A case of severe combined pathology in a late premature infant with hypoxic-ischemic damage to the central nervous system

Introduction

Congenital hypothyroidism is a heterogeneous group of thyroid disorders with various etiologies that manifest immediately after birth and are characterized by a partial or complete loss of thyroid function. Delayed brain development in children with congenital hypothyroidism occurs as a result of thyroid hormone deficiency. It should be emphasized that psychomotor and intellectual developmental delay in congenital hypothyroidism is associated with a reduced number of glial cells and neurons, as well as impaired myelination of nerve fibers [1].

In the Russian Federation, the prevalence of congenital hypothyroidism is higher compared to Europe and North America (1 case per 4,000–5,000 newborns) and Japan (1 case per 6,000–7,000 newborns), amounting to 1 case per 3,600 newborns. Furthermore, children with Down syndrome have a 35-fold increased risk of developing congenital hypothyroidism compared with the general population. The disease is 2–2.5 times more common in girls than in boys [2].

Transient hypothyroidism, depending on severity, may present in latent (subclinical) or overt forms. Based on the level of thyroid hormone production impairment in children, hypothyroidism is classified as primary (thyreogenic) or central (secondary, tertiary), the latter being associated with a deficiency of pituitary factors or isolated thyrotropin deficiency.

Congenital hypothyroidism is more common in children. The most frequent cause (85–90% of cases) is pathology of the thyroid gland itself due to defects in gland formation during embryogenesis. These include ectopy, agenesis, and hypoplasia, accounting for 30–45%, 35–45%, and 5% of cases, respectively. To date, a number of genes have been identified whose mutations lead to abnormalities in thyroid development, migration, and differentiation, as well as to defects in thyroid hormone synthesis and dysfunction of the hypothalamic–pituitary axis. Adverse environmental factors (radiation, iodine deficiency in the diet), intrauterine infections, maternal intake of certain medications during pregnancy (thyreostatics, tranquilizers, bromides, lithium salts), and a history of autoimmune thyroiditis or endemic goiter may trigger thyroid damage in the fetus. However, the exact causes of these alterations remain unknown. In 10–15% of cases, hypothyroidism in children is associated with impaired thyroid hormone synthesis or metabolism, or with damage to tissue receptors responsible for sensitivity to their action.

Secondary and tertiary hypothyroidism in children may be caused by congenital anomalies of the pituitary and/or hypothalamus, or by genetic defects in the synthesis of thyroid-stimulating hormone (TSH) and thyrotropin-releasing hormone (TRH), which regulate thyroid hormone secretion.

The primary goal of neonatal screening for congenital hypothyroidism is the earliest possible detection of all newborns with elevated blood TSH levels. Infants with abnormally high TSH require further in-depth evaluation to establish an accurate diagnosis [1, 3]. In this regard, interest in studying the specific features of early diagnosis of congenital hypothyroidism in newborns remains consistently high.

The aim of the study was the early diagnosis and treatment of congenital hypothyroidism in a newborn with hypoxic-ischemic central nervous system injury.

Clinical Case

The newborn, Sofia V., was admitted at the age of 3 days to the Department of Pathology of Newborns and Preterm Infants, Research Institute of Obstetrics and Pediatrics, Rostov State Medical University of the Ministry of Health of Russia, for examination and treatment after transfer from the maternity hospital.

The child was born to a 16-year-old mother with a history of chronic pyelonephritis in remission and chronic rhinopharyngitis in remission. This was the mother’s first pregnancy. The course of pregnancy was complicated by acute respiratory viral infection, low placentation, proteinuria, bacteriuria, bacterial vaginosis, candidiasis, gestational thrombocytopenia, and latent iron deficiency detected at 36 weeks of gestation. At 21 weeks of gestation, a left choroid plexus cyst was identified in the fetal brain.

This was the mother’s first delivery, at 37 weeks of gestation, via spontaneous vaginal birth, rapid in course. Premature rupture of membranes was noted. Birth weight was 2,650 g, length 48 cm, head circumference 34 cm, chest circumference 32 cm. Apgar scores were 8–9.

Objective findings at birth. The newborn cried immediately, with a loud cry, and became pink spontaneously. The umbilical cord was clamped; the head was molded. Mild skin icterus was noted. The anterior fontanel (1.5 × 1.5 cm) was level with the cranial bones. Respiration was rhythmic, without the use of accessory muscles; on auscultation, breath sounds were puerile, evenly conducted throughout the lungs, with no rales. Heart sounds were loud and rhythmic. The abdomen was soft. The liver and spleen were not enlarged. The external genitalia were female, normally developed. Muscle tone was slightly reduced; reflexes could be elicited.

In the neonatal ward, the condition corresponded to the early adaptation period. Neurological symptoms were observed: skin mottling, tremor of the limbs and chin, muscular dystonia, positive Babinski reflex bilaterally, spontaneous Moro reflex, and decreased oral–spinal automatism reflexes. Due to the above-mentioned symptoms, the newborn was transferred to the Department of Pathology of Newborns and Preterm Infants with the following diagnosis: “Small-for-gestational-age newborn (intrauterine growth restriction, hypoplastic type). Moderate cerebral ischemia. Neuro-reflex excitability syndrome”.

The newborn was admitted to the department on the third day of life. The general condition was of moderate severity, determined by intrauterine growth restriction of the hypoplastic type and neurological symptoms.

The heart rate was 142 beats per minute, the respiratory rate was 38 per minute, and the body temperature was 36.9 °C. At admission, weight was 2,514.0 g, length 48 cm, head circumference 34 cm, and chest circumference 32 cm. The general condition remained of moderate severity. The skin and mucous membranes were mildly icteric, with mottling observed. The subcutaneous fat layer was poorly developed. Nutritional status was reduced. Skin turgor was decreased. Pulmonary percussion revealed a normal resonant sound; on auscultation, breathing was puerile. Heart sounds were muffled but rhythmic.

The newborn was on natural feeding. She was breastfed 4 times a day and additionally received 20 ml of expressed breast milk 4 times a day. Sucking was active.

The buccal mucosa was clean. The tongue was clean. The pharynx was not hyperemic. The abdomen was soft and painless. The umbilical stump was in the stage of mummification. The liver was +2 cm below the costal margin; the spleen was not enlarged. Urination was spontaneous; the urine was straw-yellow. Stool was meconial. The urogenital system was formed according to a female type.

Neurological status: the infant responded to examination with crying. Tremor of limbs and chin was observed during agitation. Cranial nerves: the pupils were equal; the light reaction was brisk. The palpebral fissures were symmetrical. No facial asymmetry at rest or during mimic movements was observed. A full range of ocular movements was noted. Swallowing and phonation were preserved. Deviation of the tongue to the right and tongue fibrillation during agitation were observed.

Spontaneous motor activity was reduced. Muscle tone was decreased in the distal extremities. Reflexes (grasp, palm–mental, heel, sucking, cutaneous, support) were elicited but rapidly exhausted. Tendon reflexes were brisk and symmetrical. Plantar reflexes were of the flexor type. A positive Babinski reflex was observed bilaterally. Spontaneous Moro reflex, occasional scissoring of the lower extremities, and toe-standing were noted.

The newborn stayed at the Department of Pathology of Newborns and Preterm Infants for 15 days. During hospitalization, all necessary laboratory and instrumental examinations were performed, which made it possible to establish the primary and concomitant diagnoses and to determine the management and treatment strategy for this child.

The following examinations were carried out. A blood test for neonatal screening (TSH, capillary blood) on the 2nd day of life: 220 mU/L (normal range – 0.00–18.00 mU/L). A repeat neonatal screening test for hypothyroidism on the 10th day of life: TSH in capillary blood – 307.5 μU/L (normal range – <9 mU/L).

At the time of hospitalization, the complete blood count revealed monocytosis (15%) with other parameters within normal limits. Monitoring of acid–base status showed respiratory alkalosis and hyperlactatemia (2.24 mmol/L). Biochemical testing revealed hyperbilirubinemia (331.6 μmol/L) due to the indirect fraction, with the direct fraction measuring 25.5 μmol/L. C-reactive protein was 6 mg, which represents the upper limit of normal.

In the course of the disease, CBC showed progressive leukopenia (8.0×10⁹/L) with persistent monocytosis (16%). In the biochemical profile, despite a decrease in total bilirubin (125.3 μmol/L), the direct bilirubin level remained elevated (23.9 μmol/L), accounting for 19.1% of the total. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were within normal limits. Blood glucose levels decreased twice to 2.17 mmol/L and 2.7 mmol/L, followed by the normalization of these parameters. Total protein, albumin, creatinine, and urea remained within normal ranges. Coagulogram analysis did not reveal any decrease in the synthesis of blood clotting factors.

The results of the microbiological study of the intestinal microbiota revealed Staphylococcus haemolyticus 10⁵ CFU/mL and Candida albicans 10⁶ CFU/mL.

Dynamic analysis of thyroid hormone levels in serum revealed a decrease in free T4 to 5.98 nmol/L (normal range 11.4–22.2 nmol/L), followed by the normalization of this parameter during therapy. The free T3 level was 22.70 nmol/L, within the normal range. The TSH level exceeded 100 μIU/mL (normal range 0.3–2.5 μIU/mL).

An audiological screening was performed: L (+), R (+/–). The newborn underwent the instrumental examinations described below.

Neurosonography showed that the ventricular index was within normal limits. Lateral ventricles S:D – 1.0:1.0 mm, third ventricle – 3.5 mm. Increased echogenicity of the periventricular region, subcortical nuclei, and thalamus was noted. The choroid plexuses appeared heterogeneous and hyperdense. Signs of brain immaturity and initial dilatation of the interhemispheric fissure were identified.

Transcranial Doppler ultrasonography revealed pronounced cerebral venous dysgemia of the intracranial cerebrospinal fluid dynamic type.

Ultrasound examination of the abdominal organs revealed no pathology.

According to echocardiography, a functioning fetal duct (patent foramen ovale) was identified, with preserved myocardial contractility. Electrocardiography revealed a heart rate of 150–160 beats per minute and moderate changes in the ventricular myocardium.

An X-ray examination of the abdominal organs was performed. On the abdominal survey radiograph, no Kloiber’s cups or free gas were detected; intestinal loops were hyperpneumatized. Conclusion: radiographic evidence of intestinal loop hyperpneumatization.

Specialist consultations were also provided.

Endocrinology consultation (initial) on the 8th day of life. At the time of examination, the results of neonatal screening were available: markedly elevated values (SH 220 mg/dL with a normal of 18), raising concerns about the development of the disease. Diagnosis: congenital hypothyroidism. Blood sampling was performed for retesting and determination of TSH and free T4. Given the severe general condition, persistent weakness, lethargy, lack of weight gain, as well as markedly elevated NTSH levels, it was recommended to initiate replacement therapy with levothyroxine sodium at a dose of 12.5 μg once daily in the morning on an empty stomach, 30 minutes before feeding.

Pediatric endocrinology consultation (follow-up) on the 10th day of life. Laboratory tests revealed a repeated elevation of TSH >100 μIU/mL, low free T4 (5.98 pmol/L), and normal free T3 (2.06 pg/mL). A definitive diagnosis could be established: Congenital hypothyroidism without goiter (E03.1).

Treatment was recommended: continuous replacement hormone therapy with levothyroxine sodium 25 μg once daily in the morning, 30 minutes before feeding; monitoring of free T4 in 7–10 days; monitoring of TSH in 4 weeks; regular follow-up with a pediatric endocrinologist at the place of residence – at 1 month of age, 10 days after initiation of therapy, and subsequently once a month.

Pediatric neurology consultation: cerebral ischemia grade II, intraventricular hemorrhage grade I, pyramidal insufficiency syndrome.

Pediatric surgery consultation (initial) on the 4th day of life: according to the abdominal survey radiograph, hyperpneumatization of the intestinal loops was present. It was recommended to withhold feeding, insert a permanent gastric tube, and provide parenteral nutrition (consisting of 10% glucose with components 100 mL, 10% Aminoven Infant 40 mL, and 20% SMOFlipid 20 mL). Continuation of ongoing antibacterial therapy was advised.

Pediatric surgery consultation (follow-up) on the 5th day of life: considering the positive clinical dynamics, including the absence of regurgitation and vomiting, spontaneous stool passage, reduction of abdominal distension, and absence of pathological discharge through the tube, it was recommended to initiate enteral feeding.

Based on clinical, laboratory, and instrumental findings, the newborn was diagnosed with the primary clinical diagnosis: (E03.1) Congenital hypothyroidism without goiter.

A concomitant primary clinical diagnosis was also established: (P05.2) Fetal malnutrition without mention of “light-for-dates” or “small-for-gestational age.”

Concomitant clinical diagnoses: (P52.0) Intraventricular hemorrhage grade I in the fetus and newborn on the left; moderate cerebral ischemia, autonomic dysfunction syndrome; (P39.8) Other specified infection (Staphylococcus haemolyticus, Candida albicans) specific to the perinatal period; grade II intestinal dysbiosis of staphylococcal and fungal etiology; (Q21.8) Functioning fetal communication – patent foramen ovale.

The newborn received the following therapeutic interventions:

1. Feeding: expressed breast milk or PreNAN formula in cases of hypogalactia, 30 mL 8 times every 3 hours, by bottle.
2. Euthyrox 25 μg once daily.
3. Antibacterial therapy (Amibactam, Amikacin, Vancomycin, Sabvixin).
4. Antifungal therapy (Fluconazole).
5. Intravenous infusion: 10% glucose with components, 10% Aminoven Infant, 20%
6. Vitamin therapy (vitamin B1 and vitamin B6).
7. Nootropic therapy (Cortexin).
8. Prebiotic therapy (Bifidumbacterin, Bactisubtil Baby).
9. Symptomatic therapy (Espumisan).
10. Sextaphage.

During the ongoing therapy, stabilization of the condition was noted, and the general condition was satisfactory. The newborn was calm and responded to examination with a loud cry. Motor activity was preserved in full. At discharge, the newborn’s weight was 2,660.0 g (a gain of 146 g over 15 days), length – 53 cm (an increase of 1 cm over 15 days), head circumference – 36 cm (an increase of 2 cm over 15 days), and chest circumference – 33 cm (an increase of 1.5 cm over 15 days).

During therapy, stabilization of the condition was observed, along with improved appetite, positive weight dynamics, reduction of skin jaundice, resolution of abdominal distension, restoration of muscle tone, normalization of tendon reflexes, and increased spontaneous motor activity. Tendon reflexes were brisk and symmetrical (S=D). Oral–spinal automatism reflexes could be elicited. The anterior fontanel was level with the cranial bones, measuring 1.0 × 1.0 cm, not tense. Feeding consisted of expressed breast milk, 30 mL eight times daily, or PreNAN formula in cases of hypogalactia, 30 mL every 3 hours, eight times daily. No regurgitation was noted. The skin was pale pink, clean, and moderately moist. Subcutaneous fat was moderately developed. A small amount of serous discharge was present from the umbilical wound. No dyspnea, vomiting, or regurgitation was observed. Appetite was satisfactory. Percussion of the lungs revealed a normal resonant sound; auscultation showed puerile breathing. Heart sounds were rhythmic but muffled. The abdomen was soft and painless. The liver extended 2 cm below the costal margin; the spleen was not enlarged. The stool was mushy, with traces of mucus.

The newborn was discharged home at the age of 18 days in satisfactory condition with recommendations for follow-up by a pediatrician and endocrinologist, with subsequent hospitalization at the age of two months in the pediatric department for dynamic evaluation of congenital hypothyroidism and perinatal hypoxic–ischemic CNS injury, as well as for adjustment of the levothyroxine replacement therapy dosage according to the course of the primary disease and for rehabilitative treatment of perinatal hypoxic–ischemic CNS injury.

Discussion

The distinctive feature of this case is the combined nature of the pathology in the newborn: congenital hypothyroidism was observed along with grade I intraventricular hemorrhage on the left side in the fetus and newborn and moderate cerebral ischemia accompanied by autonomic dysfunction syndrome. In addition, the newborn presented with fetal malnutrition without reference to “light-for-dates” or “small-for-gestational age”, as well as a perinatal infection of staphylococcal and fungal etiology, which was accompanied by pronounced intestinal dysfunction. The development of such a complex course of disease can be explained as follows.

The development of congenital hypothyroidism in the newborn was caused by impaired formation and differentiation of the thyroid gland, which may be associated with gene mutations [1]. In addition, thyroid insufficiency had a negative impact on the fetal central nervous system and immune status. Along with this, intrauterine hypoxia developed, as evidenced by the detection of a left choroid plexus cyst in the fetal brain at 21 weeks of gestation. The fetus was also adversely affected by the maternal history of acute respiratory viral infection, bacterial vaginosis, candidiasis, and bacteriuria during pregnancy. The presence of these factors subsequently determined the severe course of the neonatal period in a newborn with congenital hypothyroidism and the development of severe concomitant pathology. Due to early screening for congenital hypothyroidism (on the second day of life), timely replacement therapy with levothyroxine was initiated alongside treatment of the concomitant conditions, which contributed to the positive clinical course of the disease and prevented progression of hypoxic–ischemic CNS injury.

Early diagnosis of congenital hypothyroidism with the prompt initiation of replacement therapy makes it possible to prevent the development of intellectual disability in this group of newborns, since thyroid hormone deficiency severely disrupts the processes of growth and differentiation of all tissues and organ systems. The central nervous system is most affected by the lack of thyroid hormones in the newborn.

Conclusion

Neonatologists should remain alert to the possibility of congenital hypothyroidism and ensure timely neonatal screening. Given the absence of specific clinical symptoms of congenital hypothyroidism in the first days of life, it is also advisable to perform early assessment of thyroid status in newborns with neurological and somatic pathology who are being treated in neonatal pathology units. Delayed diagnosis of congenital hypothyroidism aggravates the course of concomitant diseases. If congenital hypothyroidism is suspected, the newborn should be referred for consultation with an endocrinologist. Subsequently, systematic follow-up by a pediatrician and endocrinologist is required, with dosage adjustment of therapy as needed. Considering the combined nature of pathology, a multidisciplinary approach should be applied in the management of such patients.