Małgorzata Pawelec
1, A, B, D, F, Andrzej Karmowski
1, C, E, F, Mikołaj Karmowski
1, C, E,
Joanna Krzemieniewska
1, A, B, E, F, Aleksandra Kulczycka
1, C, E,
Marian Stanisław Gabryś
1, C, E, F, Jerzy Koryś
2, B, Bohdan Gworys
3, BInability 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
1 First Clinic of Obstetrics and Gynecology, Wroclaw Medical University, Poland 2 Non-Public Health Service Institution, Legnickie Pole, Poland
3 Department of Anatomy, Wroclaw Medical University, Poland
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 prze-biegających ze stanem przedrzucawkowym, a następnie z zespołem HELLP, które wydają się świadczyć o występo-waniu 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 znalezie-nie sposobu na przedłużeznalezie-nie czasu do rozwiązania ciąży (uzyskania szansy na przeżycie wcześniaków), analizu-jąc piśmiennictwo. Nawracaanalizu-jący zespół HELLP we wczesnej ciąży jest formą ciężkiej, piorunuanalizu-jącej 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
Adv Clin Exp Med 2013, 22, 5, 753–758 ISSN 1899–5276
REVIEWS
HELLP syndrome (hemolysis, elevated liver enzymes and low platelets) is a set of symptoms ex-pressing multiorgan damage in pregnancies com-plicated 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 pregnan-cy and with chronic hypertension [2]. About 15% of cases of HELLP syndrome were recognized be-fore 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 syn-drome. The only case, which we described, was of a HELLP syndrome in the 24th week of the second pregnancy, when the first pregnancy was compli-cated by gestational hypertension [3]. Preeclamp-sia affects about 5% of pregnancies [4]. The etiolo-gy 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 lead-ing 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 en-dothelial growth factor) receptor-1 sFlt-1 (solu-ble fms-like tyrosine kinase 1), solu(solu-ble 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 sen-sitivity of vessels to angiotensin II changes, and the formation of vasodilatators (nitric oxide and pros-tacyclin and endothelium-derived hyperpolarizing factor) decreases [4–12]. The endothelial dysfunc-tion results in the clinical symptoms of hyperten-sion, 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 ef-fects 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 hyper-tension and multiorgan disfunction is the reduc-tion 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 endothe-lium and vascular smooth muscle. As the final result, vascular resistance and arterial pressure increase [9].
The reduction in the flow to the placenta lead-ing to placental ischemia may be caused by com-pression 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 cyto-trophoblast invasion of the uterine spiral arteries [9, 14, 15]. Also, placental substances may increase the release of contracting factors, such as endothe-lin, 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 treat-ment to counter the effects of one condition is like-ly to aggravate those of the other” [13].
If preeclampsia is connected with deep placen-tation, then the fact that there are different types of this defect may explain why there are different de-grees of the gravity of preeclampsia [15]. If, howev-er, augmented contraction, exaggerated vasomo-tion, and selective ablation of induced relaxation in laboratory tests on omental arteries from preec-lamptic women are confirmed in vivo, we are still not able to explain why this “uniquely human dis-order” [16] appears in the same woman in ent weeks of consecutive pregnancies and in differ-ent degree [3, 17].
If, in turn, it is the excessive circulation of sFlt1 that contributes to the pathogenesis of preeclamp-sia, 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 hyper-tention, while in others to preeclampsia, and, final-ly, 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 inabil-ity 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 ki-nase-1 type receptors) in pregnant rats displayed various phenotypes of preecclampsia [4, 18]. Also,
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).
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 vaso-dilatory properties [19]. Treatment using sildenafil citrate or Kraussianone-2 improved placental per-fusion 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 multior-gan damage in the mother with the consequenc-es of PE for the fetus. It is particularly relevant for HELLP syndrome in immature pregnancy to prolong gestation. As using first-trimester mater-nal serum PP13 (placental protein 13) as a marker for risk assessment has different reliability in pre-term preeclampsia and a different, weaker, one in severe preeclampsia at term [21], it seems that pre-eclampsia is a cover term for more than one type of illness. The case described here is interesting be-cause it is the case of gestational disease, which is both recurrent and appearing so early in the preg-nancy. Does this mean that as a result of failure in two pregnancies the patient, over 40, lost all chanc-es for having children?Ischemic placenta has been shown to produce excessive amounts of sFlt1 into maternal circulation [18].
Given the multifactorial nature of preeclamp-sia 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 pregnan-cy) can in effect lead to reduction in the number of complications leading to perinatal mortality and morbidity [19].
The recurrent HELLP syndrome can be illus-trated with by the following events.
A woman with chronic hypertension be-came pregnant for the first time at the age of 42, and again at the age of 45. She had no preexist-ing proteinuria. Before and between pregnancies she received beta blocker and angiotensin con-vertase inhibitor. In the 6th week of her first preg-nancy, 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 nancy and in the 22nd week of the second preg-nancy, 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 protei-nuria (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
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. Morpho-logically both fetuses were normal. In both preg-nancies 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 respec-tively), 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 lab-oratory 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, pos-itive results of D-dimer (10 times more than nor-mal threshold), APTT: 31.5 s and 32.3 s. Mean sys-tolic 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 anti-bodies (their level met the laboratory criteria for APS). In both pregnancies, the patient had an in-fection of the urinary tract and vagina. She nev-er had bactnev-eriological culture identification. In the first pregnancy, high dosage corticosteroid thera-py (>24 mg/day) was applied. In spite of this, af-ter 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. Liv-er enzymes rose slightly: AST to 128 U/L and ALT to 84 U/L; total bilirubin rose to 30.78 µmol/L, D-dimer rose by 10%.
Only during the preparation for pregnancy termination, the mother received platelet concen-trate, frozen plasma and erythrocytes. 3 days later the number of platelets grew to 190 × 109/L, with no further treatment. A positive reaction to anti-hypertensive drugs occurred with a few hours af-ter the af-termination of pregnancy.
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 ma-ternal grandfather had a stroke. The patient her-self 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 fol-lows PE. In this case, PE and HELLP syndrome occurred simultaneously. As 5 days before, there were no clinical symptoms of PE and HELLP syn-drome, the histopathological changes found in pla-centa a few days later indicate that it was not on-ly severe, but also a fulminant form of PE. In this case PE and HELLP syndrome appeared simulta-neously, and in two consecutive pregnancies, so it cannot be excluded that HELLP syndrome is con-nected with some factors responsible for chron-ic hypertension. It seems that severe PE in early pregnancy has a different etiology than other pre-eclampsia, 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 ap-pears to be a reasonable marker for risk assess-ment 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 (imma-ture) PE is a “different disease” than other types of PE is confirmed. That is why we should con-sider a change in the classification of preeclamp-sia. The presence of PP 13 and anti-angiogenic growth factors both in pregnancies with PE with-out HELLP syndrome and in pregnancies with PE and HELLP syndrome [5, 23] indicates that it is PE and not HELLP syndrome which is the orig-inal disease. Our case does not confirm that. It seems that here the original disease was preexist-ing hypertension.
No matter whether the hypertension in preg-nancy 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 differ-ent from the factors responsible for the preexist-ing 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 con-tradicts the observation that high dosage of ste-roids raises platelet count [22] or improves platelet count and reduces liver enzyme level [23]. It cannot be excluded that different data results from differ-ent 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 caus-al relationship between PE and antiphospholipid (aPL) antibodies in the absence of clinical symp-toms of APS is not obvious [17, 27]. As antihyper-tensive drugs have no effect on placental produc-tion 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 hyper-tension than the preexisting hyperhyper-tension.
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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
