Preeclampsia affects 5–7% of all pregnancies and is a leading cause of maternal and neonatal morbidity and mortality. The classical diagnosis of preeclampsia is made when pregnant women present with new-onset hypertension (140 mm Hg systolic or higher or 90 mm Hg diastolic or higher) and proteinuria (0.3 grams protein or higher in a 24-hour urine specimen) typically after 20 weeks of gestation [
The exact pathophysiology of preeclampsia remains unclear and is a leading area of investigation. Recent studies have demonstrated angiogenic imbalance in patients with preeclampsia. Weeks before the onset of preeclampsia, circulating levels of the antiangiogenic factors soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng) rise to abnormally high levels while levels of the proangiogenic placental growth factor (PlGF) are reduced [
In this paper, we present two patients with underlying renal disease and proteinuria who were diagnosed with severe preeclampsia. Because of their preexisting medical conditions and the fact that clinical onset of disease occurred in the late second trimester, the diagnosis of preeclampsia was challenging. IRB/Ethics Committee decided approval was not required for this study.
A 34-year-old gravida 2 para 1 at 17 weeks 6 days of gestation presented to the emergency room from an office evaluation with hypertensive urgency. Her blood pressure on arrival was 164/110 mm Hg. The patient had known nephrotic syndrome with a baseline creatinine of 1.4 mg/dL and a 24-hour urine with 3.7 grams of protein prior to pregnancy. She had no preexisting hypertension. A week prior to presentation, her creatinine had risen to 2.5 mg/dL and her 24-hour urine revealed 9.1 grams of protein. The patient’s elevated blood pressures were treated with labetalol. Her worsening hypertension and renal function at the time had been attributed to worsening renal disease due to pregnancy. On presentation to the emergency room, she complained of a mild headache but denied any visual change or epigastric pain. Her physical exam was significant for 3+ deep tendon reflexes and 3+ pitting edema bilaterally.
The patient’s obstetric history included a preterm cesarean delivery at 24 weeks for severe preeclampsia with HELLP syndrome. Given her current presentation and her obstetric history, the patient was admitted and placed on intravenous magnesium sulfate for seizure prophylaxis. She had a strong desire to continue her pregnancy. During the hospital course, her blood pressures required multiple intravenous antihypertensive medications. She developed elevated transaminases, thrombocytopenia, and worsening renal function. Serum creatinine was elevated at 2.6 mg/dL, and uric acid was 7.0 mg/dL.
The patient was counseled regarding the poor prognosis of the pregnancy at this previable gestational age and the maternal risks associated with expectant management of severe preeclampsia. The patient chose to undergo an induction of labor at 18 weeks gestation.
Postpartum, her blood pressures, and elevated transaminases normalized, and her creatinine returned to baseline. Placental pathology showed a preterm placenta with accelerated villous maturation, increased perivillous and intravillous fibrin deposition, multifocal extravillous cytotrophoblast proliferation, and erythroblastosis.
A 35-year-old gravida 1 para 0 with lupus nephritis presented to the obstetrical triage unit at 21 6/7 weeks of gestation with shortness of breath. Her medical history was significant for systemic lupus erythematosus (SLE) with renal and hematological manifestations.
The patient had been recently admitted to the antepartum service at 19 weeks 4 days of gestation for worsening hypertension and thrombocytopenia. During her admission, her blood pressure reached a maximum of 170/110 mm Hg and her platelets reached a nadir of 50 K/uL from 150 K/uL baseline prior to pregnancy. A 24-hour urine was significant for 3.4 grams of protein, increased from a baseline of 1.6 grams prior to pregnancy. She was started on two oral antihypertensive medications and was administered oral and intravenous steroids for what was thought to be an acute lupus flare. The worsening proteinuria, thrombocytopenia, and hypertension were thought to be secondary to worsening SLE.
Following her first antepartum discharge, the patient presented to triage with new-onset shortness of breath and decreased breath sounds bilaterally on physical examination. A chest X-ray showed cardiomegaly and evidence of congestive heart failure. Transabdominal ultrasound revealed an intrauterine fetal demise. The patient underwent an uncomplicated dilation and evacuation. Further workup of acute heart failure revealed an ejection fraction of 30–35% as well as pulmonary edema. She was admitted to the intensive care unit for close supportive management. The patient’s blood pressure improved requiring fewer medications for control. Placental pathology showed extensive involvement of perivillous fibrin, hematomas, and infarcts. The fetus and placenta were growth restricted.
Both patient’s clinical presentations presented diagnostic challenges for experienced clinicians. We hypothesized that these patients will have an angiogenic profile unlike a normal pregnancy, but similar to patients with severe preeclampsia. We collected serum samples from both patients at the time of clinical presentation; enzyme-linked immunosorbent assays (ELISA) for sFlt1, sEng, and PlGF were performed with commercially available kits (R&D systems Inc, Minneapolis, MN). All assays were performed in duplicate and values averaged. The correlation coefficient between duplicate results for all three biomarkers was 0.99. These levels were compared to those of gestational age-matched women from a random sample of 2200 women in the trial of Calcium for Preeclampsia Prevention cohort who were normotensive at the time of the blood collection [
We found that the levels of sFlt1 and sEng were at or above the 95th percentile based on gestational age. Additionally, PlGF levels were below the detection limit (15.6 pg/mL) in both patients, which corresponded to less than the 1st percentile as matched for gestational age (Table
Gestational age (weeks) | Patient’s sFlt1 level (ng/mL) | 95–97th percentile for sFlt1 in normal pregnancies (ng/mL)* | Patient’s sEng level (ng/mL) | 95–97th percentile for sEng in normal pregnancies (ng/mL)* | Patient’s PlGF level (pg/mL) | 5th–1st percentile for PlGF in normal pregnancies (pg/mL)* | |
---|---|---|---|---|---|---|---|
Case 1 | 17.6 | 8.7 | 7.5–11.1 | 16.5 | 6.9–9.3 | 5 | 77–53 |
Case 2 | 21.6 | 21.7 | 7.7–9.1 | 120.1 | 6.6–10.1 | 3 | 136–103 |
*The percentiles for normal pregnancies were obtained from the CPEP study [
The classic diagnosis of preeclampsia is based on new-onset proteinuria and hypertension in the pregnant patient after 20 weeks of gestation [
Both patients in our report had underlying renal disease. The first patient had nephrotic syndrome. Although the patient’s new-onset hypertension and her past history of a preterm delivery for preeclampsia supported preeclampsia as the diagnosis, her underlying renal disease as well as the early gestational age at presentation made the clinical diagnosis challenging.
The second patient had a longstanding history of SLE with lupus nephritis and thrombocytopenia as manifestations of her lupus. She had baseline proteinuria of 1.6 grams over 24 hours prior to pregnancy. Pregnancies complicated by lupus nephritis are at increased risk of developing preeclampsia; similarly, there is a significant risk of lupus flare during pregnancy [
Angiogenic biomarkers have demonstrated utility in distinguishing preeclampsia from large cohorts of normotensive patients [
Qazi et al. demonstrated a difference in angiogenic factors among 52 patients with lupus who developed preeclampsia versus those that did not develop preeclampsia; the authors concluded that angiogenic biomarkers could be used prospectively to distinguish women with lupus at high risk for developing preeclampsia. Women with lupus who developed preeclampsia had significantly higher levels of sFlt1 versus patients with lupus but without preeclampsia [
Additionally, Williams et al. reported a case of a 29-year-old woman with lupus and renal failure at 20 weeks 6 days gestation who presented with renal failure. The patient’s diagnosis of preeclampsia was difficult to confirm clinically, given her preexisting renal disease. The patient’s sFlt1 levels were high, and PlGF levels in the serum were low, characteristic of the angiogenic profile of preeclampsia [
The clinical diagnosis of preeclampsia is challenging to confirm or exclude in patients with underlying renal disease and proteinuria who also develop hypertension. However, accurate diagnosis is critical for appropriate obstetrical management particularly at early gestational ages.
Our two cases demonstrate that the measurement of angiogenic biomarkers may help clinicians diagnose preeclampsia in patients with underlying renal disease with proteinuria and hypertension that overlap with the classic diagnosis of preeclampsia. This is especially useful at previable gestational ages where accurate and timely diagnosis is critical, as there is no fetal benefit from prolongation of pregnancy. Prospective studies are needed to better characterize the utility of these angiogenic biomarkers in real-time clinical situations in which the patient’s comorbidities make the classic diagnosis of preeclampsia difficult to confirm.
No conflict of interests is reported by any authors.
The authors would like to thank Alexander Friedman, M. D. and Saira Salahuddin, Ph. D., for their assistance in sample collection. They also thank Dr. S Ananth Karumanchi for his assistance with assays. S. Rana is supported by Harvard Diversity and Community Partnership Faculty Fellowship Award.