Free
Case Report  |   March 2019
Death of a Fetus With Myeloproliferative Disorder and Trisomy 21
Author Notes
  • From the Department of Obstetrics and Gynecology at St Anthony Hospital in Oklahoma City, Oklahoma (Drs Prentice and Deiter) and the Perinatal Center of Oklahoma in Oklahoma City (Dr Stanley). Dr Prentice is a fourth-year resident. 
  • Financial Disclosures: None reported. 
  • Support: None reported. 
  •  *Address correspondence to Danielle Prentice, DO, St Anthony Hospital, 1000 N Lee Ave, Oklahoma City, OK 73102-1036. Email: dkirch8@gmail.com
     
Article Information
Obstetrics and Gynecology / Pediatrics / Psychiatry
Case Report   |   March 2019
Death of a Fetus With Myeloproliferative Disorder and Trisomy 21
The Journal of the American Osteopathic Association, March 2019, Vol. 119, 208-211. doi:https://doi.org/10.7556/jaoa.2019.032
The Journal of the American Osteopathic Association, March 2019, Vol. 119, 208-211. doi:https://doi.org/10.7556/jaoa.2019.032
Abstract

A 27-year-old woman, gravida 2, para 1, presented at 24 weeks gestation with an intrauterine death. She previously consulted with maternal-fetal medicine because of a high suspicion of trisomy 21 after abnormal maternal serum screen and cell-free DNA test results. The patient elected to have chromosomal analysis following the death of the fetus, which confirmed a trisomy 21 diagnosis. Placental pathologic findings suggested that the cause of fetal death was total occlusion of the major vessels due to the accumulation of myeloid precursor cells, a novel mechanism. This case report discusses the rare finding of myeloproliferative disorder as a cause of death of a fetus with trisomy 21.

Myeloproliferative disorder (MPD) is well described in children with trisomy 21 (Down syndrome).1-3 Two cases of fetal MPD in live neonates with trisomy 214 and 3 cases of MPD in intrauterine fetal death with confirmed trisomy 215 have been described. These cases occurred after documented hydrops fetalis on ultrasonography.4,5 The current patient consented to chromosomal analysis and placental pathologic analysis, which enabled the identification of a novel mechanism of fetal death. 
Report of Case
A 27-year-old woman, gravida 2, para 1, with previous term cesarean delivery presented to the maternal-fetal medicine clinic at 20 weeks and 4 days of gestation. Noninvasive cell-free DNA screening revealed a high risk of trisomy 21. Confirmatory testing by amniocentesis was declined. Ultrasonography at 20 weeks showed no fetal anomalies and growth within normal limits. The bowel was slightly echogenic (Figure). Maternal physical examination findings were normal, and osteopathic structural examination showed slightly increased lumbar lordosis, a common finding in pregnancy. The patient was scheduled for serial ultrasonography every 4 weeks. 
Figure.
Slightly echogenic bowel noted on level II ultrasonography. Myeloproliferative disorder was determined to be the cause of death in this fetus with trisomy 21.
Figure.
Slightly echogenic bowel noted on level II ultrasonography. Myeloproliferative disorder was determined to be the cause of death in this fetus with trisomy 21.
The fetal death was discovered at 24 weeks during a routine obstetrics and gynecology appointment. Labor was induced, and delivery was uncomplicated. Because of the trisomy 21 screening finding, the patient elected for fetopsy and placental pathologic testing. Chromosomal analysis confirmed a diagnosis of trisomy 21. Pathologic analysis of the placenta revealed umbilical and intravillous vascular distention/obliteration by myeloblasts, consistent with placental involvement in fetal MPD. The findings were accordant with MPD observed in children with trisomy 21. The cause of death was attributed to extensive involvement and obliteration of the fetal vessels of the placenta by atypical cells due to MPD. 
Discussion
Myeloproliferative disorder involves abnormalities in the hematopoietic cells. Evidence suggests that MPD is caused by aberrant fetal liver hematopoiesis. Diagnosis typically occurs at birth or within a few weeks of birth.1-3 Myeloproliferative disorder is most prevalent in newborns with trisomy 21 at an incidence of approximately 10%. This estimate is likely low, owing to missed diagnoses after fetal death.6 Reported case studies attributing fetal death to MPD or congenital leukemia are rare, likely because of missed diagnosis by pathologic analysis, low fetopsy rates, and no standard protocol for histopathologic examination in these types of cases.7 
The pathophysiologic findings in patients with MPD show proliferation of clonal blasts, often expressing megakaryocytic or erythroid markers. In both MPD and acute megakaryocytic leukemia, blast cells arise from the megakaryocytic cell lineage or myeloid progenitor cells, which can differentiate into megakaryocytic cells.4 In newborns and infants, MPD is often self-limited but may result in hepatosplenomegaly or cutaneous infiltrates.1 However, this condition may cause significant morbidity and mortality in the fetus. Myeloproliferative disorder is associated with hydrops fetalis due to anemia and tissue infiltration by leukemoid cells, which may lead to pericardial, peritoneal, or pleural effusions. When multiple organs are affected, fetal death can occur.1 
Zerres et al4 and Smrcek et al5 reported the first 2 cases of MPD in fetuses with trisomy 21. These cases were found in the prenatal period in conjunction with fetal hydrops, and both resulted in live births. Fetal MPD diagnosis was confirmed after delivery.4,5 The present case showed no evidence of fetal hydrops on ultrasonography before fetal death. A retrospective case series between 1993 and 1999 reported 79 cases of trisomy 21, 11 of which had fetal hydrops. In 3 of these cases, hepatosplenomegaly and MPD were diagnosed. Of the 3 cases, 1 presented with ultrasonographic findings characteristic of trisomy 21, fetal hydrops, and MPD, but karyotyping was unsuccessful. All incidences that they found had previous findings of fetal hydrops or hepatosplenomegaly. The study speculated but did not find evidence of MPD in the absence of fetal hydrops or hepatosplenomegaly findings as a precursor to fetal death.5 The current case provides direct evidence for this theory. 
The current case illustrates the importance of prenatal care and screening. The MPD case reports that we found in our analysis of the literature were published before the current standard of care (genetic screening and regular ultrasonography). In most reported cases, the first sign of disease was fetal death. Our case differs because the patient had adequate prenatal care and close follow-up with maternal-fetal medicine. Furthermore, the patient was offered second trimester genetic screening as recommended by the American Congress of Obstetrics and Gynecology.8 Genetic screening results indicated an increased risk for trisomy 21 in concordance with cell-free DNA results. Amniocentesis was denied. Despite normal anatomy on level II ultrasonography, fetal death was discovered 4 weeks later. Pathologic test results revealed distention/obliteration of the umbilical cord and the intravillous space by myeloid blasts, which was revealed to be the ultimate cause of death—a cause not previously reported, to the authors’ knowledge. 
The current case establishes a mechanism of fetal death and provides insight for future treatment or management protocols. Currently, once fetal trisomy 21 is diagnosed, there are no clear guidelines for monitoring. A study9 reported that 10.2% of fetuses with trisomy 21 died at an average gestational age of 28.9 weeks, and 37.1% died prior to viability at 24 weeks. This finding suggests that a large population of fetuses with trisomy 21 die after viability, and close fetal monitoring may lead to increased deliveries of viable neonates. 
Placental infiltration of myeloid blast cells in fetuses with trisomy 21 could be indicated by reduced blood flow to the placenta via a nonstress test, biophysical profile, and umbilical artery Doppler modalities. If reduced placental blood flow is detected, viable fetuses could be delivered to prevent fetal death. The patient in the current case presented with fetal death at 24 weeks. The American College of Obstetricians and Gynecologists Obstetrics Consensus 610 defines the periviable period between 20 and 25 weeks and 6 days' gestation. Many hospitals consider 24 weeks' gestation as viable, yet some hospitals consider viability at 22 to 23 weeks. Although death likely occurred too soon in the present case, increased surveillance of fetuses with trisomy 21 is indicated based on an average 28.9 weeks' gestational age of death.9 
Placental fetopsy and pathologic and genetic analysis after the death of a fetus with trisomy 21 is critical for understanding MPD. While MPD is treatable in children and adults,1,3,6 to the author's knowledge, no treatments are suggested for fetuses. Intrauterine treatment in these cases would be ideal to allow for delivery of neonates closer to term and thus increase survival rates. However, current available therapies (eg, low–molecular weight heparin) do not cross the placenta and offer no benefit for this indication.11 Currently, the best way to manage MPD in a fetus is delivery and administration of traditional treatments. 
A core principle of osteopathic medicine states that rational treatment is based on an understanding of the basic principles of body unity, self-regulation, and the interrelationship of structure and function. Although osteopathic physicians often apply this principle to adult and pediatric patients, it should also be applied to the fetus. 
Conclusion
The present case describes a novel mechanism of action for death of a fetus with trisomy 21, which, when applied to the interrelationship of structure and function of the placenta, promotes surveillance and possible treatment. The case stresses the importance of obtaining chromosomal and placental pathologic analysis after fetal death regardless of previous test results or diagnoses. When pathologic analysis of a placenta shows MPD, it should suggest a high likelihood of trisomy 21 in a fetus. These findings suggest that resistance to blood flow through the umbilical cord may be increased owing to accumulation of myeloid precursor cells. Increased fetal monitoring, including umbilical artery Doppler velocimetry, may be useful. Future translational and observational studies are needed to determine its utility in fetuses with trisomy 21. 
References
Dixon N, Kishnani PS, Zimmerman S. Clinical manifestations of hematologic and oncologic disorders in patients with Down syndrome. Am J Med Genet C Semin Med Genet. 2006;142C(3):149-157. [CrossRef] [PubMed]
Crispino JD. GATA1 mutations in Down syndrome: implications for biology and diagnosis of children with transient myeloproliferative disorder and acute megakaryoblastic leukemia. Pediatr Blood Cancer. 2005;44(1):40-44. doi: 10.1002/pbc.20066 [CrossRef] [PubMed]
Hayashi Y, Eguchi M, Sugita K, et al Cytogenetic findings and clinical features in acute leukemia and transient myeloproliferative disorder in Down's syndrome. Blood. 1988;72(1):15-23. [PubMed]
Zerres K, Schwanitz G, Niesen M, Gembruch U, Hansmann M, Waldherr R. Prenatal diagnosis of acute non-lymphoblastic leukaemia in Down syndrome. Lancet. 1990;335(8681):117. [CrossRef] [PubMed]
Smrcek JM, Baschat AA, Germer U, Gloeckner-Hofmann K, Gembruch U. Fetal hydrops and hepatosplenomegaly in the second half of pregnancy: a sign of myeloproliferative disorder in fetuses with trisomy 21. Ultrasound Obstet Gynecol. 2001;17(5):403-409. [CrossRef] [PubMed]
Zipursky A, Brown EJ, Christensen H, Doyle J. Transient myeloproliferative disorder (transient leukemia) and hematologic manifestations of Down syndrome. Clin Lab Med. 1999;19(1):157-167. [CrossRef] [PubMed]
Gray ES, Balch NJ, Kohler H, Thompson WD, Simpson JG. Congenital leukaemia: an unusual cause of stillbirth. Arch Dis Child. 1986;61(10):1001-1006. [CrossRef] [PubMed]
Screening for fetal aneuploidy. Practice Bulletin No. 163. American College of Obstetricians and Gynecologists. Obstet Gynecol. 2016:127:e123-e137. [CrossRef] [PubMed]
Won RH, Currier RJ, Lorey F, Towner DR. The timing of death in fetuses with trisomy 21 and trisomy 18. Prenat Diagn. 2005;25(7):608-611. [CrossRef] [PubMed]
Periviable birth. Obstetric Care Consensus No. 6. American College of Obstetricians and Gynecologists. Obstet Gynecol. . 2017;130:e187-e199. [CrossRef] [PubMed]
Barbui T, Finazzi G. Myeloproliferative disease in pregnancy and other issues. Am Soc Hematol Educ Program. 2006:246-252. doi: 10.1182/asheducation-2006.1.246
Figure.
Slightly echogenic bowel noted on level II ultrasonography. Myeloproliferative disorder was determined to be the cause of death in this fetus with trisomy 21.
Figure.
Slightly echogenic bowel noted on level II ultrasonography. Myeloproliferative disorder was determined to be the cause of death in this fetus with trisomy 21.