Abstract
Massive perivillous fibrin deposition (MPVFD) is a potentially devastating complication of pregnancy that occurs in 0.03–0.5% of deliveries and is associated with severe fetal growth restriction, stillbirth, and neurologic injury due to uteroplacental insufficiency. The management of patients with recurrent pregnancy loss secondary to MPVFD has not been widely studied. We describe the case of a healthy 19-year-old with a history of two prior intrauterine fetal demises at 35w6d and 36w6d secondary to MPVFD of the placenta who subsequently delivered a healthy infant at 33w6d after she had been treated in the prenatal period with aspirin and prophylactic enoxaparin. Antenatal treatment with daily aspirin and prophylactic enoxaparin as well as close antenatal follow-up may be an option for patients with recurrent pregnancy loss due to MPVFD.
Keywords: Massive perivillous fibrin deposition, Adverse perinatal outcomes, Stillbirth, Placental pathology, Maternal fetal medicine
Highlights
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Massive perivillous fibrin deposition (MPVFD) is a potentially devastating complication
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The optimal management of MPVFD is not well known.
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Antenatal treatment with daily aspirin and enoxaparin may be an option for patients with recurrent pregnancy loss due to MPVFD.
1. Introduction
Massive perivillous fibrin deposition (MPVFD) is a potentially devastating complication of pregnancy that occurs in 0.03–0.5% of deliveries [1,2]. Pathologic criteria for MPVFD include a placenta that is small for gestational age, dense and friable, and that has abundant fibrinoid material seen on histopathology with a mean placental area involvement of 30–50%. Additionally, the definition of MPVFD involves fetal sequelae secondary to reduced placental function. The condition has been associated with severe fetal growth restriction, stillbirth, and neurologic injury due to uteroplacental insufficiency [3] [4]. The specific etiology of MPVFD is unknown, though various case reports cite associations with chronic intervillositis as well as infections (coxsackie virus, syphilis, herpes simplex virus-2, cytomegalovirus, and coronavirus disease 2019 [1,5,6]), preeclampsia [7,8] and maternal autoimmune disease [9]. Treatment for MPVFD has not been widely studied.
2. Case Presentation
A 19-year-old woman, G3P0301, had had two previous pregnancies complicated by MPVFD of the placenta, both resulting in third-trimester intrauterine fetal demise (IUFD). She subsequently delivered a healthy, late preterm infant after she had had treatment during the prenatal period.
In the patient's first pregnancy, her prenatal course was largely unremarkable. Past medical and surgical history was significant only for mild persistent asthma and an initial prenatal body mass index (BMI) of 26.85 kg/m2. The patient's prenatal labs were significant only for rubella and varicella non-immunity and her routine anatomy scan showed normal growth and no structural anomalies. The patient ultimately presented at 35w6d for labor and was subsequently diagnosed with an IUFD. The patient underwent induction of labor and had an uncomplicated spontaneous vaginal delivery. On autopsy, the fetal exam was notable for maceration and organs small for gestational age. There were no signs of intrauterine infection. However, placental pathology was notable for MPVFD covering 75% of the placenta. APLS work-up including anticardiolipin antibodies, anti-beta-2-glycoprotein antibodies, and lupus anticoagulant testing was negative. Infectious testing for syphilis, hepatitis B, cytomegalovirus, toxoplasma gondii, rubella and herpes simplex were negative, as were the patient's Kleihauer Betke (K—B), hemoglobin A1c (HbA1c), thyroid function testing (TFT), and tests evaluating for preeclampsia including a complete blood count, complete metabolic panel, and a protein to creatinine ratio.
The patient was seen for a new obstetric visit at a community clinic with a certified nurse midwife for the second pregnancy two months after the previous delivery. This pregnancy was complicated by an initial body mass index of 40 kg/m2 and asthma but was otherwise unremarkable. She was transferred to an obstetrician at the community practice at 28 weeks due to her history of an IUFD. The patient ultimately self-transferred to a tertiary care facility at 31 weeks and was referred to Maternal Fetal Medicine (MFM) after counseling regarding her previous IUFD. The patient had inconsistent prenatal care and was subsequently seen at 36w6d for a routine obstetrics appointment and had not yet scheduled an appointment with MFM nor had antepartum testing at this time. She was then immediately sent to an MFM clinic for a biophysical profile (BPP) and growth ultrasound. At that time, the fetus was found to have severe fetal growth restriction with reverse end diastolic flow and reverse ductus venosus flow. Fetal heart tones were additionally noted to be in the 90s. The patient was urgently transferred to labor and delivery triage, where no fetal heart tones were auscultated and an IUFD was diagnosed approximately 20 min after the initial ultrasound was performed in the MFM clinic. The patient then underwent induction of labor and had a vaginal delivery of a grossly normal-appearing male fetus. Infectious workup, repeat antiphospholipid (APLS) testing, HbA1c, TFTs and K—B were again negative, and the patient had no signs or symptoms of preeclampsia. Pathology showed a placenta that was small for gestational age with multifocally firm areas with increased intervillous fibrin and infarct, again consistent with MPVFD. She was counseled on the importance of contraception and the recommendation for preconception counseling with MFM as well as close prenatal follow-up in any subsequent pregnancies. Preconception counseling was not pursued by the patient.
For the third pregnancy, the patient had an initial prenatal visit at 8w1d and established care with MFM at 11w4d. The patient was counseled on treatment options based on the few available case reports, including primarily thrombolytic therapies (aspirin, heparin) with or without combining immunologically directed treatments, such as intravenous immunoglobulin therapy (IVIG). The patient ultimately opted for treatment with aspirin 81 mg and enoxaparin 40 mg daily, to be started immediately, in addition to maternal serum alpha-fetoprotein testing, serial growth ultrasound scans every 4 weeks beginning at 20w0d and weekly BPPs starting at 32w0d. Delivery was recommended between 34w0d and 36w0d with betamethasone administration prior. The patient received betamethasone at 33w4d and 33w5d for planned delivery at 34w0d. However, while at antenatal testing at 33w5d, the patient was sent to labor and delivery triage for induction of labor due to a BPP of 6/8, minus two for gross movement.
Ultimately, the patient delivered a live male infant via cesarean section at 33w6d for recurrent late decelerations unresolved with resuscitative measures in the setting of prolonged rupture of membranes after a 26-h induction of labor. Apgar scores were 7 and 9 at 1 and 5 min respectively. Placental pathology again showed increased intervillous fibrin, intervillous thrombus, and calcifications (Fig. 1A,B) in addition to gross description with pink-yellow, rubbery tissue comprising approximately 90% of the total placental volume consistent with recurrent MPVFD (Fig. 1C,D). The infant was admitted to the neonatal intensive care unit secondary to prematurity and was ultimately discharged home on day of life 23. The infant was seen for a 2-month checkup and was noted to be doing well with appropriate growth and development. The patient was seen for a postpartum visit and was additionally noted to be doing well from a postpartum standpoint.
Fig. 1.
A: fibrinoid deposits surrounding villi; B. Cross-section of the placenta, 34 0/7 weeks: Maturing third-trimester placenta with infarct, increased intervillous fibrin, intervillous thrombus and calcifications; C. Fetal Surface; D. Maternal surface with yellow-pink rubbery tissue. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
3. Discussion
The etiology for MPVFD remains unknown but it can recur in future pregnancies (12–78% reported [8]), as was the case in this patient. The pathogenesis remains unclear, but there is some evidence to suggest that a maternal autoimmune or alloimmune condition may be contributory. Treatment modalities with some success have been reported, including primarily thrombolytic therapies (aspirin, heparin) with or without combining immunologically directed treatments (e.g., IVIG, prednisolone) [1,9]. One report notes a live birth with normal postnatal follow-up at 2 years in a woman with a history of four consecutive losses, presumably all due to MPVFD, who was treated with a combination of thrombolytic therapy (aspirin and heparin), IVIG, and pravastatin to correct the angiogenic/antiangiogenic imbalance thought to be causational of recurrent MPVFD [10]. These reports of isolated successes, but also failures, with a variety of treatments, are not without concerns and there is need for further study.
Based on the success in the case reported here with recurrent MPVFD, we propose treatment with daily aspirin and prophylactic enoxaparin beginning after confirmation of an intrauterine pregnancy in addition to assessment of fetal growth beginning at 20 weeks, at least weekly biophysical profiles starting at 32 weeks, and ultimately delivery for non-reassuring fetal status in patients with a history of MPVFD.
Acknowledgments
Contributors
Baillie A. Bronner contributed to patient care, conception of the case report, the literature review, acquiring patient data and consent, and drafting the manuscript.
Margaret Schermerhorn contributed to the literature review and drafting the manuscript.
Anna McCormick contributed to patient care, drafting the manuscript, and revising the manuscript for important intellectual content.
Juliana Sung contributed to drafting the manuscript and revising the manuscript for important intellectual content.
Samantha de los Reyes contributed to patient care, the conception of the case report, drafting the manuscript and revising the manuscript for important intellectual content.
All authors approved the final submitted manuscript.
Funding
This work did not receive any specific grant from funding agencies.
Patient consent
Written informed consent was obtained from the patient for publication of this case report and the use of accompanying images.
Provenance and peer review
This article was not commissioned and was peer reviewed.
Acknowledgments
Acknowledgements
The authors thank the patient, who agreed to allow us to publish the clinical data, as well as Ms. Mari Kiedysz, MS, PA (ASCP)CM and Dina Hassan, MD for gross and microscopic pathology assistance.
Conflict of interest statement
The authors declare that they have no conflict of interest regarding the publication of this case report.
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