The case reports are summarized in and .
Summary of mutations and complications in pregnant patients with GSD type Ib (UTI, urinary tract infection)
Summary of birth parameters and complications in newborn infants of mothers with GSD Ib
Patient 1 was diagnosed with GSD Ib at 2 months of age during an evaluation for lethargy. The diagnosis was confirmed by liver biopsy, and type Ib GSD was subsequently confirmed by mutation analysis, which revealed that she was a compound heterozygote for the S55R/Q218X mutations. She had been hospitalized for hypoglycemia once in childhood. Her medical history was otherwise remarkable for intermittent neutropenia not requiring G-CSF. Patient 1 had never developed inflammatory bowel disease, and she was not on any medications prior to her pregnancies. She was not on cornstarch, and she maintained euglycemia by intermittent glucose administration.
During her first pregnancy, her glucose concentrations were maintained with hourly doses of dextrose solutions taken orally throughout the day and via nasogastric tube at night. She monitored her own glucose and lactic acid levels frequently, using portable home monitors, and the dosage of dextrose was increased appropriately throughout the pregnancy to maintain glucose concentrations above 75 mg/dl (4.2 mmol/l) and lactic acid levels below 2.0 mmol/l. Her glucose requirement increased consistently throughout pregnancy, from the second trimester onwards. Her kidney function and liver ultrasounds remained normal throughout the pregnancies. Despite having neutropenia, she did not develop any infections, but chronic oropharyngeal ulcers were problematic.
The first baby was delivered at 39 weeks gestational age via a spontaneous vaginal delivery with a prolonged latent stage of labor. Active pushing progressed for 2.5 h. Two doses of meperidine hydrochloride were given in early labor, followed by increased doses of oxytocin. Her blood glucose was maintained above 108 mg/dl (6 mmol/l) throughout delivery with intravenously administered 10% dextrose (D10 half-normal saline solution) run at 110 ml/h. Lactic acid was also monitored during delivery and remained below 2 mmol/l. Continuous epidural analgesia was provided. A 3,325 g baby girl was born with Apgar scores of 6 after 1 min and 7 after 5 min. She was hypotonic following delivery, and she was admitted to the neonatal intensive care unit, where she required continuous positive airway pressure (CPAP) support for 24 h. She remained in the hospital for 1 week to establish feeding and for treatment of neonatal jaundice with phototherapy. The post-partum course was uneventful, and the mother was weaned off the intravenously administered dextrose within 4 h. Several weeks following discharge, patient 1 was readmitted with epiglotitis in the setting of neutropenia, and transient G-CSF therapy was required.
During the second pregnancy, patient 1 experienced frequent nausea that was not associated with vomiting. Once again, her blood glucose and lactic acid levels were monitored closely throughout the pregnancy, and the patient self-titrated her glucose to maintain normal glucose and lactate concentrations. During the course of the pregnancy, her glucose requirement steadily increased, from the second trimester onwards. At baseline, she required 14.4 g of glucose per hour to maintain normoglycemia at rest. Her glucose requirement rose to 19.8 g per hour at night during the second trimester and peaked in the third trimester, at 20.5 g per hour. An uncomplicated spontaneous vaginal delivery occurred at 39 weeks gestational age. The patient was again given an intravenous infusion of D10 half-normal saline solution during labor. She had continuous epidural analgesia and an oxytocin infusion. The labor involved 30 min of active pushing before the delivery. Her 3,238 g son earned Apgar scores of 9 and 9 at 1 min and 5 min, respectively.
In the third pregnancy, as with her prior pregnancies, the patient monitored her glucose and lactate levels and self-adjusted with the advice of the medical team to maintain normal concentrations. Her glucose requirement increased from 14.4 g/h to 21.6 g/h through the pregnancy, starting in the second trimester. She had significant discomfort related to varicose veins in the lower extremities, starting at 13 weeks of gestation. A color Doppler ultrasound of the lower extremities after 5 months of gestation was remarkable for superficial varicosities. At 34 weeks of gestation, the patient noticed a tender mass in her right groin, accompanied by a significant increase in size of her right thigh compared to her left. A diagnosis of venous thrombosis was made, and low molecular weight heparin therapy was initiated. Labor was induced at 35 weeks of gestation, and a baby girl was born weighing 2,528 g. The baby was admitted to the neonatal intensive care unit for CPAP support. She remained in the hospital for 2 weeks and required feeding by nasogastric tube. The venous thrombosis in patient 1 resolved shortly after delivery.
Abdominal ultrasound performed after each pregnancy demonstrated hepatomegaly with no focal lesions or adenomas. The patient had neutropenia during all of her pregnancies. Occasional oral ulcers were the only manifestation, and the patient was not given G-CSF during the pregnancies. Her hepatic transaminases, triglycerides, and uric acid concentrations remained normal through all three pregnancies.
Patient 2 was of Afro-Caribbean heritage. Records of her clinical course throughout childhood were not available. It is believed that she had been diagnosed with type I glycogen storage disease by liver biopsy. Type Ib GSD was suggested as a result of her history of intermittent neutropenia and recurrent infections. Mutation analysis confirmed the presence of the R415X mutation on one allele. The second mutation was not identified.
Patient 2 had outstanding metabolic control, and, at 30 years of age, she became pregnant. Cornstarch therapy was used as the primary treatment modality, but precise dosing of cornstarch was not part of her treatment regimen. At 19 weeks of gestation, she had moderate microscopic hematuria noted on a screening urinalysis, and she was empirically treated for a urinary tract infection. Subsequent testing performed as a result of persistence of the hematuria revealed the presence of albuminuria, which remained stable throughout the pregnancy. Her hematuria continued to worsen, progressing to frank hematuria in the third trimester. Anemia and iron deficiency also worsened throughout pregnancy. Hemoglobin was 9.2 g/dl, 7.3 g/dl, 6.9 g/dl and 6.9 g/dl at 10 weeks, 19 weeks, 30 weeks and 35 weeks, respectively. Her mean corpuscular volume and mean corpuscular hemoglobin concentration were, respectively, 67.8 fl and 20.5 pg at 30 weeks and 64.4 fl and 19 pg at 35 weeks. At 30 weeks of gestation, a comprehensive evaluation for anemia was performed, including normal hemoglobin electrophoresis, and only iron deficiency was identified. Neither neutropenia nor additional infections developed.
At 36 weeks and 5 days, she had an elective C-section performed due to uterine fibroids. Intravenous administration of glucose was commenced prior to her surgery, and she did well, with no documented hypoglycemia. Her 2,940 g son emerged vigorously, with a pH of 7.4, and he earned Apgar scores of 9 and 9 after 1 min and 5 min, respectively. There were no difficulties with the post-natal transition. Following the delivery, the patient remained with persistent hematuria, and an intravenous pyelogram performed 6 weeks after delivery confirmed the presence of a left renal calculus.
Patient 3 had been diagnosed as having type I GSD by liver biopsy at 13 months of age. Her presenting signs and symptoms were hepatomegaly, irritability, difficulty sleeping, and hypoglycemia. Molecular testing showed that she was homozygous for the G339C mutation. During infancy, the patient developed frequent infections at her gastrostomy site. She was maintained on overnight pump feeds until 11 years of age, at which time she was started on frequent intermittent cornstarch feeds administered throughout the day and night. At the same visit, G-CSF was started for a short period as part of a study. Beyond the study period, the patient was not given G-CSF, and her absolute neutrophil count ranged from 1,495/µl at 15 years of age to 570/µl at 17 years of age. Normal microalbumin:creatinine ratios were noted until she reached 14 years of age. Just prior to becoming pregnant, the patient was found with albuminuria with a microalbuminin:creatinine ratio of 149 mg/g. Hypertension was not present, and she was not placed on an angiotensin-converting enzyme (ACE) inhibitor for GSD nephropathy.
At 17 years and 5 months of age, the patient was found to be 6 weeks pregnant. Her absolute neutrophil count during pregnancy was found to be 947 at 6 weeks, 626 at 17 weeks and 3,974 at 33.5 weeks of gestation. During her pregnancy, she had two episodes of tonsillo-pharyngitis, and one episode of oral ulceration following a dental procedure. She needed antibiotics for all of the infections, but G-CSF was not used. In addition, she developed a urinary tract infection at the time of delivery. Her hemoglobin level before pregnancy was 12.6 g/dl, and it dropped to 10.7 g/dl at 33.5 weeks. At 29 weeks of gestation, hematuria was noted. The patient was diagnosed by renal ultrasound as having a kidney stone and was started on nitrofurantoin, which led to the subsequent resolution of the hematuria. Levels of liver enzymes and uric acid remained stable, but inconsistent follow-up did not allow the assessment of her renal function. At 33.5 weeks of gestation, she required an increase in her cornstarch dose from 35 g per dose twice at night to 42 g per dose twice at night, due to hypoglycemia (50–60 mg/dl) in the early morning hours and a rise in triglyceride levels to 420 mg/dl from 153 mg/dl. She maintained her blood glucose level during the day by frequent feeding. No cornstarch was used during the day. The patient delivered her baby after 39 weeks and 2 days of gestation. Her labor was induced, and she endured 7–10 h of labor. Epidural analgesia was administered through this duration. A boy was born weighing 4,260 g. He had mild physiological jaundice that did not require treatment. One low blood sugar reading of 50 mg/dl was noted within 24 h of the birth. The baby was fed and the blood sugar level normalized. The newborn infant did well, and there were no complications. The mother had had no liver adenomas prior to pregnancy, and a repeat ultrasound after her pregnancy was normal.