Introduction

Dengue is a disease caused by infection with one of the four variants of the dengue virus (DENV), which is transmitted by mosquitoes, mainly Aedes aegypti. It should be noted that each variant has serotype-specific immunity¹. During pregnancy, the infection, although rare, can manifest asymptomatically or present with severe symptoms and high morbidity². Transmission to the newborn can be vertical or horizontal. Vertical transmission of dengue is rare, with an estimated prevalence of 1.6-10.5%. The incubation period varies from 3 to 25 days, most commonly being 5-8 days. This transmission usually occurs in endemic areas and occurs mainly when the mother is infected during the third trimester of pregnancy. The health implications of the maternal-fetal binomial have been documented since the early 2000s². It should be noted that in Mexico there are no epidemiological studies that report the exact prevalence of neonatal dengue. Machain (Mexico, 2018) conducted a study of patients from Veracruz, Tabasco, and Tamaulipas with immunoglobulin M (IgM) or NS1 for dengue positive during pregnancy in 82 patients, 31 were during the last trimester and all those that were severe occurred between gestational week 34 and 36, of these last patients, five died. Of the reported newborns, only one was low birth weight and none developed symptoms during their hospital stay³.

The antibody response to DENV infection is primarily directed at specific serotype determinants, but there is a substantial level of serotype E cross-reactive antibodies, with the precursor membrane (pre-M) and NS1 being the main viral proteins targeted. In vitro, specific antibodies to the E protein can mediate infection neutralization, complement-mediated direct lysis, or antibody-dependent cellular cytotoxicity of DENV-infected cells and block the binding of the virus to cell receptors⁴.

Pre-M-specific antibodies only bind to virions that have not fully matured and have remaining pre-M protein uncleaved. NS1 is not found in the virion; Thus, NS1-specific antibodies are unable to neutralize viral infection, but they can direct complement-mediated lysis of infected cells. To date, the basis for neutralization of the virus by antibodies is not well understood⁴.

Clinical manifestations

It is estimated that more than 390 million DENV infections occur each year and approximately 96 million are clinically evident. Clinically apparent dengue is more common among adults, while among children, most infections are usually asymptomatic or minimally symptomatic and may occur with persistent vomiting. Clinical accumulation of fluid (ascites, pleural effusion), bleeding from the mucous membranes, lethargy or restlessness, hepatomegaly > 2 cm concurrent increase in hematocrit with a rapid decrease in platelet count. Severe plasma leak causing: shock, fluid accumulation with respiratory distress. May also present with severe bleeding⁴.

It is also feasible to present severe organ involvement through aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 1000 units/L and deterioration of alertness. A primary DENV infection is defined as the first wild-type infection that an individual suffers from, while a secondary infection is the second wild-type infection caused by a different serotype of DENV. Secondary infections separated in time by more than 18 months represent the greatest risk of causing a serious clinical outcome⁴.

The incubation period for DENV infection ranges from 3 to 14 days; symptoms usually develop 4-7 days after an infected mosquito bite. Phases of infection: there are three phases that can be observed in the context of a DENV infection: a febrile phase, a critical phase, and a recovery phase; however, the critical phase is not observed in all infection categories⁴.

Within the 1997 WHO classification scheme, the three phases of infection occur in the context of dengue hemorrhagic fever and dengue shock syndrome; dengue fever (DF) includes febrile and recovery phases, but no critical phases. Within the WHO’s 2009 classification scheme, the three phases of infection occur in the context of severe dengue and dengue with warning signs; dengue without warning signs includes febrile and recovery phases, but no critical phases⁵.

Febrile phase: the febrile phase of DENV infection is characterized by sudden onset high fever (≥ 38.5°C) accompanied by headache, vomiting, myalgia, arthralgia, and transient macular rash in some cases. Children have a high fever but are usually less symptomatic than adults during the febrile phase. The febrile phase lasts 3-7 days, after which most patients recover without complications. Headache, eye pain (i.e., pain with eye movement), and joint pain occur in 60-70% of cases. The rash occurs in about half of the cases, being more common during the primary infection than during the secondary infection. When present, the rash usually occurs 2-5 days after the onset of fever⁶-⁸.

In children, clinically significant bleeding rarely occurs, usually associated with prolonged, deep shock. It should be noted that there is not always significant thrombocytopenia when hemorrhagic manifestations occur and when it is present, the risk of bleeding increases. Physical examination may demonstrate conjunctival injection, pharyngeal erythema, lymphadenopathy, and hepatomegaly. Facial edema, petechiae (on the skin and/or palate), and bruising (particularly at venipuncture sites) may be observed⁹,¹⁰.

A biphasic ("saddle") fever curve has been described in about 5% of cases; in these patients, acute febrile illness remits and then recurs about a day or two later; the second febrile phase lasts 1 or 2 days. Leukopenia and thrombocytopenia (≤ 100,000 cells/mm) are common¹¹,¹² (Fig. 1). Serum aspartate transaminase (AST) concentrations are usually elevated and these elevations are usually moderate (2-5 times the upper limit of normal), but marked elevations (5-15 times the upper limit of normal) occasionally occur. Elevated liver enzymes are common in the febrile phase; synthetic liver dysfunction (i.e., elevated activated partial thromboplastin time) and fibrinogen decreases are not frequently identified.

Figure 1 The image shows the natural evolution of the disease where first there is a febrile phase that lasts approximately 5 days and then presents changes in the blood count where the progressive decrease of the platelet count stands out, this being the critical stage of the disease. 

Between days 3 and 7 of the disease, significant vascular leakage reduces intravascular volume and decreases organ perfusion. Corresponding clinical manifestations may include persistent vomiting, increasingly severe abdominal pain, painful hepatomegaly, development of pleural effusions and/or ascites, mucosal hemorrhage, and lethargy or restlessness; laboratory findings may include a high or increasing hematocrit level (≥ 20% from baseline) concurrent with a rapid decrease in platelet count¹³-¹⁶ (Fig. 1).

Critical phase: The vast majority of infections that progress to a critical phase are the result of second DENV infections that occur more than 18 months after a first resolved infection. However, a subset of critical infections occurs in children under 1 year of age, at the time when maternal antibodies are below protective levels and the child experiences a primary wild-type infection. The critical phase lasts 24-48 h. Initially, adequate circulation can be maintained by physiological compensation, resulting in a narrowing of pulse pressure (systolic pressure minus diastolic pressure ≤ 20 mmHg). In confirmed cases of dengue in the mother, most newborns do not show symptoms, but they may present with neonatal sepsis and present with fever, rash, irritability, and bleeding¹⁷.

Presentation of the case

This is a full-term male newborn, son of a 21 year old woman, G1, P0, C1, A0. The mother received antenatal care at her local health center, with a total of 8 consultations, and underwent 3 reported ultrasounds with no obvious abnormalities. In addition, TdPA immunizations were administered during pregnancy, although immunization against influenza and COVID-19 was denied by the patient.

During pregnancy, the patient denied having presented threats of abortion, threat of pre-term delivery, pre-eclampsia, gestational diabetes, or other complications of pregnancy. She developed a urinary tract infection at 32 weeks of gestation, receiving unspecified antimicrobial treatment and finding improvement in symptoms. In addition, he presented cervicovaginitis on two occasions, which were managed with unspecified antimicrobial treatment with improvement of symptoms. Three days before the resolution of the pregnancy, the patient experienced headache, photophobia, myalgias, arthralgias, and unquantified fever. She self-medicated with paracetamol, without finding improvement. 24 h after the onset of symptoms, they decide to go for evaluation at their health center, where dengue is probably diagnosed, given the typical manifestations and its location in an endemic area of Morelos. The patient was admitted to the General Hospital of Jojutla where she was kept under surveillance and laboratory studies were taken which reported: Leukopenia (4 thousand) and a decrease in platelets (150 thousand, previously 180 thousand) for which a polymerase chain reaction (PCR) test was performed for the detection of dengue. Given the clinical suspicion of the diagnosis and maternal complications, it was decided to terminate the pregnancy by cesarean section.

A male product of 40 SDG per Capurro was obtained through the abdomen, who cried and breathed at birth presenting a weak cry and a heart rate > 100 beats/min, with a report of meconium-stained fluid. The product had a weight of 3700 g height: 52 cm APGAR: 8/8, at 10 min of life the product presents data of respiratory distress at the expense of: discrete intercostal retraction, discrete nasal flaring, and respiratory whine receiving a Silverman score of 3, so it was decided to transfer him to the neonatal intensive care unit (NICU) where a chest X-ray was taken, which showed evidence of horizontal costal arches and an increase in intercostal spaces, in addition to a predominant nodular infiltrate in the right lung. An umbilical catheter was placed in an intrahepatic position and laboratory studies were taken, identifying in the blood count a hemoglobin of 12.7 g/dL, a hematocrit of 39.3%, a leukocyte count of 15.1 (94.1% neutrophils, 38.2% lymphocytes, 6.1% monocytes, 1.2% eosinophils, 0.4% basophils) and platelets of 222 thousand. Cord blood gases reported: a pH of 7.3, PCO₂ of 47 mm Hg, pO₂ of 10 mm Hg, lactate of 2.6 mmol/L, DB - 3.3 mmol/L, and HCO₃ of 23.1 mmol/L.

The product was admitted to the NICU with the diagnosis of "full-term newborn (40 weeks of gestation) with high weight for gestational age, meconium aspiration syndrome and child of a mother with dengue without alarm data". Antimicrobial treatment with ampicillin and amikacin was initiated due to meconium aspiration and the patient was kept fasting receiving supplemental oxygen through nasal CPAP due to the persistence of respiratory distress that did not improve with supplemental oxygen supply through nasal tips.

At 24 h of life, nasal CPAP was removed and nasal prongs were progressed due to improvement of the ventilatory pattern, presenting adequate tolerance, and PCR test results for dengue were collected from the mother, which reported positive NS1 with DENV-3 serotype. The product presented adequate clinical evolution, however, on the 5^th day of life the newborn presented a fever quantified up to 39°C, so new blood biometry was taken that reported: hemoglobin of 14.9 g/dL, a hematocrit of 46.5%, a leukocyte count of 1500, (29.9% neutrophils, 29.9% lymphocytes, 26% monocytes, 2.4% eosinophils, 11.8% basophils, platelets of 32 thousand and liver function tests that reported ALT/TGP: 38.0 U/L, serum albumin: 3.10 g/dL evidencing a decrease in platelet count (Table 1) so it was decided to perform a specific PCR test for dengue and water support was started at 110 mL/kg/day with dynamic management of intravenous fluids and thermal control with paracetamol and starting management with vitamin K. The patient continued to be feverish, irritable, but remained without bleeding data. 24 h later, new control laboratory studies were taken which reported hemoglobin of 14.6 g/dL, a hematocrit of 43.4%, a leukocyte count of 3900, (33.7% neutrophils, 50.1% lymphocytes, 13.5% monocytes, 2.1% eosinophils, 0.6% basophils,) platelets of 16 thousand (Fig. 2). TP: 14.62, APTT: 64.09, INR: 1.09, so it was decided to transfuse platelets and fresh plasma, on the 7^th day of life the PCR report for dengue was collected, identifying reactive Ag. NS1 confirming the infection in the neonate (Fig. 3).

Figure 2 The graph shows a downward curve of the platelet count in the newborn during the course of the disease in which a clear decrease in the platelet count can be seen that becomes more pronounced between days 5 and 6 of the disease with a significant increase in the platelet count from day 7 of the disease evidencing the recovery stage. 

Figure 3 The report of the diagnostic test performed on the newborn whose result was positive for dengue when Ag. NS1 was positive and is shown. NS1 is one of the 7 non-structural proteins of the dengue virus that are thought to be involved in viral replication, so a positive result for NS1, with negative immunoglobulin M (IgM) and IgG indicates recent infection, probably with a disease time of < 5 days. 

Discussion

This clinical case presents a complex scenario in which maternal dengue during pregnancy conditions complications in the pregnant woman, causing the resolution of the pregnancy urgently through the abdominal route, associating neonatal complications, in particular a meconium aspiration syndrome and a clinical picture that initially suggested neonatal sepsis. Although the diagnosis of dengue in the mother was clinical, the clinical picture of the newborn was larval in the first hours of life, representing a real challenge for the diagnosis since, as previously described, vertical transmission is rare, once the newborn began with a picture of persistent high-grade fever, complementary laboratory studies were repeated, evidencing the development of thrombocytopenia In addition, it was possible to collect the result of the confirmatory tests for dengue carried out on the mother, which yielded a positive result, so diagnostic tests were carried out on the newborn, thus confirming the diagnosis. Another of the challenges identified in this clinical condition was the adequate water management of the newborn since, as described, there is no evidence or guidelines that guide the most appropriate water management in these patients, having opted in this case to carry out a dynamic water management similar to that of any other newborn, carrying out fluid increases of 12.5 mL/kg/day every 24 h maintaining strict control of water balance and diuresis, another challenge during the course of the disease in the newborn was the risk of developing bleeding data, so it was decided to initiate management with Vitamin K and once a thrombocytopenia of 16,000 was identified, it was decided to transfuse platelets. A transfontanelar ultrasound was performed where hemorrhage at this level was ruled out. It should be noted that at no time was there any data of bleeding at another level. Temperature management was carried out with alternating paracetamol and metamizole, thus achieving adequate thermal control.

The relationship between maternal dengue infection and the risk of meconium aspiration syndrome in the newborn is a question that requires further investigation. Dengue is a mosquito-borne disease that affects people of all ages, but the focus on neonatal dengue is focused on newborns who acquire the virus during birth or shortly after birth. Although neonatal dengue is rare, it is important to understand its clinical characteristics, diagnosis, and management to ensure adequate care and prevent complications, it should be noted that the management of the patient with dengue involves a high intake of fluids which, so far, has not been fully studied in the newborn, making it a real challenge for the treating physician.

Conclusion

Mother-to-child transmission of dengue is a rare but important route of infection. Neonatal top-down dengue can present with a variety of symptoms, and its diagnosis and management require careful clinical evaluation and laboratory testing.