Etiologia posibilă a hidropsului fetal non-imun – consideraţii pe baza unui caz clinic

Introduction

The accumulation of fetal fluid in at least two anatomical body compartments, known in medical literature as fetal hydrops, has a multifactorial etiology: Rh/ABO or other rare blood groups incompatibility are responsible for only 15-20% of cases nowadays, when specific prophylaxis is available. Non-immune hydrops fetalis (NIHF) became more prevalent as a severe condition that can lead to loss of pregnancy, stillbirth or severely depressed infant needing extensive resuscitation. The outcome depends on both the etiology and early intrauterine diagnosis and intervention.

Material and method - clinical case

We were faced with the case of a 30-week gestation fetus, of female sex, weighing 3000 g, with generalized cyanosis, generalized subcutaneous edema, with dysmorphic appearance, atone, non-reactive, without spontaneous breaths, a heart rate of 70 beats/minute and Apgar scores of 1/1/0/0 at 1, 5, 10 and 20 minutes respectively.

The maternal history reveals a 22-year-old healthy mother, gesta 2, para 1, with AII positive blood type and 2 provoked abortions in the obstetrical history. The current pregnancy was monitored by 4 fetal ultrasounds, at 5, 6, 20 and 28 weeks of gestation. The last examination revealed polyhydramnios and fetal hydrops. The gravida was referred to the proximal level III center, as a high risk pregnancy, but she presented for admission only at 30 weeks of gestation. The ultrasound performed at the level III center confirmed the diagnosis (Figures 1, 2).
 

The following day after admission, bilateral fetal thoracic drainage was performed and 50 ml of fluid were extracted. Upon microscopic examination, the fluid was shown to contain abundant red and white cells, but no bacterial organisms were isolated. No viral tests were performed at this time.

An amniocentesis was performed and 2 L of amniotic fluid were evacuated. The FISH test excluded trisomy 13, 18 and 21, but the karyotype could not be determined because of a high microbiological contamination of the sample. At this moment, we sampled the amniotic fluid for parvovirus B19. Later results infirmed the viral etiology.

After the spontaneous rupture of membranes, an emergency C-section was performed and a female fetus of 3000 g was extracted (Figures 3, 4).
 

At birth, the infant had a heart rate of 70 beats/minute, no muscle tone or reactivity and no spontaneous breaths. Immediate complex resuscitation was started. At 1 and 5 minutes, the Apgar score was 1. After 10 minutes of resuscitation with intubation, positive pressure ventilation, chest compressions, 3 doses of i.v. epinephrine, there was no response and the Apgar score was 0. The procedure continued for another 10 minutes, with no success. Blood gases at 10 minutes after birth showed severe respiratory acidosis with no metabolic component and normal values for hemoglobin and hematocrit: pH=7.07, pCO₂=99.7 mmHg, pO₂=10.4 mmHg, BE=-3.2 mmol/L, HCO₃-=29.3 mmol/L, Hb=14.5 g/L and Ht=43%.

The chest X-Ray showed severe subcutaneous edema, generalized thoracic and abdominal opacification, suggesting severe antenatal hydrops (Figure 5).
 

At that moment, based on the clinical status, X-ray and maternal history, the diagnosis was congenital hydrops, bilateral hydrothorax and polyhydramnios.

The pathology exam revealed bilateral hypoplastic lungs (Figures 6 and 7) and hepatomegaly.
 

Discussions

Based on the clinical status, a differential diagnosis was done. Fetal hydrops was confirmed according to the definition, by the presence of fluid in at least two sites from the following locations: cutaneous edema, ascites, pleural effusion, pericardial effusion, hepatosplenomegaly or cardiomegaly. As the mother was AII positive, Rh incompatibility was excluded, so we reasonably assumed it was a non-immune hydrops fetalis (NIHF). In a recent study published by Bellini⁽¹⁾, which analyzed 24 relevant publications describing 1338 patients with NIHF, the affected individuals were divided into 14 groups based on the cause of NIHF (percentage of the total group): cardiovascular (20.1%), hematologic (9.3%), chromosomal (9%), syndromic (5.5%), lymphatic dysplasia (15%), inborn errors of metabolism (1.3%), infections (7%), thoracic (2.3%), urinary tract malformations (0.9%), extra thoracic tumors (0.7%), TTTF-placental (4.1%), gastrointestinal (1.3%), miscellaneous (3.6%) and idiopathic (19.8%).

In the presented case, several causes were discussed:

A. Severe non-immune anemia (ex.: alpha-thalasemia) - excluded based on normal hemoglobin at birth.

B. Congenital cardiac defects (tetralogy of Fallot, atrio­ventricular septal defect, Ebstein disease), intracardiac tumors – excluded by the pathology exam.

C. Adenomatous pulmonary malformation, diaphragmatic hernia, pulmonary sequestration, congenital hydro or chylothorax, bronchogenic chysts - excluded by the pathology exam. Some of these situations may associate pulmonary hypoplasia, which was a finding in our case too.

D. No trisomy was proven, nor Turner syndrome.

E. A large amount of cases were associate with congenital TORCH infections, that in our case was explored, but the maternal tests for toxoplasma, cytomegalovirus, herpes, HIV, hepatitis viruses and Treponema pallidum were negative.

F. A special concern was parvovirus infection, for which the intrathoracic fluid extracted at birth was tested. As known, parvovirus B19 is widespread in general population, especially in school-aged children, where the major manifestation is erythema infectiosum (fifth disease)⁽²⁾. If the mother becomes infected during pregnancy, transplacental transmission to the fetus is 33-50%, but the overall risk of adverse outcome after primary infection is less than 10%⁽³⁾. About 50% of pregnant women are immune to parvovirus B19 infection, if they already had the infection in the past⁽⁴⁾. The primary infection is most common among women at childbearing age who have school-aged children at home, schoolteachers or daycare workers. Until 20 weeks of gestation, the erythrocyte’s lifetime is short and there is a lack of adequate immune response against this infection. As a result, the fetus can develop acute severe anemia or chronic anemia, leading to spontaneous abortion. Other authors affirm a less severe incidence of anemia, stating that in very rare cases, the virus can affect the unborn baby’s ability to make red blood cells, only sometimes leading to a dangerous form of anemia.

The risk is lower for exposures in the second half of pregnancy than in the first half⁽⁴⁾. For women infected between 9 and 20 weeks of gestation, an overall risk of 10.6% of fetal hydrops exists⁽⁵⁾.

In our case, we assumed the infection took place in the second trimester of pregnancy, knowing that it can evolve with severe fetal hydrops and less anemia that without treatment usually results in stillbirth.

However, the test results did not confirm parvovirus B19 in the lung fluid.

Lung malformations and hypoplasia are not commonly associated with the parvovirus B19 infection. Based on large epidemiologic studies, parvovirus B19 is considered non-teratogenic, despite some clinical case reports. The management of parvovirus B19 infection in pregnant women consists in immediate diagnosis and intrauterine transfusion in hydropic fetuses, that can decrease the risk of fetal death⁽⁶⁾, as there is no drug treatment available.

The limitation of the present case consisted mainly in the impossibility to efficiently evacuate the hydrothorax at the moment of admission after the diagnosis was confirmed, due to a placenta praevia with a great risk of bleeding during the procedure.

Also, we were not able to perform the test for parvovirus B19 by PCR from the first day of admission, by thoracic drainage, which although expensive, could better elucidate this etiology. In this specific situation, we concluded that the hydrops was idiopathic.

Specific management for NIHF has recently been summarized in different protocols⁽⁷⁾. In our case, according to limitations of tests available, the recommendations were applied, but the late addressability since the first diagnosis and the rapidly developing hydrops dramatically affected the outcome.

The occurrence of pulmonary hypoplasia is an unusual association and cannot be explained by the compression due to the hydrothorax, as it developed unexpectedly fast and at a short time before birth and could not alter very much the lung development.

Conclusion

The key point for fast developing hydrops cases may consist in early intrauterine detection by more frequent ultrasound monitoring, to allow easier access for fetal thoracic drainage with a higher chance of success. More rigorous follow-up of pregnancies with hydrops including parvovirus B19 PCR determination and karyotype to exclude different rare etiologies should become common practice, as genetic counseling may be very helpful for avoiding recurrence.