Clinical cure of severe, early onset preeclampsia with low molecular weight heparin therapy in primigravida with hyperreactio luteinalis and thrombophilia
Clinical cure of severe, early onset preeclampsia with low molecular weight heparin therapy in primigravida with hyperreactio luteinalis and thrombophilia
Terhi Saisto 0
Aila Tiitinen 0
Veli-Matti Ulander 0
Risto Kaaja 0
0 Department of Obstetrics and Gynaecology, Helsinki University Central Hospital , PO Box 140, FIN-00290 HUS Helsinki , Finland
1To whom correspondence should be addressed. E-mail: terhi.saisto@hus. Inherited thrombophilias, suggested to be risk factors for ovarian hyperstimulation syndrome and known to be associated with venous thromboembolism during pregnancy, may also increase the risk for preeclampsia (PE). We describe the case of a 29-year-old woman with primary infertility with no history of thrombosis, hypertension or renal disorders. In her rst pregnancy, achieved by frozen embryo transfer, she developed severe early-onset (23rd gestational week) PE with heavy proteinuria, and at the same time was found to have enlarged ovaries with hyperreactio luteinalis. After admission we found that she was a heterozygotic carrier of the factor V Leiden mutation. After administering low molecular weight heparin (LMWH) therapy, her blood pressure normalized, proteinuria diminished and her D-dimer values returned to that of a normal pregnant level. The fetus grew normally. Her ovaries normalized during the pregnancy, as determined by ultrasound examinations. At term she delivered spontaneously a normal weight, healthy girl. Previously, only prophylactic LMWH, in subsequent pregnancy, have been administered in patients with thrombophilia and a history of severe PE. We describe a case of spontaneous hyperreactio luteinalis, where the clinical characteristics of PE improved after beginning LMWH therapy in severe, very early onset PE. Inherited thrombophilia, spontaneous hyperreactio luteinalis and PE may be associated phenomena.
hyperreactio luteinalis/low molecular weight heparin/preeclampsia/thrombophilia
Hyperreactio luteinalis is a rare condition complicating
pregnancy. It is characterized by varying degrees of bilateral
ovarian enlargement due to theca lutein cyst formation,
whereby it mimics ovarian hyperstimulation syndrome
(OHSS), which is an iatrogenic complication of ovulation
induction. OHSS is typically identied very early during the
rst trimester, whereas hyperreactio luteinalis often occurs in
patients without any precipitating history and during the
second or third trimester (Foulk et al., 1997). There is also
potential for confusion in diagnosis and even unnecessary
surgery. Hyperreactio luteinalis usually complicates those
pregnancies in which higher concentrations of maternal
serum HCG are found, such as gestational trophoblastic
disease, multiple pregnancies, maternal diabetes or rhesus
isoimmunization. It has also been described in a rare situation
with chronic renal failure, where due to diminished clearance
of HCG, the ovaries had been exposed to HCG for a prolonged
period. Also, increased ovarian sensitivity to gonadotrophins
has been suggested as a mechanims for hyperreactio luteinalis
(Schnorr et al., 1996). One recent paper reported that the
prevalence of thrombophilia markers is signicantly increased
in women who develop OHSS after ovulation induction
(Dulitzky et al., 2002).
Inherited thrombophilic disorders are associated with an
increased risk of venous thromboembolism during pregnancy.
Preliminary research suggested that these disorders might also
increase the risk for preeclampsia (PE) (Kahn, 1998;
Kupferminc et al., 2001). PE is known to be associated with
an imbalance in coagulation and brinolysis that results in a
hypercoagulable state in both maternal and placental
circulation (de Boer et al., 1988; Estelles et al., 1991). It has been
suggested that the hypercoagulable state in severe PE is
strongly related to the onset of intrauterine growth retardation
(IUGR) through the deterioration of placental circulation.
Furthermore, it has been suggested that patients with severe PE
or IUGR and an inherited thrombophilia may benet from
prophylactic treatment with low molecular weight heparin
(LMWH), probably combined with aspirin, in subsequent
pregnancies (Kupferminc et al., 2001). Previously, heparin or
antithrombin (AT) therapy has been given to treat severe, early
onset PE for 7 days, but neither treatment was able to postpone
the delivery after the 32nd gestational week (Nakabayashi
et al., 1999).
Human Reproduction vol. 19 no. 3 European Society of Human Reproduction and Embryology 2004; all rights reserved
Gestational age (weeks + days)
Our patient was a 29-year-old woman with 4 years'
unexplained primary infertility. She did not have any history of
renal disease or hypertensive disorder, her blood pressure was
118/70 mmHg. The basic infertility investigations showed
ovulatory cycles; however, late ovulation with a short luteal
phase was seen infrequently. Transvaginal ultrasound (TVUS)
examination revealed normal-sized ovaries, with a few follicles
exceeding 7 mm, and a normal uterus. IVF was planned, and
during the rst cycle 28 mature oocytes were retrieved, but
they were not fertilized. The next cycle was carried out
after ovarian suppression with GnRH analogue, nafarelin
(Synarela, Syntex Nordica AB, Sodertalje, Sweden),
commenced during the mid-luteal phase of the previous cycle, and
ovarian stimulation was conducted with 100 IU of recombinant
FSH (Puregon, Organon, Oss, The Netherlands) for 10 days.
ICSI was performed, resulting in 12 normally cleaving
embryos. The rst fresh embryo transfer and the rst frozen
thawed embryo transfer cycle were unsuccessful. The next
frozenthawed embryo transfer was carried out during the
hormone substitution cycle. Estradiol (E2) valerate (4 mg/day)
was commenced on period day 1; after 13 days the
endometrium was 7-mm thick and the ovaries showed no
growing follicles. Intravaginal micronized progesterone
(600 mg/day) was given. Three days later, two embryos were
transferred, and 12 days later the patient's serum HCG level
was 111.9 IU/l. The rst TVUS 5 weeks after embryo transfer
showed a normal single intrauterine pregnancy with fetal
heartbeat. The ovaries were normal sized. The hormone
substitution was given until pregnancy week 10, at which
point TVUS still showed normal ovaries and a normally
At gestational age 22 weeks and 5 days the patient was
referred to our tertiary clinic because of severe PE
[hypertension, proteinuria and extreme oedema in lower extremities
(weight gained 8000 g in last 2 weeks)]. The reduced diuresis
was normalized after 2 days' forced oral administration of
uids. On ultrasound examination, the fetus was moving
actively, and the measurements of biparietal diameter,
abdominal circumference and femur length were all normal
according to the gestational age. The amount of amniotic uid
was normal, and the placenta was thick and homogenous. The
ultrasound examination revealed large ovaries, both up to 10 3
6 3 7 cm, with multicystic appearance without any solid
Because of a manifest severe PE of early onset, extreme
oedema, immobilization and high levels of D-dimer (21 mg/l),
therapy with LMWH was started at the dose of dalteparin
5000 IU/day at the gestational age of 23 weeks and 1 day. The
values of the main parameters followed are shown in Table I.
In laboratory studies, serum transaminases and
haptoglobulin were repeatedly normal, and lupus anticoagulant and other
phospholipid antibodies were negative. There were no signs of
either hypo- or hyperthyroidism. Factor V Leiden point
mutation was found in coagulation factor V in heterozygotic
form. Tests for protein C, protein S, factor II mutation and
ATIII showed normal pregnancy-related values. Protein S was
also retested post-partum, and was normal. In hormonal
analyses, serum HCG was exceptionally high at 153 790 IU/l
(expected to be <15 000 IU/l), E2 54.13 nmol/l, progesterone
1257.2 nmol/l, testosterone 6.2 nmol/l and free testosterone
25 pmol/l. Serum FSH was, as expected, <0.10 IU/l, and LH
was 38.6 IU/l, as measured by specic immunouorimetric
assays. The level of LH presumably reected cross-reaction
with the high level of HCG. To examine the possible causes of
the early onset PE and multicystic ovaries, radiological
examinations were also performed. Magnetic resonance
imaging of the pituitary gland was normal, as was the
ultrasound examination of the liver, pancreas and kidneys.
No renal vein thrombosis was shown.
During the next 2 weeks, the patient lost 10 kg in weight,
blood pressure was normalized to the level of 130/80 mmHg
without any antihypertensives, and proteinuria diminished to
the level of 1.3 g/day. The fetus grew as expected, and the
mother was free of symptoms. After 4 weeks the patient was
discharged from hospital, and the situation was monitored in
the out-patient clinic every 1014 days. In serial ultrasound
measurements the fetus grew normally, and cardiotocography
tracings and Doppler measurements were normal. The size of
the ovaries diminished slowly, being 4 3 5 cm at 37th
gestational week. LMWH therapy was continued. Other values
are shown in Table I.
At the gestational age of 38 weeks and 6 days the patient had
spontaneous deliverery of a healthy girl weighing 3175 g. The
delivery was otherwise uneventful, but the placenta had to be
removed manually under general anaesthesia and the blood
loss was 1500 ml. Unfortunately, we were unable to retain
the placenta for further investigation. LMWH therapy was
discontinued 6 weeks after delivery. At that time, the left ovary
was normal sized, and the right ovary was enlarged (46 3
31 mm). All anti-DNA antibodies were again negative. Other
main values are shown in Table I. Three months later the
nephrologist reported normal renal function, with no signs of
A severe OHSS-like syndrome occurring in a spontaneously
conceived pregnancy has been reported in the literature
(Lambers and Rosenn, 1996; Bidus et al., 2002). Our patient
had received ovulation induction during the infertility
treatment, but not during the cycle she conceived. Indeed, during
that cycle her ovaries were suppressed with exogenous
hormones and the pregnancy resulted from transfer of frozen
thawed embryos. We could nd only one case report where
hyperreactio luteinalis occurred in the rst trimester in a
similar situation, during frozenthawed embryo transfer
(Check et al., 2000). Both of these cases indicate that
hyperreactio luteinalis can develop even without a single
corpus luteum of pregnancy, probabaly because of some
intrinsic sensitivity to gonadotrophins (Perez Mayorga et al.,
Many patients with hyperreactio luteinalis have undergone
exploratory operations because of ovarian masses, or even
oophorectomies during Caesarean sections (Wajda et al., 1989;
Schnorr et al., 1996; Bidus et al., 2002). Usually the
pregnancies have otherwise been uncomplicated, although
predisposition to venous thrombosis has been reported in
association with both iatrogenic and spontaneous OHSS (Kaaja
et al., 1989; Todros et al., 1999; Dulitzky et al., 2002).
Hormonal changes in OHSS and hyperreactio luteinalis may
contribute to alterations in coagulation factors and predispose
to thromboembolic complications (Belaen et al., 2001;
Delvigne et al., 2002). Todros et al. (1999) reported one case
with factor V Leiden mutation and deep venous thromboses
with hyperreactio luteinalis, even while administering LMWH.
Early severe PE has been diagnosed in a 25-year-old
primigravida during gestational week 22, and both her ovaries
had been enlarged for 6 weeks. In that case, the pregnancy was
terminated due to worsening maternal conditions (Regi et al.,
1996). Our case is unique, with a combination of hereditary
(factor V Leiden) and acquired (hyperreactio lutealis)
thrombophilia, which lead to `transient' PE. We believe that the
thrombotic process in the placenta was the key mechanism by
which PE developed. The brin formation in the placenta was
stopped by LMWH, as witnessed by normalization of D-dimer,
and the pregnancy continued until term.
PE is most common in primigravidas, and its epidemiology
suggests that genetic factors can be important in its
pathogenesis (Dekker and Sibai, 1999). It is possible that increased
thrombosis in the placenta impairs the normal transformation
of spiral arteries, and thus heritable thrombophilias are to
blame for at least some of the predisposition to PE. However,
the evidence currently available shows no clear association
LMWH therapy for early onset preeclampsia
between PE and thrombophilias, other than factor V Leiden in
severe PE (Morrison et al., 2002; Walker, 2002).
The incidence of factor V Leiden mutation in Europe is 2
5% in unselected populations and 1020% in patients with
venous thrombosis (Lockwood, 2002). Our patient did not have
any previous or actual thrombosis, or any other risk factor for
PE other than primigravidity. High D-dimer levels indicated at
least subclinical activation of coagulation, and after
administering the treatment, D-dimer levels continually decreased with
resolving clinical symptoms. One of the major diseases
excluded was renal vein thrombosis. Furthermore, no deep
venous thrombosis of the legs was shown. One of the suspected
sites for thrombosis could have been placenta, and after
treatment with LMWH, no IUGR was observed. To our
knowledge this is the rst case where PE was cured by
treatment with LMWH during pregnancy in a patient with
It has been suggested that screening for thrombophilia might
be worthwhile in women with a family history of thrombosis
who undergo infertility treatments and in women who develop
severe OHSS (Dulitzky et al., 2002). Although in most of the
cases this is done to avoid venous thromboembolic
complications, in our case the site of thrombosis was placenta, which
lead to severe, early onset PE. We would further suggest that
women with severe, early onset PE are advised to be tested for
both inherited and acquired thrombophilias (phospholipid
antibodies), and that randomized controlled trials for LMWH
treatment in severe, early onset PE should be conducted.
Al-Ramahi M and Leader A ( 1998 ) Hyperreactio luteinalis associated with chronic renal failure . Hum Reprod 14 , 416 418 .
Belaen B , Geerinckx K , Vergauew P and Thys J ( 2001 ) Internal jugular vein thrombosis after ovarian stimulation . Hum Reprod 16 , 510 512 .
Bidus MA , Ries A , Magann EF and Martin JN ( 2002 ) Markedly elevated betahCG levels in a normal singleton gestation with hyperreactio luteinalis . Obstet Gynecol 99 , 958 961 .
Check JH , Choe JK and Nazari A ( 2000 ) Hyperreactio luteinalis despite the absence of a corpus luteum and suppressed serum follicle stimulating concentrations in a triplet pregnancy . Hum Reprod 15 , 1043 1045 .
deBoer K , Lecander I , ten Cate JW , Borm JJ and Treffers PE ( 1988 ) Placentaltype plasminogen activator inhibitor in preeclampsia . Am J Obstet Gynecol 158 , 518 522 .
Dekker GA and Sibai BM ( 1999 ) The immunology of preeclampsia . Semin Perinatol 23 , 24 33 .
Delvigne A , Kostyla K , de Leener A , Lejeune B , Cantiniaux B , Bergmann P and Rozenberg S ( 2002 ) Metabolic characteristics of women who developed ovarian hyperstimulation syndrome . Hum Reprod 17 , 1994 1996 .
Dulitzky M , Cohen SB , Inbal A , Seidman DS , Soriano D , Lidor A , Mashiach S and Rabinovici J ( 2002 ) Increased prevalence of thrombophilia among women with severe ovarian hyperstimulation syndrome . Fertil Steril 77 , 463 467 .
Estelles A , Gilabert J , Espana F , Aznar J and Galbis M ( 1991 ) Fibrinolytic parameters in normotensive pregnancy with intrauterine fetal growth retardation and in severe preeclampsia . Am J Obstet Gynecol 165 , 138 142 .
Foulk RA , Martin MC , Jerkins GL and Laros RK ( 1997 ) Hyperreactio luteinalis differentiated from severe ovarian hyperstimulation syndrome in a spontaneously conceived pregnancy . Am J Obstet Gynecol 176 , 1300 1302 , discussion 1302 1304 .
Kaaja R , Siegberg R , Tiitinen A and Koskimies A ( 1989 ) Severe ovarian hyperstimulation syndrome and deep venous thrombosis . Lancet ii , 1043 .
Kahn SR ( 1998 ) Severe preeclampsia associated with coinheritance of factor V Leiden mutation and protein S deciency . Obstet Gynecol 91 , 812 814 .
Kupferminc MJ , Fait G , Many A , Lessing JB , Yair D , Bar-Am A and Eldor A ( 2001 ) Low-molecular-weight heparin for the prevention of obstetric complications in women with thrombophilias . Hypertens Pregnancy 20 , 35 44 .
Lambers DS and Rosenn B ( 1996 ) Hyperreactio luteinalis complicating a normal singleton pregnancy . Am J Perinatol 13 , 491 494 .
Lockwood CJ ( 2002 ) Inherited thrombophilias in pregnant patients: detection and treatment paradigm . Obstet Gynecol 99 , 333 341 .
Morrison ER , Miedzybrodzka ZH , Campbell DM , Haites NE , Wilson BJ , Watson MS , Greaves M and Vickers MA ( 2002 ) Prothrombotic genotypes are not associated with pre-eclampsia and gestational hypertension: results from a large population-based study and systematic review . Thromb Haemost 87 , 779 785 .
Nakabayashi M , Asami M and Nakatani A ( 1999 ) Efcacy of antithrombin replacement therapy in severe early-onset preeclampsia . Semin Thromb Hemost 25 , 463 466 .
Perez Mayorga M , Gromoll J , Behre HM , Gassner C , Nieschlag E and Simoni M ( 2000 ) Ovarian response to follicle-stimulationg hormone (FSH) stimulation depends on the FSH receptor genotype . J Clin Endocrinol Metab 85 , 3365 3369 .
Regi A , Mathai M , Jasper P , Krishnaswami H , Prem S and Peedicayil A ( 1996 ) Ovarian hyperstimulation syndrome (OHSS) in pregnancy not associated with ovulation induction . Acta Obstet Gynecol Scand 75 , 599 600 .
Schnorr JA Jr, Miller H , Davis JR , Hatch K and Seeds J ( 1996 ) Hyperrreactio luteinalis associated with pregnancy: a case report and review of the literature . Am J Perinatol 13 , 95 97 .
Todros T , Carmazzi CM , Bontempo S , Gaglioti P , Donvito V and Massobrio M ( 1999 ) Spontaneous ovarian hyperstimulation syndrome and deep vein thrombosis in pregnancy . Hum Reprod 14 , 2245 2248 .
Wajda KJ , Lucas JG and Marsh WL Jr ( 1989 ) Hyperreactio luteinalis . Benign disorder masquerading as an ovarian neoplasm . Arch Pathol Lab Med 113 , 921 925 .
Walker ID ( 2002 ) Prothrombotic genotypes and pre-eclampsia . Thromb Haemost 87 , 777 778 .
Submitted on June 27, 2003 ; accepted on October 22 , 2003