REVIEWS - Advances in Clinical and Experimental Medicine

REVIEWS - Advances in Clinical and Experimental Medicine

REVIEWS
Adv Clin Exp Med 2013, 22, 5, 753–758
ISSN 1899–5276
© Copyright by Wroclaw Medical University
Małgorzata Pawelec1, A, B, D, F, Andrzej Karmowski1, C, E, F, Mikołaj Karmowski1, C, E,
Joanna Krzemieniewska1, A, B, E, F, Aleksandra Kulczycka1, C, E,
Marian Stanisław Gabryś1, C, E, F, Jerzy Koryś2, B, Bohdan Gworys3, B
Inability to Have Children Caused
by Recurrent HELLP Syndrome in Early Pregnancies
– Implications for a Review of Literature
Niezdolność do posiadania dzieci spowodowana nawracającym zespołem
HELLP we wczesnej ciąży – implikacje dla przeglądu piśmiennictwa
First Clinic of Obstetrics and Gynecology, Wroclaw Medical University, Poland
Non-Public Health Service Institution, Legnickie Pole, Poland
3
Department of Anatomy, Wroclaw Medical University, Poland
1
2
A – research concept and design; B – collection and/or assembly of data; C – data analysis and interpretation;
D – writing the article; E – critical revision of the article; F – final approval of article; G – other
Abstract
This review is inspired by a case of two pregnancies of the same patient complicated by HELLP syndrome, which
suggests that there is a predisposition for the occurrence of preeclampsia and HELLP syndrome in early pregnancy.
HELLP syndrome, uncommon below the 20th week and rarer still in two consecutive pregnancies, appeared in two
pregnancies of the same woman. The aim of our work is to try to understand the cause of heterogeneity of HELLP
syndrome and help find a way of prolonging such pregnancies. Recurrent HELLP syndrome in early pregnancy is
a form of severe, fulminant preeclampsia. The preceding symptom is a surge in blood pressure. The hypertension
becomes resistant to antihypertensive drugs, which indicates that preexisting hypertension is later accompanied by
other factors contributing to the rise in blood pressure. Different effects of high dosage of corticosteroids on liver
and platelets show that there are different factors responsible for liver damage and for thrombocytopenia. It seems
that the symptoms have various origins, so the therapy with one drug only is not sufficiently effective. Nicotine
analogues or a plant extract (from rootstock of Eriosema kraussianum) used by South African traditional healers
for erectile dysfunction seem to give a chance of prolonging pregnancy and, consequently, having children (Adv
Clin Exp Med 2013, 22, 5, 753–758).
Key words: recurrent HELLP syndrome, preeclampsia, APS, chronic hypertension, nicotine analogues, angiogenic
factors.
Streszczenie
Asumptem do tego przeglądu piśmiennictwa stał się przypadek dwóch kolejnych ciąż u tej samej pacjentki przebiegających ze stanem przedrzucawkowym, a następnie z zespołem HELLP, które wydają się świadczyć o występowaniu osobistej predyspozycji do stanu przedrzucawkowego i zespołu HELLP we wczesnej ciąży. Zespół HELLP
(przypomnienie aut. hemoliza, zwiększone stężenie enzymów wątrobowych, a małe płytek płytek krwi) spotyka się
rzadko w ciążach poniżej 20. tygodnia, a jeszcze rzadziej w dwóch kolejnych ciążach u tej samej kobiety. Celem
tej pracy była próba zrozumienia różnorodności zespołu HELLP (inny przebieg u tej samej kobiety) i znalezienie sposobu na przedłużenie czasu do rozwiązania ciąży (uzyskania szansy na przeżycie wcześniaków), analizując piśmiennictwo. Nawracający zespół HELLP we wczesnej ciąży jest formą ciężkiej, piorunującej preeklampsji
(stanu przedrzucawkowego). Objawem zwiastującym wystąpienie tego zespołu jest skok wartości ciśnienia krwi.
Nadciśnienie staje się oporne na leki obniżające ciśnienie krwi, co może wskazywać na to, że do nadciśnienia
uprzednio istniejącego dołącza się zwiększenie ciśnienia wywołane innymi czynnikami. Różna reakcja wątroby
i płytek u tej samej pacjentki, po podaniu dużych dawek kortykosteroidów, wskazuje, że inne czynniki odpowiadają
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za uszkodzenie wątroby, inne natomiast za małopłytkowość. Objawy zespołu HELLP mogą mieć więc różne źródło
i dlatego próby leczenia jednym lekiem są niewystarczające. Analogi nikotyny lub ekstrakty z korzeni Eriosema
kraussianum stosowane w Afryce do leczenia zaburzeń erekcji wydają się szansą dla takich ciężarnych kobiet, jak
opisana pacjentka, w wydłużeniu czasu trwania ciąży, a w konsekwencji dają szansę na posiadanie dzieci (Adv Clin
Exp Med 2013, 22, 5, 753–758).
Słowa kluczowe: nawracający zespół HELLP, preeklampsja (stan przedrzucawkowy), APS (zespół antyfosfolipidowy), przewlekłe nadciśnienie, analogi nikotyny, czynniki naczyniotwórcze.
HELLP syndrome (hemolysis, elevated liver
enzymes and low platelets) is a set of symptoms expressing multiorgan damage in pregnancies complicated by preeclampsia (PE). A prospective study
indicates that HELLP syndrome develops solely in
patients with PE (in 19.3% of them) [1]. The risk
of recurrence for HELLP syndrome is 3–5%, while
the recurrence risk for PE is 19.5–25% [2]. The risk
is higher if the occurrence is early in the pregnancy and with chronic hypertension [2]. About 15%
of cases of HELLP syndrome were recognized before the 27th week of pregnancy [our unpublished
data]. During 30 years of practice in our clinic we
have never had a case of recurrent HELLP syndrome. The only case, which we described, was of
a HELLP syndrome in the 24th week of the second
pregnancy, when the first pregnancy was complicated by gestational hypertension [3]. Preeclampsia affects about 5% of pregnancies [4]. The etiology of PE is still unclear. Some studies suggest that it
is the excess of circulating anti-angiogenic growth
factors produced in the placenta that is responsible
for the occurrence of PE [5]. The early event leading to preeclampsia is placental ischemia, which
in turn leads to the production of factors causing
endothelial dysfunction [4]. There are many such
factors, for example, soluble VEGF (vascular endothelial growth factor) receptor-1 sFlt-1 (soluble fms-like tyrosine kinase 1), soluble endoglin
(sEng), the angiotensin II type-1 autoantibody
(AT1-AA), and cytokines: interleukin 6, TNF-a
(tumor necrosis factor) changing the function of
maternal endothelium. As a consequence, the sensitivity of vessels to angiotensin II changes, and the
formation of vasodilatators (nitric oxide and prostacyclin and endothelium-derived hyperpolarizing
factor) decreases [4–12]. The endothelial dysfunction results in the clinical symptoms of hypertension, proteinuria, and edema [4].
“Preeclampsia is condition where the mother
and her child experience two opposite but related
conditions, one an excessive level of stimulation by
the negative neutrophic and pharmacological effects of microcirculatory norepinephrine and the
other by a deficiency of those effects” [13].
Summing up, the common core of different
theories of the development of gestational hypertension and multiorgan disfunction is the reduction in uteroplacental perfusion pressure leading
to placental ischemia/hypoxia which triggers the
release of placental factors initiating a cascade of
processes affecting a disfunction of the endothelium and vascular smooth muscle. As the final
result, vascular resistance and arterial pressure
increase [9].
The reduction in the flow to the placenta leading to placental ischemia may be caused by compression of aorta and the neighbouring arterias by
an enlarged uterus, which is accompanied by an
increase of blood flow to the tissues proximal to
the vascular compression [13] or inadequate cytotrophoblast invasion of the uterine spiral arteries [9, 14, 15]. Also, placental substances may increase
the release of contracting factors, such as endothelin, thromboxane, and angiotensin II, which increase
the intracellular concentration of calcium ions and
stimulate smooth muscle contractions [9].
“The combination creates a critical dilemma
for anyone treating preeclampsia, since a treatment to counter the effects of one condition is likely to aggravate those of the other” [13].
If preeclampsia is connected with deep placentation, then the fact that there are different types of
this defect may explain why there are different degrees of the gravity of preeclampsia [15]. If, however, augmented contraction, exaggerated vasomotion, and selective ablation of induced relaxation
in laboratory tests on omental arteries from preeclamptic women are confirmed in vivo, we are still
not able to explain why this “uniquely human disorder” [16] appears in the same woman in different weeks of consecutive pregnancies and in different degree [3, 17].
If, in turn, it is the excessive circulation of sFlt1
that contributes to the pathogenesis of preeclampsia, then why does it occur in the same woman at
different ages of consecutive pregnancies; why in
some patients does it lead only to gestational hypertention, while in others to preeclampsia, and, finally, in our patient to HELLP syndrome [3–5, 17]?
An experienced obstetrician cannot but wonder
at the diversity of clinical pictures and the rate of
development of preeclampsia, as well as the inability to predict the occurrence of HELLP syndrome.
An animal model can be of help here. Exogenous
gene transfer of sFlt-1 (soluble form of tyrosine kinase-1 type receptors) in pregnant rats displayed
various phenotypes of preecclampsia [4, 18]. Also,
Recurrent HELLP Syndrome
co-administration of sEng caused hemolysis and
thrombocytopenia (like HELLP syndrome), which
are also the phenotypes of the disease [19].
Two bioactive compounds (pyranoisoflavones)
extracted from Eriosema kraussianum have vasodilatory properties [19]. Treatment using sildenafil
citrate or Kraussianone-2 improved placental perfusion in animal model, decreasing levels of sFlt1
and sEng [19, 20].
The predominant view is that PE is an illness
of placenta with the consequences for the fetal
well-being while HELLP syndrome is a multiorgan damage in the mother with the consequences of PE for the fetus. It is particularly relevant
for HELLP syndrome in immature pregnancy to
prolong gestation. As using first-trimester maternal serum PP13 (placental protein 13) as a marker
for risk assessment has different reliability in preterm preeclampsia and a different, weaker, one in
severe preeclampsia at term [21], it seems that preeclampsia is a cover term for more than one type
of illness. The case described here is interesting because it is the case of gestational disease, which is
both recurrent and appearing so early in the pregnancy. Does this mean that as a result of failure in
two pregnancies the patient, over 40, lost all chances for having children? Ischemic placenta has been
shown to produce excessive amounts of sFlt1 into
maternal circulation [18].
Given the multifactorial nature of preeclampsia and the elusive nature of its etiology, it is hard
to predict if the attempts to use substances which
reduce the level of sFlt1 and sEng (in some patients
increased even before the 20th week of pregnancy) can in effect lead to reduction in the number
of complications leading to perinatal mortality and
morbidity [19].
The recurrent HELLP syndrome can be illustrated with by the following events.
A woman with chronic hypertension became pregnant for the first time at the age of 42,
and again at the age of 45. She had no preexisting proteinuria. Before and between pregnancies
she received beta blocker and angiotensin convertase inhibitor. In the 6th week of her first pregnancy, these drugs were replaced by methyldopa
and dihydralazine. In the second pregnancy, the
patient refused to take antihypertesive drugs until
the 18th week. In the 18th week of the first pregnancy and in the 22nd week of the second pregnancy, there appeared life-threatening surges in
blood pressure, resistant to antihypertensive drugs
(180/130 mmHg, 200/110 mmHg, 190/120 mmHg)
as well as acute chest pain. There was also proteinuria (3.0 g/L in the first pregnancy and 3.5 g/L
in the second pregnancy). HELLP syndrome was
diagnosed in the 18th week of the first and in the
755
22nd week of the second pregnancy. Each time it
appeared simultaneously with PE. 5 days earlier,
routine tests of blood and urine did not indicate
PE or HELLP syndrome. The first pregnancy was
terminated on the 18th week because of HELLP
syndrome with very low platelet levels resistant to
treatment. The second pregnancy was missed on
the 22nd week, at a higher platelet level. Morphologically both fetuses were normal. In both pregnancies the patient was found to have hemolytic
anemia with the level of haptoglobin 0.08 g/L and
0.07 g/L (here and in the following, the numbers
refer to the first and the second pregnancy respectively), while the normal range is 0.34–2.0 g/L. In
blood smear reticulocytosis was 0.0413 and 0.0355,
lymphopenia 0.112 and 0.146, monocytosis 0.103
and 0.102, and there was anisocytosis. Other laboratory findings were: PLT: 33 × 109/L and 60.3 ×
109/L, HGB: 106 g/L and 96.9 g/L, HCT: 0.301 and
0.295, RBC: 3.24 × 1012/L and 3.01 × 1012/L, WBC:
6.42 × 109/L and 8.77 × 109/L, AST: 120 U/L and
105 U/L, ALT: 75 U/L and 64 U/L, total bilirubin:
26.85 µmol/L and 35.06 µmol/L, LDH: 700 U/L
and 720 U/L, total protein: 60 g/L and 54 g/L, positive results of D-dimer (10 times more than normal threshold), APTT: 31.5 s and 32.3 s. Mean systolic pressure: 165 mmHg and 164.4 mmHg, mean
diastolic pressure: 115.7 mmHg and 105.6 mmHg.
Both pregnancies were negative for HBsAG
and HCV, and positive for anticardiolipin antibodies (their level met the laboratory criteria for
APS). In both pregnancies, the patient had an infection of the urinary tract and vagina. She never had bacteriological culture identification. In the
first pregnancy, high dosage corticosteroid therapy (>24 mg/day) was applied. In spite of this, after 5 days the following dropped: platelets to
13 × 109/L, HGB to 99 g/L, RBC to 3.05 × 1012/L,
HCT to 0.275. Proteinuria rose to 4.0 g/L and there
was no reaction to i.v. antihypertensive drugs. Liver enzymes rose slightly: AST to 128 U/L and ALT
to 84 U/L; total bilirubin rose to 30.78 µmol/L, Ddimer rose by 10%.
Only during the preparation for pregnancy
termination, the mother received platelet concentrate, frozen plasma and erythrocytes. 3 days later
the number of platelets grew to 190 × 109/L, with
no further treatment. A positive reaction to antihypertensive drugs occurred with a few hours after the termination of pregnancy.
In the second pregnancy, 3 days after admission to hospital, the fetus died in utero. Until then
there was a considerable rise in the level of liver
enzymes: ALT to 100 U/L and AST to 218 U/L; total bilirubin rose to 63.8 µmol/L. Platelets dropped
only to 52 × 109/L, HGB to 85.1 g/L, RBC do 2.55 ×
1012/L, HCT to 0.25 and D-dimer rose by 100%. In
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both pregnancies, histopathological examination
of placenta showed: fibrosis and ageing of villi and
pale infarcts. The patient’s mother is obese and has
hypertension and diabetes, and the patient’s maternal grandfather had a stroke. The patient herself was born prematurely. The patient did not try
to conceive the third time.
Discussion
HELLP syndrome is a severe form of PE [22].
Usually data suggests that HELLP syndrome follows PE. In this case, PE and HELLP syndrome
occurred simultaneously. As 5 days before, there
were no clinical symptoms of PE and HELLP syndrome, the histopathological changes found in placenta a few days later indicate that it was not only severe, but also a fulminant form of PE. In this
case PE and HELLP syndrome appeared simultaneously, and in two consecutive pregnancies, so it
cannot be excluded that HELLP syndrome is connected with some factors responsible for chronic hypertension. It seems that severe PE in early
pregnancy has a different etiology than other preeclampsia, or that there is a short path from the
moment when the factor begins to apply to the first
symptoms. What is more, for this short path to be
taken, the maturity of placenta is not necessary, so
severe PE and HELLP syndrome could develop in
the 18th and 22nd week of gestation.
If “maternal serum first-trimester PP13 appears to be a reasonable marker for risk assessment for preterm preeclampsia but a weak marker
for severe preeclampsia at term and for ineffective
for identifying mild preeclampsia at term” [21],
then our observation that severe and early (immature) PE is a “different disease” than other types
of PE is confirmed. That is why we should consider a change in the classification of preeclampsia. The presence of PP 13 and anti-angiogenic
growth factors both in pregnancies with PE without HELLP syndrome and in pregnancies with PE
and HELLP syndrome [5, 23] indicates that it is
PE and not HELLP syndrome which is the original disease. Our case does not confirm that. It
seems that here the original disease was preexisting hypertension.
No matter whether the hypertension in pregnancy was treated or not, severe PE and HELLP
syndrome occurred, and in the second pregnancy,
with no treatment until the 18th week, it occurred
4 weeks later. This would indicate that high blood
pressure is not per se an initializing factor for PE
and HELLP syndrome. A surge in blood pressure
and resistance to antihypertensive drugs confirm
the existence of a vasoconstrictive factor different from the factors responsible for the preexisting hypertension. In the first pregnancy, HELLP
syndrome occurred with a significant drop in the
platelet level but with a lower hemolysis and a less
radical increase in liver enzyme level, which contradicts the observation that high dosage of steroids raises platelet count [22] or improves platelet
count and reduces liver enzyme level [23]. It cannot
be excluded that different data results from different effects of corticosteroids on toll-like receptors
(TLRs) during infection [24]. In that case, nicotine
or nicotine analogues, are more likely to prevent
preeclampsia or surges in blood pressure [25, 26].
In our patient, PE and HELLP syndrome could
be a secondary criterion for APS, although causal relationship between PE and antiphospholipid
(aPL) antibodies in the absence of clinical symptoms of APS is not obvious [17, 27]. As antihypertensive drugs have no effect on placental production of soluble fms-like tyrosine kinase1 (sFIt-1)
and soluble endoglin from preeclamptic placenta
(sEng) [28], and in our patient high blood pressure
was resistant to drugs, which changed soon after
labor or fetal death, then hypertension considered
to be part of PE must be a different kind of hypertension than the preexisting hypertension.
Recurrent HELLP syndrome in early pregnancy is a form of severe and fulminant preeclampsia.
It is preceded by a surge in blood pressure a few
days earlier. The resistance to antihypertensive
drugs indicates the presence of other factors than
the factors responsible for preexisting hypertension. Different effect of corticosteroids on hemolysis and platelet count suggests different basis
for hemolysis and liver damage. That is why other drugs should be sought. Recurrent HELLP syndrome in immature pregnancies may constitute evidence for its causal relationship with APS or with
familial history of hypertension. The time of appearance of severe preeclampsia and HELLP syndrome in immature pregnancies confirms the correctness of the line of research aiming at finding
predictive markers for preeclampsia and HELLP
syndrome in the first trimester. Nicotine analogues or plant extractive from Eriosema kraussianum could be helpful in prevention or treatment
of PE in early pregnancies.
Recurrent HELLP Syndrome
757
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Address for correspondence:
Malgorzata Pawelec
First Clinic of Gynecology and Obstetrics
Wroclaw Medical University
Chałubińskiego 3
50-368 Wrocław
Poland
Tel.: +48 602 253 158
E-mail: [email protected]
Conflict of interest: None declared
Received: 20.06.2012
Revised: 19.09.2012
Accepted: 3.10.2013