Hypertension and Proteinuria in a Pregnancy: A Quiz

A 17-year-old woman with a medical history of miscarriages at age 14 and 16 and 1 noncomplicated pregnancy at age 15 was hospitalized at 30 gestational weeks owing to the development of hypertension, proteinuria, and edema, with a weight gain of 17 kg, mainly in the last few weeks. Her prepregnancy body weight, height, and body mass index were 86 kg, 1.70 m, and 29.75 kg/m2, respectively. She had no history of autoimmune phenomena. Biochemical data are shown in Table 1.Table 1Biochemical Data at Admission, At Delivery, and 4 Months After DeliveryAdmissionDeliveryFollow-up (4 Months After Delivery)Reference RangeHemoglobin (g/dL)8.39.912.012.0-16.0Leukocytes (g/L)10.623.78.64.0-10.0Platelets (g/L)234264370150-400Creatinine (mg/dL)0.700.890.530.50-0.95Aspartate aminotransferase (IU/L)1926140-35Alanine aminotransferase (IU/L)86140-35Serum albumin (g/L)18163832-45Haptoglobin (g/L)0.630.15-0.50-2.00Uric acid (mg/dL)8.12-4.762.39-6.54LDH (IU/L)-375128135-214Proteinuria (mg/g creatinine)2,033.80-Absent0.00-5.65 Open table in a new tab At 23 weeks' gestation, the fetus was found to have a severe malformation (single ventricle, with pericardial effusion, ascites, and intestinal hyperechogenicity), and the patient and her husband had decided to continue the pregnancy despite the poor fetal prognosis. At referral, she was oliguric and blood pressure control was difficult, so a cesarean delivery was performed 2 days after admission, delivering a stillborn baby with anasarca weighing 2,880 g.•What is the differential diagnosis of hypertension and proteinuria during pregnancy?•Which are the diagnostic clues to differentiate etiology of hypertension and proteinuria during pregnancy?•What is the final diagnosis and what are the implications for the mother's long-term health and subsequent pregnancies? In order to disentangle this clinical case, we must consider the presence or absence of 4 main elements: hypertension, proteinuria, extracellular volume expansion, and hemolysis. The first differential diagnosis to be considered is pre-eclampsia. Pre-eclampsia can complicate 3%-5% of all pregnancies, and the onset of proteinuria, edema, and high blood pressure in the third trimester of pregnancy should point toward this most common diagnosis. HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome is an alternative diagnosis owing to the urgent presentation. The presence of edema could also point toward a new-onset nephrotic syndrome, but the degree of proteinuria (about 2 grams) is against this hypothesis despite the low serum albumin levels. Finally, a rarer diagnosis to consider is Ballantyne syndrome, which is characterized by severe edema in both the mother and the fetus. Table 2 presents a comparison of the differential diagnoses. Pre-eclampsia usually presents after 20 weeks' gestation and is based on the presence of hypertension (blood pressure ≥140/90 mm Hg) and proteinuria. In the absence of proteinuria, 1 of the following additional criteria is needed: platelet count <100,000/mmc, acute kidney injury, transaminases ≥2× the upper normal limit, pulmonary edema, new-onset headache.1Gestational Hypertension and Preeclampsia: ACOG Practice Bulletin Summary, Number 222.Obstet Gynecol. 2020; 135: 1492-1495https://doi.org/10.1097/AOG.0000000000003892Crossref PubMed Scopus (261) Google Scholar HELLP syndrome is characterized by lactate dehydrogenase >600 IU/L, transaminases >2× the upper normal limit, and platelets <100,000/mmc.1Gestational Hypertension and Preeclampsia: ACOG Practice Bulletin Summary, Number 222.Obstet Gynecol. 2020; 135: 1492-1495https://doi.org/10.1097/AOG.0000000000003892Crossref PubMed Scopus (261) Google Scholar However, the normal platelet count and transaminase values in our patient ruled out this hypothesis (Table 2).Table 2Some Clues for the Differential DiagnosisBallantyne SyndromePre-eclampsiaHELLP SyndromeHypertension++++++++Proteinuria+/-+++++Edema++++++/-Hemodilution+++--Platelet countNormalNormal/decreasedDecreasedHemolysis--+++Hepatic enzymesNormalNormal/elevatedElevatedUric acid+/-++++Acute kidney injury-++Hyper-reflexia-+-Abbreviation: HELLP, hemolysis, elevated liver enzymes, low platelet counts. Open table in a new tab Abbreviation: HELLP, hemolysis, elevated liver enzymes, low platelet counts. Ballantyne syndrome, described for the first time by John William Ballantyne in 1892 and also known as mirror syndrome or triple edema, is a rare occurrence, presents overlapping features with pre-eclampsia, and is characterized by maternal, fetal, and placental edema. The delivery of a stillborn baby presenting anasarca confirmed the diagnosis of Ballantyne (mirror) syndrome. It has both immune (red cell alloimmunization) and nonimmune causes.2Teles Abrao Trad A. Czeresnia R. Elrefaei A. Ibirogba E.R. Narang K. Ruano R. What do we know about the diagnosis and management of mirror syndrome?.J Matern Fetal Neonatal Med. 2022; 35: 4022-4027https://doi.org/10.1080/14767058.2020.1844656Crossref Scopus (1) Google Scholar The reported incidence is probably underestimated, as it is often misdiagnosed as pre-eclampsia. The etiopathogenetic mechanism is unknown; some authors hypothesize that an overproduction of human chorionic gonadotropin leads to placental ischemia and activation of the renin-angiotensin-aldosterone system that, in turn, causes hypertension.3Carbillon L. Oury J.F. Guerin J.M. Azancot A. Blot P. Clinical biological features of Ballantyne syndrome and the role of placental hydrops.Obstet Gynecol Surv. 1997; 52: 310-314https://doi.org/10.1097/00006254-199705000-00023Crossref Scopus (86) Google Scholar A previous study suggested that endothelial dysfunction and an overproduction of sVEGFR-1 could also contribute to the development of edema and hemodilution.4Espinoza J. Romero R. Nien J.K. et al.A role of the anti-angiogenic factor sVEGFR-1 in the 'mirror syndrome' (Ballantyne's syndrome).J Matern Fetal Neonatal Med. 2006; 19: 607-613https://doi.org/10.1080/14767050600922677Crossref PubMed Scopus (92) Google Scholar The syndrome can occur in the presence as well as in the absence of fetal structural abnormalities, and further risk factors are multiparity, elevated body mass index, and anemia.5Mogharbel H. Hunt J. D'Souza R. Hobson S.R. Clinical presentation and maternal-fetal outcomes of Mirror Syndrome: a case series of 10 affected pregnancies.Obstet Med. 2022; 15: 190-194https://doi.org/10.1177/1753495x211058043Crossref Google Scholar The syndrome has also been associated with fetal viral infections.5Mogharbel H. Hunt J. D'Souza R. Hobson S.R. Clinical presentation and maternal-fetal outcomes of Mirror Syndrome: a case series of 10 affected pregnancies.Obstet Med. 2022; 15: 190-194https://doi.org/10.1177/1753495x211058043Crossref Google Scholar Although cases of mirror syndrome have been reported between the 16th and the 39th week of gestation, the syndrome typically develops between 26 and 28 gestational weeks. The fetal prognosis is poor, and mortality exceeds 65%.2Teles Abrao Trad A. Czeresnia R. Elrefaei A. Ibirogba E.R. Narang K. Ruano R. What do we know about the diagnosis and management of mirror syndrome?.J Matern Fetal Neonatal Med. 2022; 35: 4022-4027https://doi.org/10.1080/14767058.2020.1844656Crossref Scopus (1) Google Scholar In the absence of genetic causes, recurrence of Ballantyne syndrome is rare. In our patient, a fifth pregnancy, at 19 years of age, was closely followed up in nephrology and obstetrics and was uneventful (delivery of a female baby at 39 weeks of gestation, 42.1 centile). Ballantyne syndrome Massimo Torreggiani, MD, PhD, Maria Rita Stancanelli, MD, Linda Njandjo, MD, Antioco Fois, MD, and Giorgina Barbara Piccoli, MD. None. The authors declare that they have no relevant financial interests. The authors declare that they have obtained written consent from the patient reported in this article for publication of the information about her that appears within this Quiz. Received August 1, 2023. Direct editorial input from a consulting editor and the Engagement Editor. Accepted in revised form October 8, 2023.