Case Studies - LabMedicine

Case Studies
Recurrent Pregnancy Loss and Infertility
in an Apparently Healthy 23-Year-Old Woman
Diana L. Cochran-Black, DrPH, MT(ASCP)SH
(Department of Medical Technology, Wichita State University, Wichita, KS)
DOI: 10.1309/LM2PH47CUPEBKPEM
Submitted 9.21.09 | Accepted 10.19.09
Clinical History
Patient: 23-year-old Caucasian female.
Chief Complaint: The patient presented to
a reproductive specialist with concerns of
recurrent pregnancy loss and subsequent
secondary infertility.
Past Medical History: The patient
experienced 2 unexplained miscarriages in 1
year. The first occurred at 12 weeks gestation
and the other at 13 weeks. After the second
miscarriage, a dilation and curettage was
performed with no complications. Since this
time she experienced problems with infertility.
She had a history of oligo-ovulation and
irregular menstrual cycles, which were treated
with fertility drugs. Previous laparoscopic
surgery to investigate unexplained pelvic pain
revealed no abnormalities and no evidence of
endometriosis. The patient denied any history
of headaches, visual changes, or galactorrhea.
Family History: She had no family history of
pregnancy loss and no personal or family history
of a clotting disorder or autoimmune disease.
Physical Examination: No physical
abnormalities were noted and results
of a transvaginal ultrasound and
hysterosalpingogram were normal.
Principal Laboratory Findings:
Table 1.
Questions
1. What is the definition of recurrent pregnancy loss?
2. What risk factors have been linked to recurrent pregnancy
loss?
3. What are the most likely reason(s) for this patient’s recurrent
pregnancy loss and secondary infertility?
4. What other thrombophilic mutations have been associated
with recurrent pregnancy loss?
5. What therapy should be employed for patients with recurrent
pregnancy loss due to thrombotic disorders?
6. What is the prognosis for this patient?
Possible Answers
1. Traditionally, recurrent pregnancy loss (RPL) has been
defined as 3 or more consecutive pregnancy losses. However,
it is now recognized that 2 consecutive losses are sufficient to
define RPL. 1
2. The risk factors associated with RPL include parental
and fetal chromosome abnormalities, abnormal uterine pathology,
endocrine dysfunction, immunologic disease, and
thrombophilic disorders (Table 2). 2-15
3. The patient’s difficulties with RPL and secondary
infertility are most likely multifactorial. Laboratory tests revealed
she is heterozygous for the Factor V Leiden mutation
which has been linked to RPL. 12,16,17 The Factor V Leiden
mutation is an autosomal dominantly inherited defect resulting
from an amino acid switch of glutamine for arginine at
position 506 of the factor V molecule. The mutated factor
V molecule is resistant to inactivation by activated protein C
(APC), which leads to an increased risk of thrombosis in the
affected patient by increasing the persistence of prothrombin
activity. 18 It has been postulated that this defect can cause
microthrombi in the placenta leading to multiple placental
infarctions. These infarctions can cause a myriad of problems
including placental abruption, intrauterine growth restriction,
and RPL. 15 Also, the patient in this case was found to have
elevated thyroid stimulating hormone (TSH) and prolactin
levels. Elevated TSH and prolactin levels have been associated
with amenorrhea and anovulatory infertility. 6,19 In addition,
hypothyroidism during pregnancy has been linked to RPL,
prematurity, congenital malformations, and neurological
dysfunction. 20,21
4. Pregnancy itself is considered a hypercoagulable state
with elevations of procoagulant factors and decreased levels
of some naturally occurring anticoagulants. 22 Thrombotic
mutations associated with RPL, besides the Factor V Leiden
mutation, include the prothrombin G20210A gene mutation
and the methylenetetrahydrofolate reductase (MTHFR) mutation.
23 The prothrombin gene mutation elevates prothrombin
activity and, along with other thrombophilic risk factors, can
contribute to thrombosis of the placental vessels and subsequent
pregnancy loss. 24 The MTHFR mutation leads to
elevated homocysteine levels, which has been associated with
atherosclerosis, venous thrombosis, neural tube defects, placental
abruption, pre-eclampsia, and recurrent miscarriages.
The exact mechanism linking the MTHFR mutation to recurrent
miscarriages is unknown. 25
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Case Studies
5. The therapy of choice for women
with thrombotic tendencies before and during
pregnancy includes low dose aspirin and
either unfractionated (UHF) or low molecular
weight heparin (LMWH). 26-28
6. The prognosis for this patient is very
good. Patients with RPL due to thrombotic
tendencies that are treated with aspirin and
heparin have a 72%–80% chance of having a
successful pregnancy outcome. 28,29
Patient’s Treatment and Follow Up
The patient’s hypothyroidism was well
controlled with Synthroid. Bromocriptine was
used to lower her prolactin level. She conceived
spontaneously and due to her history
of RPL and the Factor V Leiden mutation,
she was placed on daily, low-dose aspirin and
LMWH therapy. The aspirin therapy was discontinued
early in the pregnancy due to vaginal
bleeding. Her pregnancy was uneventful,
and she recently delivered a healthy baby.
Acknowledgements: The author wishes to
express her appreciation to the patient and Dr.
Tiffany VonWald for providing permission to
access medical records and to the laboratory
staff at the Center for Reproductive Medicine
for their assistance with this case study.
Keywords: recurrent pregnancy loss, thrombophilia,
infertility, Factor V Leiden mutation,
activated protein C resistance, thrombophilic
gene mutations
Table 1_Laboratory Findings
Test Patient’s Result “Normal” Reference Range
Lupus anticoagulant reflex
PTT-LA(s) 36.2 0.0-50.0 seconds
dRVVT(s) 38.5 0.0-44.5 seconds
Phosphatidylserine antibodies
IgM 13 0-25 MPS IgM
IgG 4 0-11 GPS IgG
APTT Mixing studies
APTT 26.4 23.4-36.4 seconds
APTT 1:1 normal plasma 26.1 23.4-36.4 seconds
APTT 1:1 mix saline 28.4 0.0-37.0 seconds
APTT 1:1 NP mix, 60 min. incubation 27.6 23.4-36.4 seconds
APTT 1:1 mix NP incubation mix Ctl 28.3 23.4–36.4 seconds
Anticardiolipin antibodies
IgG

Case Studies
1. Practice Committee of the American Society for Reproductive Medicine.
Definitions of infertility and recurrent pregnancy loss. Fertil Steril.
2008;89:1603.
2. Carp HJ. Recurrent miscarriage: Genetic factors and assessment of the embryo.
IMAJ. 2008;10:229–231.
3. Migeon BR. Non-random X chromosome inactivation in mammalian cells.
Cytogenet Cell Genet. 1998;80:142–148.
4. Porter TF, Scott JR. Evidence-based care of recurrent miscarriage. Best Pract
Res Clin Obstet Gynaecol. 2005;19:85–101.
5. Abalovich M, Gutierrez S, Alcaraz G, et al. Overt and subclinical
hypothyroidism complicating pregnancy. Thyroid. 2002;12:63–68.
6. Kalro BN. Impaired infertility caused by endocrine dysfunction in women.
Endocrinol Metab Clin North Am. 2003;32:573–592.
7. Craig LB, Ke RW, Kutteh WH. Increased prevalence of insulin resistance
in women with a history of recurrent pregnancy loss. Fertil Steril.
2002;78:487–490.
8. Hanson U, Persson B, Thunell S. Relationship between hemoglobin A1C
in early type 1 (insulin dependent) diabetic pregnancy and the occurrence
of spontaneous abortion and fetal malformation in Sweden. Dibetologia.
1990;33:100–104.
9. Szekeres-Bartho J, Balasch J. Progesterone therapy for recurrent pregnancy
loss. Hum Reprod Update. 2008;14:27–35.
10. Lin PC. Reproductive outcomes in women with uterine anomalies. J Women
Reprod Health. 2004;13:33–39.
11. Pihusch R, Buchholz T, Lohse P, et al. Thrombophilic gene mutations and
recurrent spontaneous abortion: Prothrombin mutation increases the risk in
the first trimester. AJRI. 2001;46;124–131.
12. Glueck CJ, Gogenini S, Munjal J, et al. Factor V Leiden mutation: A treatable
etiology for sporadic and recurrent pregnancy loss. Fertil Steril. 2008;89:410–
416.
13. Ornoy A, Chen L, Silver RM, et al. Maternal autoimmune diseases and
immunologically induced embryonic and fetoplacental damage. Birth Defects
Res A Clin Mol Teratol. 2004;70:371–381.
14. Vinatier D, Dufour P, Cosson M, et al. Antiphospholipid syndrome and
recurrent miscarriages. Eur J Obstet Gynecol Reprod Biol. 2001;96:37–50.
15. Raziel A, Kornberg Y, Friedler R, et al. Hypercoagulable thrombophilic defects
and hyperhomocysteinemia in patients with recurrent pregnancy loss. AJRI.
2001;45:65–71.
16. Rai R, Backos M, Elgaddal S, et al. Factor V Leiden and recurrent miscarriageprospective
outcome of untreated pregnancies. Hum Reprod. 2002;17:442–
445.
17. Grandone D, Margaglione M, Colaizzo D, et al. Factor V Leiden is associated
with repeated and recurrent unexplained fetal losses. Thromb Haemost.
1997;77:822–24.
18. Dahlback B. Activated protein C resistance and thrombosis: Molecular
mechanisms of hypercoagulable state due to FVR506Q mutation. Semin
Thromb Hemost. 1999;25:273–289.
19. Hirahara U, Andoh N, Sawai K, et al. Hyperprolactinemic recurrent
miscarriage and results of randomized bromocriptine treatment trials. Fertil
Steril. 1998;70:246–252.
20. Davis LB, Leveko KJ, Cunningham FG. Hypothyroidism complicating
pregnancy. Obstet Gynecol. 1988;72:108–112.
21. Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency
during pregnancy and subsequent neuropsychological development of the
child. NEJM. 1999;341:549–555.
22. Clark P, Brennand J, Conkle JA, et al. Activated protein C sensitivity,
protein C, protein S and coagulation in normal pregnancy. Thromb Haemost.
1998;79:1166–1170.
23. Goodman CS, Coulam CB, Jeyendran RS, et al. Which thrombophilic gene
mutations are risk factors for recurrent pregnancy loss? Am J Reprod Immunol.
2006;56:230–236.
24. Pihusch R, Buchholz T, Lohse P, et al. Thrombophilic gene mutations and
recurrent spontaneous abortion: Prothrombin mutation increases the risk in
the first trimester. AJRI. 2001;46:124–131.
25. Unfried G, Griesmach A, Weismuller W, et al. The C677T polymorphism
of the methylenetetrahydrofolate reductase gene and idiopathic recurrent
miscarriage. Obstet Gynecol. 2002;99:614–619.
26. Badaway AM, Khiary M, Sherril, LS, et al. Low-molecular weight heparin
in patients with recurrent early miscarriages of unknown aetiology. J Obstet
Gynaecol. 2008;28:280–284.
27. Stephenson MD, Ballem PJ, Tsang P, et al. Treatment of antiphospholipid
syndrome (APS) in pregnancy: A randomized pilot trial comparing low
molecular weight heparin to unfractionated heparin. J Obstet Gynaecol Can.
2004;26:729–734.
28. Rai R, Cohen H, Dave M, et al. Randomized controlled trial of aspirin and
aspirin plus heparin in pregnant women with recurrent miscarriage associated
with phospholipid antibodies (or antiphospholipid antibodies). Br Med J.
1997;31:253–257.
29. Kutteh WH. Antiphospholipid antibody-associated recurrent pregnancy loss:
Treatment with heparin and low-dose aspirin is superior to low dose aspirin
alone. Am J Obstet Gynecol. 1996;174:1584–1589.
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