger et al. described a normal pregnancy in a similar case (13).

There are some other publications about patients with acromegaly treated with somatostatin analogs during pregnancy. Maffei et al. reported an acute decrease in uterine blood supply after octreotide injection, but it did not affect the fetal development or the pregnancy outcome (16). Menis et al. applied lanreotide for 1 month and reported an uneventful pregnancy (16).

Long-acting somatostatin analogs may also be considered a therapeutic option (17).

The patient is still treated with octreotide instead of the earlier-applied diazoxide.

The mother feels that her mood is significantly better since octreotide therapy even though she has to give herself subcutaneous injections instead of oral medication. Earlier, she experienced depressive periods on a monthly basis while she was taking diazoxide therapy. Since the therapy changed, such episodes did not occur. It is yet unclear whether it is due to the medication or the change in living conditions.

She plans to have a second child, though it is necessary to draw conclusions from this pregnancy and reevaluate the possible risks.

Our case presents successful management of pregnancy with somatostatin analog octreotide in a patient with endogenous hyperinsulinemic hypoglycemia.

Patients were often advised to avoid pregnancy because of the high risk of hypoglycemia and because adequate protocols are missing. Since it is a very rare condition, and the literature is very limited, only two case reports are available.

There are some data about somatostatin analogs used in patients with acromegaly during pregnancy; however, no therapeutic guideline is available.

Our case provides a possible treatment option for patients living with endogenous hyperinsulinemic hypoglycemia.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

AdB, BS researched data and wrote the manuscript. BS, AdB, ArB contributed to the discussion. ArB contributed to patient examination and obstetrical follow-up. BS reviewed the manuscript. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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