Course and outcome of pregnancy in a woman with Epstein-Barr virus infection: clinical case

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Introduction

Epstein–Barr virus (EBV) is a ubiquitous pathogenic virus of the Herpesviridae family. According to various researchers, EBV infection rates among newborns are 17.7 %, increasing to 90 % or higher in older age groups [1–3]. Moreover, EBV-induced infection is the main cause of infectious mononucleosis [4] and can also be a cause of cancer, in particular Burkitt's lymphoma [5].

EBV is mainly transmitted through saliva, but in rare cases it can be transmitted through semen or blood during sexual intercourse [6; 7]. Transmission of EBV through oral secretions leads to infection of the epithelial cells of the oropharynx [8; 9], as a result of which the virus can move between different types of cells [10; 11]. In addition, EBV can switch between latent and lytic life cycles [12–14]. Systemic autoimmune diseases often manifest themselves in the form of overlapping syndromes
[15–17] with diagnosable autoantibodies. Due to the fact that EBV can move between epithelial cells and B-lymphocytes, EBV localizes in endometrial glandular epithelial cells of the placenta [18; 19].

In recent years, the problem of EBV has become quite relevant due to the increasing number of cases of transmission of the virus from mother to child. According to world literature, currently, in the structure of intrauterine infections, infection caused by EBV occupies a leading position [20–23], which is especially important when considering this clinical case.

The purpose of the study is to analyze the clinical case of pregnancy and emergency delivery of a woman with an infection caused by the Epstein–Barr virus.

Clinical case

Patient M., 32-years-old female. Menarche began at the age of 13, menstrual function is not impaired. The patient has been sexually active since the age of 17. Gynecological history: diathermocoagulation of the cervix for erosion was performed in 2019. Obstetric history: multiparous. The first pregnancy ended in 2018 with timely operative delivery at 38 weeks and 5 days. Caesarean section was performed in the lower uterine segment due to pathology of the visual analyzer. Somatic pathology is represented by the presence of high myopia; mixed-type vegetovascular dystonia; chronic gastritis in remission. No history of allergies, no bad habits. Childhood infections are represented by a history of chickenpox. The patient is prone to acute respiratory viral infections (ARVI) incidence with a frequency of 1–2 times during the year. The patient was under outpatient observation of the current pregnancy from 7 weeks of gestation. At 8 weeks of pregnancy, she complained of fever up to 39 °C and headache (which she stopped using non-steroidal anti-inflammatory drugs), so she consulted a physician at the antenatal clinic. The doctor diagnosed her with acute respiratory viral infection and prescribed treatment with antiviral drugs (Grippferon and Ingavirin).

The course of pregnancy since 17 weeks was complicated by mild gestational anemia. A screening ultrasound examination at 20 weeks and 3 days of gestation revealed cardiomegaly (slight enlargement of the right atrium) and hydropericardium (minor).
A perinatal consultation was held at 21 weeks and one day. According to antenatal ultrasound data, pathological changes were detected: congenital heart defect (CHD) in the fetus; double origin of great vessels from the right ventricle, right ventricular myocardial hypertrophy, hydropericardium (Fig. 1).

 

Fig. 1. Photographic images of antenatal ultrasound examination of the fetus at the 20th week of pregnancy

 

The patient was evaluated at the Federal Center of Cardiovascular Surgery in Penza during the 22nd week of gestation. Based on a recent antenatal ultrasound, the following fetal congenital heart defects (CHD) were diagnosed: subaortic ventricular septal defect, dextraposition of the aorta, cardiomegaly, and a moderate amount of fluid in the pericardial cavity. It was recommended to conduct follow-up echocardiography at 25 and 30–32 weeks of pregnancy, with specific attention to monitoring the fluid level in the pericardial cavity.

At 23 weeks of gestation, a comprehensive analysis of the urogenital scraping by PCR for common sexually transmitted infections revealed no pathological changes, Ultrasound monitoring was performed at 23 weeks: polyhydramnios was detected with an amniotic fluid index level of 24 cm. Empirical therapy for polyhydramnios was carried out on an outpatient basis (antibacterial therapy). Ultrasound monitoring was repeated at 25 weeks. The amount of amniotic fluid was within the acceptable norm. The level of fluid in the pericardial region remained unchanged (6 mm). However, fetal ascites with a small amount of ascitic fluid (5 mm) was detected.

At 28 weeks of pregnancy, the patient visited a physician at the antenatal clinic with complaints of a fever reaching up to 39 °C. During the medical history, it was revealed that she had been in contact with a child diagnosed with an acute respiratory viral infection (ARVI) in the past two weeks. An antenatal ultrasound examination revealed a pelvic presentation of the fetus. The fetal congenital heart defect was identified as Fallot’s tetrad type, along with cardiomegaly (myocardial hypertrophy of both ventricles) and a moderate amount of fluid in the pericardial cavity. Additionally, the fetus showed signs of bilateral hydrothorax, ascites, and ultrasound indicators of non-immune fetal hydrops. Complications included fetoplacental insufficiency and polyhydramnios (Fig. 2).

 

Fig. 2. Ultrasound images of the fetus at the 28th week of pregnancy

 

The microbiological screening was expanded. A study for viral infections revealed the presence of antibodies to the Epstein–Barr virus capsid antigen (in the amount of 67.58 copies) and the presence of B-19 parvovirus antibodies (in the amount of 7.97 copies).

The non-immune hydrops (ascites, bilateral hydrothorax, hydropericardium) detected in the fetus was decided to be regarded as a complication caused by Epstein – Barr virus infection. Treatment with semisynthetic penicillins and antiviral drugs with immunomodulatory action was carried out. Given the stable condition of the fetus, there were no indications for early delivery.

At the 32nd week of pregnancy, during a follow-up visit to the antenatal clinic, an antenatal ultrasound examination was performed, taking into account the complicated obstetric and gynecological history. The examination revealed the cephalic presentation of the fetus, fetal congenital heart defect of Fallot's tetrad type, cardiomegaly (myocardial hypertrophy of both ventricles, moderate amount of fluid in the pericardial cavity), bilateral hydrothorax, ascites, ultrasound signs of non-immune fetal hydrops (Fig. 3).

 

Fig. 3. Ultrasound images of the fetus at the 32d week of pregnancy

 

At 32 weeks of gestation, a follow-up consultation was held at the Federal Center of Cardiovascular Surgery (Penza). The examination confirmed the presence of fetal congenital heart defect of Fallot's tetrad type, cardiomegaly, myocardial hypertrophy of both ventricles, bilateral hydrothorax, ascites and non-immune fetal hydrops. It was recommended to refer the patient to a federal obstetric institution (FSBI «National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov»).

At 33 weeks and 3 days of gestation, a telemedicine consultation was held with the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I.Kulakov. The telemedicine consultation confirmed congenital heart defect: double origin of great vessels from the right ventricle of the Fallot's tetrad type (subaortal ventricular septal defect with a patent foramen ovale, subvalvular stenosis of the pulmonary artery). The positive dynamics in the course of non-immune fetal hydrops was noted: insignificant hydropericardium, residual ascites, fetal hepatomegaly (vertical liver size 67 mm). Feto-placental and uteroplacental blood flow were within normal limits. Considering the ultrasound examination data and anamnesis data, there was a high probability of intrauterine infection (with B-19 parvovirus) with the development of non-immune fetal hydrops due to anemia. In addition, when assessing the blood flow velocity in the fetal middle cerebral artery (MCA), a high likelihood of moderate anemia was revealed. Persistent polyhydramnios is noted at the level of amniotic fluid index values of 27 cm.

Recommendations included: admission to a level III obstetric hospital, further evaluation, dynamic monitoring, repeat testing for viral infections (enzyme-linked immunosorbent assay), including B-19 parvovirus, cytomegalovirus, herpes virus, Epstein–Barr virus, antibodies to the novel coronavirus infection, a repeat microbiological examination of the vagina and a second consultation after 7 days or sooner if fetal condition worsened, were advised.

The patient was subsequently admitted to the Clinical Perinatal Center of the Saratov Region due to the above. During hospitalization, a complete clinical and laboratory examination, preparation of the surfactant system of the fetus with dexamethasone were carried out. Daily dynamic monitoring of blood flow velocity along the fetal middle cerebral artery and cardiotocography were performed to monitor the state of intrauterine development of the fetus. During further clinical and laboratory examinations, antibodies to the capsid antigen of the Epstein–Barr virus (in the amount of 54.56 copies) and antibodies to parvovirus B-19 (in the amount of 2.34 copies) were again detected. At week 34 of pregnancy during repeated antenatal ultrasound examination (Fig. 4), a longitudinal position of the fetus in cephalic presentation was observed. Bacterial examination of the cervical canal revealed 10³ lactobacilli which confirmed the normal vaginal microflora.

 

Fig. 4. Ultrasound images of the fetus at the 34th week of pregnancy

 

Due to the complicated obstetric and gynecological history and the risk of emergency delivery, a repeat telemedicine consultation with the the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov was scheduled for March 9, 2023. During the consultation, it was recommended to continue monitoring and managing the patient in hospital settings. It was necessary to continue assessing the fetal middle cerebral artery blood flow velocity, monitoring with Doppler ultrasound and cardiotocography (CTG), keeping a fetal movement diary, repeat testing for viral infections using enzyme-linked immunosorbent assay (ELISA), repeating the bacteriological examination of the vagina, and having another telemedicine follow-up in 10–14 days or if there was a deterioration in the fetus' condition.

During the repeated telemedicine consultation on March 20, 2023, at the 36th week of pregnancy, positive dynamic was noted during an ultrasound examination conducted on March 20, 2023 (Fig. 5): a decrease in fetal hydrops, no ultrasound signs of anemia were detected which was associated with a decrease in the number of copies of antibodies to parvovirus B-19 (the number of copies at the time of the telemedicine consultation is 0.70), the congenital heart defect (CHD) detected during antenatal ultrasound was not critical. Recommendations were given for continuing monitoring and management of the patient in hospital settings, continuing assessment of fetal middle cerebral artery blood flow velocity, Doppler ultrasound and cardiotocography (CTG) monitoring, and keeping a fetal movement diary. The timing and method of delivery should be carried out according to obstetric indications, followed by echocardiography after birth.

 

Рис. 5. Ultrasound images of the fetus at the 36th week of pregnancy

 

On March 30, 2023, due to fetal intrauterine decompensation and severe ischemia at a gestational age of 38 weeks and 3 days, an emergency surgical delivery was performed.

A Caesarean section was carried out in the lower segment of the uterus with a transverse incision according to the Pfannenstiel technique, with excision of the old skin scar. The condition of the uterus was consistent with full-term pregnancy, and the caesarean section was performed without technical difficulties. The fetus was in cephalic presentation, and the amniotic fluid was clear. A full-term male infant was delivered, weighing 2940 g and measuring 46 cm in length. His Apgar score was 4–5. Upon examination, the newborn exhibited chest deformity, pronounced ascites, pallor of the skin, and multiple petechiae on the back and abdomen. A reduction in physiological reflexes of the spinal group was also noted, along with skull deformities: the skull was asymmetric, with protruding frontal and parietal tubercles. The child was urgently delivered to the neonatal intensive care unit and connected to a ventilator.

The child's condition has been critical since birth. Due to hemodynamic instability, 44 ml of 0.9 % sodium chloride solution was administered at a rate of 15 ml/kg for anti-shock purposes, followed by inotropic support with dopamine and dobutamine, which continued for 5 days. Due to severe anemia (hemoglobin level of 56 g/L), an urgent blood transfusion was performed with the intravenous administration of 50 ml of red blood cell suspension (O (I) Rh (+)). To prevent hemorrhagic disease, Vikasol 1 % (menadione sodium bisulfite 1 %) was also administered intramuscularly on the first day of life. In addition, given the mother's history of a previous Epstein – Barr virus infection and the risk of bacterial infection, antibacterial therapy was initiated on the first day of life. This included ampicillin (75 mg/kg/day intravenously) in combination with gentamicin (2.5 mg/kg/day intravenously). Antiviral therapy was also started, consisting of Viferon 150,000 IU twice daily, administered per rectum, for 5 days (from March 30, 2023, to April 4, 2023).

On the second day of life, convulsive syndrome appeared, and anticonvulsant therapy was started with intravenous administration of 10 % Convulex at a dose of 1 mg/kg/h for 5 days. There was also a decrease in tolerance to enteral nutrition, which required the appointment of parenteral nutrition.

On the 8th day, the child was extubated and transitioned to spontaneous breathing with oxygen support.

On the 11th day, he was transferred to the department of pathology for newborns and premature babies. During an initial consultation with a neurologist, ophthalmologist, surgeon, and cardiologist, the following conclusion was made: a full-term newborn boy with an Apgar score of 4–5. His condition remained severe. After a blood transfusion (March 30, 2023), slight motor activity was observed, and no convulsive seizures were present. There was a reduction in physiological spinal reflexes, as well as skull deformity: the skull was asymmetric, with protruding frontal and parietal tubercles. The fontanel measures 1x1 cm and was not tense. The diagnosis included hypoxic damage to the central nervous system (CNS), depression syndrome, a history of neonatal seizures, a history of infectious-toxic shock, and angiopathy of hypoxic-ischemic origin. Congenital heart defect (patent foramen ovale, 2 mm ventricular septal defect, hypertrophy of the walls of the right and left ventricles, and interventricular septum without outflow tract obstruction). Doppler echocardiography monitoring and a follow-up consultation with a cardiologist were recommended in two months. The results of clinical, laboratory, and instrumental examinations confirmed anemia of mixed origin, enteral insufficiency, intraamniotic infection of the fetus and newborn, non-immune fetal hydrops of mild degree, and mild respiratory failure in the newborn.

Due to the conclusions and taking into account the mother's history, antibacterial and preventive antifungal therapy was continued with a transition to the following combination: meropenem (20 mg/kg / 8 h) + vancomycin (10 mg/kg / 12 h) + fluconazole (6 mg/kg / 72 h). To further correct anemia, the child received epoetin alfa (epocrin), iron (III) hydroxide polymaltosate (maltofer) and folic acid.

At discharge (May 12, 2023), activation in the neurological status was noted. During the hospital stay, the child began to gain weight, and no respiratory disorders were observed. The skin was clean and moist, with the visible mucous membranes appearing pink. Heart sounds were rhythmic, with a regular rhythm. The abdomen was soft and painless in all areas, and subcutaneous fat was evenly distributed. Bowel movements were independent, with a yellow, gruel-like stool. At discharge, the following diagnosis was made: the primary diagnosis was hypoxic damage to the central nervous system. Concomitant conditions included congenital heart disease (CHD) with a 2 mm ventricular septal defect (VSD), hypertrophy of the walls of the right and left ventricles, and the interventricular septum, as well as a patent foramen ovale (PFO). Angiopathy of hypoxic-ischemic origin and anemia of mixed origin were also diagnosed. The condition was noted after a blood transfusion on March 30, 2023. The child had a history of neonatal seizures, depression syndrome, and infectious-toxic shock. Additionally, enteral insufficiency, intraamniotic infection of the fetus and newborn, and non-immune hydrops of the fetus and newborn were recorded along with mild respiratory failure in the newborn.

The following recommendations were provided: follow-up with a pediatrician, neurologist, ophthalmologist, and orthopedist at the place of residence. Outpatient electroencephalography (EEG) was recommended, as well as Doppler echocardiography monitoring in the second month of life, followed by a cardiologist consultation at the Saratov Regional Children's Clinical Hospital. Neurosonography should also be performed. A complete blood count, biochemical blood analysis, and general urine analysis should be repeated 10–14 days after discharge, followed by a pediatrician consultation at the Saratov Regional Children's Clinical Hospital. At 6 months of age, testing for markers of viral hepatitis B and C, HIV, and TORCH infections was advised. Transition to full breastfeeding on demand was recommended. If maternal lactation was insufficient, Nestle Nestogen 1 formula should be given, starting with 72 ml per feeding and gradually increasing the volume. For anemia prevention, folic acid 0.001 g should be taken orally once a day for one month. To prevent rickets, vitamin D (cholecalciferol) 2 drops (1000 IU) should be administered orally once a day continuously during the first year of life.

After discharge, outpatient follow-up of the newborn continued at the follow-up clinic, with visits scheduled once a month. During the observation period, the child demonstrated below-normal weight gain for his age, persistent severe normochromic anemia, bronchopulmonary dysplasia, ventricular septal defect (VSD), and patent foramen ovale (PFO). Additionally, a funnel chest deformity was noted. Due to the severity of the anemia, the patient was referred for consultation at the Dmitry Rogachev National Medical Research Center for Pediatric Hematology, Oncology, and Immunology. After further clinical and laboratory evaluation, Pearson syndrome was ruled out.

At the age of eight months, he had acute respiratory infection with convulsive syndrome. At the age of 10 months, he was re-consulted at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. A complete sequencing of the child and parents was performed. The patient had constitutional aplastic anemia.

As of May 17, 2024, the child's condition is satisfactory. Breathing is normal, though the funnel-shaped chest deformity persists. Breath sounds are heard throughout all lung fields and are puerile, with no wheezing detected. Moderate dyspnea occurs during periods of anxiety, with retraction of the lower third of the sternum. Hemodynamics are stable, with a systolic murmur heard at Botkin's point and the apex of the heart, without radiation. The abdomen is soft and painless on palpation, and the liver and spleen are not enlarged. There is a full range of motion in the hip joints. Stool shows no pathological impurities, and urination is regular. Facial muscle function is intact, though there is a slight head tilt toward the left shoulder. A high palate is observed. No meningeal signs are present. Muscular hypotonia of the back muscles is noted, but muscle strength is sufficient. Sensitivity is intact. The child has good eye fixation, holds his head, began crawling at 10.5 months, started sitting at 10 months, and has been standing with support since 11.5 months. He walks along support freely, manipulates toys, throws and rolls cars forward and backward, assembles and disassembles blocks, and interacts emotionally (laughs and smiles). Active babbling is noted, along with the unconscious pronunciation of short words. He responds to his name and recognizes some animals. The unconditioned (sucking) reflex is well-developed. Based on the catamnesis (objective data and specialist evaluations), the final diagnosis is as follows: consequences of perinatal hypoxic central nervous system (CNS) damage with movement disorder syndrome, showing improvement. A history of neonatal seizures and febrile seizures (since October 17, 2023) is noted.

Concomitant conditions include functional bowel disorders, with improvement, congenital heart defect (CHD) featuring a muscular ventricular septal defect (VSD) and patent foramen ovale (PFO), constitutional aplastic anemia, and funnel chest deformity. The child belongs to health group 3, with risk groups 2, 3, and 6. Normosomia and hypotrophy are present.

Conclusions

This clinical case clearly demonstrates the obvious course of EBV infection and complications resulting from it. Despite the early gestational age when the pregnant woman's body experienced a viral attack, this pregnancy was not terminated. The high prevalence of EBV infections, the frequency of atypical forms of the course, the variety of transmission routes, insufficient diagnosis, poorly understood mechanisms of immunopathogenesis, a colossal impact on the course of pregnancy, a high rate of premature births and severe pathologies of fetal intrauterine development, and the lack of clear criteria for managing pregnancy complicated by EBV infection substantiate the relevance of further study of this pathology.

About the authors

I. A. Salov

Saratov State Medical University named after V.I. Razumovsky

Email: maksim.polidanoff@yandex.ru
ORCID iD: 0000-0003-3438-7859

DSc (Medicine), Professor, Honored Doctor of Russia, Head of the Department of Obstetrics and Gynecology of the Medical Faculty

Russian Federation, Saratov

A. V. Romanovskaya

Saratov State Medical University named after V.I. Razumovsky

Email: maksim.polidanoff@yandex.ru

DSc (Medicine), Professor, Professor of the Department of Obstetrics and Gynecology of Pediatric Faculty

Russian Federation, Saratov

A. V. Parshin

Saratov State Medical University named after V.I. Razumovsky

Email: maksim.polidanoff@yandex.ru
ORCID iD: 0000-0001-8793-4786

PhD (Medicine), Associate Professor, Associate Professor of the Department of Obstetrics and Gynecology of the Medical Faculty

Russian Federation, Saratov

I. A. Arzhaeva

Saratov State Medical University named after V.I. Razumovsky

Email: maksim.polidanoff@yandex.ru

PhD (Medicine), Associate Professor, Associate Professor of the Department of Obstetrics and Gynecology of the Medical Faculty

Russian Federation, Saratov

I. G. Krotova

Saratov State Medical University named after V.I. Razumovsky; Clinical Perinatal Center of Saratov Region

Email: maksim.polidanoff@yandex.ru

Assistant of the Department of Obstetrics and Gynecology of the Medical Faculty, Obstetrician-gynecologist

Russian Federation, Saratov; Saratov

K. G. Eliseeva

Saratov State Medical University named after V.I. Razumovsky; Clinical Perinatal Center of Saratov Region

Email: maksim.polidanoff@yandex.ru

Assistant of the Department of Obstetrics and Gynecology of the Medical Faculty, Deputy Chief Physician for Obstetrics and Gynecology

Russian Federation, Saratov; Saratov

Yu. A. Fedorova

Clinical Perinatal Center of Saratov Region

Email: maksim.polidanoff@yandex.ru

Head of the Department of Neonatal Resuscitation and Intensive Care

Russian Federation, Saratov

M. A. Polidanov

University «Reaviz»

Author for correspondence.
Email: maksim.polidanoff@yandex.ru
ORCID iD: 0000-0001-7538-7412

Research Department Specialist, Assistant of the Department of Biomedical Disciplines

Russian Federation, Saint Petersburg

References

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