Correspondence
Elevated sFlt1 Level and Preeclampsia with Parvovirus-Induced Hydrops
N Engl J Med 2006; 354:1857-1858April 27, 2006
- Article
To the Editor:
Previous reports have described an association between hydropic placentas and the occurrence of preeclampsia.1,2 One proposed explanation is that an enlarged placenta may cause a systemic inflammatory response by shedding an increased amount of trophoblast debris into the maternal blood, although the mediators of such a response have been unclear. One potential mediator is soluble fms-like tyrosine kinase 1 (sFlt1). In animal models, infusion of sFlt1 induces manifesations of preeclampsia, including hypertension and proteinuria.3 In humans, sFlt1 is dramatically up-regulated in the preeclamptic placenta, and a marked increase in the levels of circulating sFlt1 has been noted weeks before the development of clinical manifestations of preeclampsia.4,5
We report the case of a 26-year-old woman (gravida 1, para 0) who was referred at 24 weeks' gestation because of fetal ascites. Ultrasonography showed a hydropic placenta (diameter, 69 mm; normal, ≤50 mm) and generalized fetal hydrops. The systolic velocity in the middle cerebral artery was increased (48.7 cm per second), an indication of fetal anemia. Cordocentesis confirmed severe fetal anemia and parvovirus B19 infection. The patient's blood pressure was 170/110 mm Hg; the rate of urinary protein excretion was 2 g per 24 hours. The plasma level of sFlt1 was 14,117 pg per milliliter; this value exceeded that reported in both normal and preeclamptic pregnancies. (The mean sFlt1 level in patients with preeclampsia was 4382 pg per milliliter in the study by Levine et al.4 and 7247 pg per milliliter in our study,5 with both values measured with the use of the same commercial kit.)
The patient was treated twice with intravascular transfusion. Serial ultrasonography showed that hydrops of placenta and fetus started to improve after 1 week; fetal hydrops had completely resolved at 27 weeks 6 days of gestation. A follow-up examination (at 36 weeks 4 days) revealed normal blood pressure (100/60 mm Hg) and resolution of proteinuria. On repeated measurement, the plasma sFlt1 level was 7489 pg per milliliter, a value still in the range reported for patients with preeclampsia4,5 but markedly lower than the earlier measurement in the setting of hypertension and proteinuria.
This report demonstrates an association between enlargement of the placenta in the setting of parvovirus infection, extremely high maternal plasma levels of sFlt1, and signs of preeclampsia. With resolution of hydrops after transfusion, the sFlt1 level fell, and signs of preeclampsia resolved. These findings suggest that elevated levels of sFlt1 may be triggered by various forms of placental pathology. Although we do not have data to indicate whether the increase in sFlt1 levels preceded the resolution of the manifestations of preeclampsia, this case supports the need for further study of the potential role of interventions to reduce sFlt1 levels in the treatment of preeclampsia.
5 ReferencesHolger Stepan, M.D.
Renaldo Faber, M.D.
University of Leipzig, 04103 Leipzig, Germany
holger.stepan@medizin. uni-leipzig. de 1
Anand A ,Gray ES ,Brown T ,Clewley JP ,Cohen BJ . Human parvovirus infection in pregnancy and hydrops fetalis. N Engl J Med 1987;316:183-186
Full Text | Web of Science | Medline2
Zaki M ,Greenwood C ,Redman CW . The spontaneous reversal of pre-eclampsia associated with parvovirus-induced hydrops and the placental theory of pre-eclampsia: a case report. BJOG 2003;110:1125-1126
CrossRef | Web of Science | Medline3
Maynard SE ,Min JY ,Merchan J , et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 2003;111:649-658
Web of Science | Medline4
Levine RJ ,Maynard SE ,Qian C , et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004;350:672-683
Full Text | Web of Science | Medline5
Stepan H ,Geide A ,Faber R . Soluble fms-like tyrosine kinase 1. N Engl J Med 2004;351:2241-2242
Full Text | Web of Science | Medline
- Citing Articles (18)
Citing Articles
1
Kristin Bixel, Michelle Silasi, Carolyn M. Zelop, Kee-Hak Lim, Zsuzsanna Zsengeller, Isaac E. Stillman, Sarosh Rana. (2011) Placental Origins of Angiogenic Dysfunction in Mirror Syndrome. Hypertension in Pregnancy1-7
CrossRef2
Ali Gedikbasi, Kazim Oztarhan, Ziya Gunenc, Gokhan Yildirim, Oguz Arslan, Dogukan Yildirim, Yavuz Ceylan. (2011) Preeclampsia Due to Fetal Non-immune Hydrops: Mirror Syndrome and Review of Literature. Hypertension in Pregnancy 30:3, 322-330
CrossRef3
Daniel B. DiGiulio, MariaTeresa Gervasi, Roberto Romero, Shali Mazaki-Tovi, Edi Vaisbuch, Juan Pedro Kusanovic, Kimberley S. Seok, Ricardo Gómez, Pooja Mittal, Francesca Gotsch, Tinnakorn Chaiworapongsa, Enrique Oyarzún, Chong Jai Kim, David A. Relman. (2010) Microbial invasion of the amniotic cavity in preeclampsia as assessed by cultivation and sequence-based methods. Journal of Perinatal Medicine 38:5, 503-513
CrossRef4
Jimmy Espinoza, John E. Uckele, Robert A. Starr, David E. Seubert, Andres F. Espinoza, Stanley M. Berry. (2010) Angiogenic imbalances: the obstetric perspective. American Journal of Obstetrics and Gynecology 203:1, 17.e1-17.e8
CrossRef5
Michelle A. Hladunewich, Guy Steinberg, S. Ananth Karumanchi, Richard J. Levine, Sarah Keating, John Kingdom, Johannes Keunen. (2009) Angiogenic factor abnormalities and fetal demise in a twin pregnancy. Nature Reviews Nephrology 5:11, 658-662
CrossRef6
Jimmy Espinoza, John E. Uckele, Robert A. Starr, Robert P. Lorenz, Richard A. Bronsteen, Stanley M. Berry. (2009) Insights Into Angiogenic Imbalances During Pregnancy. Obstetrics & Gynecology 114:Supplement, 437-440
CrossRef7
Alexandre Hertig, Guillaume Lefevre, Karine Toumi, Eric Rondeau, Jacqueline Capeau, Serge Uzan, Nadia Berkane. (2008) Soluble endoglin levels during normotensive and hypertensive pregnancies. European Journal of Obstetrics & Gynecology and Reproductive Biology 140:1, 138-140
CrossRef8
Mathias Fasshauer, Jeannette Seeger, Theresa Waldeyer, Susanne Schrey, Thomas Ebert, Ulrike Lossner, Matthias Bluher, Michael Stumvoll, Renaldo Faber, Holger Stepan. (2008) Endogenous soluble receptor for advanced glycation endproducts is increased in preeclampsia. Journal of Hypertension 26:9, 1824-1828
CrossRef9
Roberto Romero, Juan Pedro Kusanovic, Nandor Gabor Than, Offer Erez, Francesca Gotsch, Jimmy Espinoza, Samuel Edwin, Ilana Chefetz, Ricardo Gomez, Jyh Kae Nien, Marei Sammar, Beth Pineles, Sonia S. Hassan, Hamutal Meiri, Yossi Tal, Ido Kuhnreich, Zoltan Papp, Howard S. Cuckle. (2008) First-trimester maternal serum PP13 in the risk assessment for preeclampsia. American Journal of Obstetrics and Gynecology 199:2, 122.e1-122.e11
CrossRef10
Mathias Fasshauer, Theresa Waldeyer, Jeannette Seeger, Susanne Schrey, Thomas Ebert, Jurgen Kratzsch, Ulrike Lossner, Matthias Bluher, Michael Stumvoll, Renaldo Faber, Holger Stepan. (2008) Serum levels of the adipokine visfatin are increased in pre-eclampsia. Clinical Endocrinology 69:1, 69-73
CrossRef11
Mathias Fasshauer, Jeannette Seeger, Theresa Waldeyer, Susanne Schrey, Thomas Ebert, Jürgen Kratzsch, Ulrike Lössner, Matthias Blüher, Michael Stumvoll, Renaldo Faber, Holger Stepan. (2008) Serum Levels of the Adipokine Adipocyte Fatty Acid–binding Protein Are Increased in Preeclampsia. American Journal of Hypertension 21:5, 582-586
CrossRef12
Juan Pedro Kusanovic, Roberto Romero, Jimmy Espinoza, Jyh Kae Nien, Chong Jai Kim, Pooja Mittal, Sam Edwin, Offer Erez, Francesca Gotsch, Shali Mazaki-Tovi, Nandor G. Than, Eleazar Soto, Natalia Camacho, Ricardo Gomez, Ruben Quintero, Sonia S. Hassan. (2008) Twin-to-twin transfusion syndrome: an antiangiogenic state?. American Journal of Obstetrics and Gynecology 198:4, 382.e1-382.e8
CrossRef13
D Wurm, G Löffler, A Lindinger, L Gortner. (2007) Congenital disorders of glycosylation type Ia as a cause of mirror syndrome. Journal of Perinatology 27:12, 802-804
CrossRef14
Thomas Walther, Holger Stepan. (2007) Agonist autoantibodies against the angiotensin AT1 receptor in renal and hypertensive disorders. Current Hypertension Reports 9:2, 128-132
CrossRef15
S A Karumanchi, F H Epstein. (2007) Placental ischemia and soluble fms-like tyrosine kinase 1: Cause or consequence of preeclampsia?. Kidney International 71:10, 959-961
CrossRef16
Holger Stepan, Gerd Wallukat, Heinz-Peter Schultheiss, Renaldo Faber, Thomas Walther. (2007) Is parvovirus B19 the cause for autoimmunity against the angiotensin II type receptor?. Journal of Reproductive Immunology 73:2, 130-134
CrossRef17
M. Fasshauer, M. Blüher, M. Stumvoll, P. Tönessen, R. Faber, H. Stepan. (2007) Differential regulation of visfatin and adiponectin in pregnancies with normal and abnormal placental function. Clinical Endocrinology 66:3, 434-439
CrossRef18
Sarosh Rana, Shivalingappa Venkatesha, Monique DePaepe, Edward K. Chien, Michael Paglia, S Ananth Karumanchi. (2007) Cytomegalovirus-Induced Mirror Syndrome Associated With Elevated Levels of Circulating Antiangiogenic Factors. Obstetrics & Gynecology 109:Supplement, 549-552
CrossRef
