Research Article Pregnancy Associated · pregnancy associated microangiopathies was 36.9 per 10000 in the 3 years studied (table 1) with monthly cumulative incidence showing two peaks;

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Cite this article: Mostafa FG, Ihab FS, Hassan AB, Wael S, Maha AS (2014) Pregnancy Associated Thrombotic Microangiopathies Overlap Syndrome: 3 Years Experience at a Tertiary Hospital. Med J Obstet Gynecol 2(1): 1034.

*Corresponding authorsMostafa Fouad Gomaa, Department of Obstetrics and Gynecology, AIN Shams University Cario, Egypt, Tel: 01226188993; Email:

Submitted: 15 July 2014

Accepted: 07 August 2014

Published: 09 August 2014

ISSN: 2333-6439

Copyright© 2014 Mostafa et al.

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Research Article

Pregnancy Associated Thrombotic Microangiopathies Overlap Syndrome: 3 Years Experience at a Tertiary HospitalMostafa FG*, Ihab FS, Hassan AB, Wael S and Maha ASDepetment of Obstetrics and Gynecology, AIN Shams university Cairo, Egypt

Keywords•Thrombotic microangiopathies•AFLP•HELLP syndrome•TTP•HUS

Abstract

Objective: To study the incidence of thrombotic microangiopathies during late pregnancy at a tertiary hospital in Egypt, the frequency of its different etiologies as well as to evaluate the strategy used in management of such cases.

Study design: The study was a retrospective hospital record based study carried at Ain Shams University maternity hospital between the years 2008 and 2010. Numerical data were presented as mean ± SD and categorical data were presented by percentage. Chi square test, ANOVA and Kruskal-wallis tests were used for comparison. In all circumstances P value is considered significant when < 0.05.

Results: We found that the incidence of cases with suspected thrombotic microangiopathies during late pregnancy was 36.9 per 10000 with 2 peaks a broad one over summer and a smaller one over early winter months. 49% were diagnosed as HELLP syndrome, 21% as TTP, in 9 cases no definitive diagnosis could be reached (10.8%), 2 cases as AFLP and only one case as HUS. 12 cases died (14.4%) in spite of being managed according to the widely accepted obstetric recommendations.

Conclusion: Thrombotic microangiopathies during pregnancy can hardly be differentiated from case of HELLP$, AFLP and ICP. These disorders should be considered a continuum and a spectrum of a single disorder. Early termination of pregnancy with the start of plasma exchange, pulsed steroid therapy and plasmapharesis can result in marked reduction of maternal mortality in such cases.

ABBREVIATIONSTTP: Thrombotic Thrombocytopenic Purpura; HELLP$:

Hemolysis Elevated Liver Enzymes Low Platelet Syndrome; AFLP: Acute Fatty Liver Syndrome; HUS: Hemolytic Uremic Syndrome

INTRODUCTIONThrombotic microangiopathies presenting during late

pregnancy at our obstetric emergency department represent a devastating problem with potentially fatal maternal and neonatal outcome. Thrombotic microangiopathies which include Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic Uremic Syndrome (HUS) can be imitated by some pregnancy peculiar diseases as Acute Fatty Liver of Pregnancy (AFLP), Preeclampsia (PET) and HELLP haemolysis elevated liver enzymes and low blood platelet count syndrome [1].

Unfortunately, in spite that each disease has its specific characteristics, but their clinical characters are so closely related that we can hardly differentiate between them especially during late presentation [1,2].

In all of the above conditions, during late presentation, there is evidence of haemolysis, DIC, elevated amino transferases, impaired renal functions and disturbed level of consciousness [2].

Not only pregnancy acts as the causative agent of PET, HELLP$ and AFLP but also it acts as a precipitating event for acute episodes of TTP and HUS because of the association of pregnancy with increased procoagulant factors concentration, increased ADAMTS 13 activity, decreased fibrinolytic activity and loss of endothelial thrombomodulin effect. These changes reach their maximum at delivery and immediately postpartum [3]. In


Mostafa et al. (2014)Email:

Med J Obstet Gynecol 2(1): 1034 (2014) 2/8

Files

Files recruited 98

15 executed due to misting data

83 analyzed

41HELLP $ 18 TTP 7 ICP 3 HAV 2 AFL P

1 HUS 9 undiagnosed 1 focal hepatic lesion

1Biliary obstruction

Figure 1 Flow chart representing the analyzed.

some series, 10% of TTP cases occur in pregnant women during pregnancy or postpartum [4].

Whereas termination of pregnancy is the definitive treatment of HELLP$ and AFLP, it does not affect the course of TTP-HUS and in the absence of plasma exchange they are almost fatal. Early recognition and prompt initiation of plasma exchange may result in marked reduction of maternal mortality [2,5].

With this diagnostic dilemma and the high mortality rates of such diseases, our objective was to report on the incidence of such spectrum of disease and evaluate our strategy in the management of such cases.

Study objectives

To study the incidence of pregnancy associated microangiopathies at a tertiary centre in Egypt.

To assess the strategy used in the management of such cases in our tertiary centre.

MATERIALS AND METHODSThis study is a hospital record based retrospective study

in which we revised the files of patients admitted with the provisional diagnosis of HELLP$, AFLP, TTP and HUS from January 2007 to January 2010. The files included in the study were only those of patients more than 20 weeks of gestation and with no history of liver disease.

Data recruited from the files included patient age, parity,

mode of delivery, maternal mortality and morbidity, neonatal outcome, final diagnosis and management plan.

The study was approved by the local research committee of Ain Shams university maternity hospital.

Statistics

Numerical data were presented as mean ± SD and categorical data were presented by percentage. Chi suare test , ANOVA and Kruskal-wallis tests were used for comparison. In all circumstances P value is considered significant when < 0.05.

RESULTS AND DISCUSSION

Results

This study was a retrospective record based study that included 98 files from the year 2007 to the year 2010. 15 files were excluded due to missing data and lack of registration sufficiency. We found that the incidence of suspected cases of pregnancy associated microangiopathies was 36.9 per 10000 in the 3 years studied (table 1) with monthly cumulative incidence showing two peaks; a broader one over summer months and another narrow and smaller one over early winter months (table 2).

The mean age of the studied cases was 26 years, with 67.5% being multiparous and only 32.5% were nulliparous. The average duration of hospital stay was one week. The frequency of different etiologies of suspected cases of pregnancy associated microangiopathies is shown in tables 3 and 4 with the most




Year FrequencyTotal year admission Incidence (per ten thousand)

No %2007 12 14.5 10727 11.22008 31 37.3 4263 72.72009 40 48.2 7508 53.3Total 83 100.0 22498 36.9

Table 1: Frequency and incidence of cases with suspected pregnancy associated thrombotic microangiopathies in late pregnancy among pregnant females admitted > 20 weeks.

N Cumulative monthly admission Cumulative Incidence (per ten thousand)

January 5 2334 21.4

February 6 1948 30.8

March 2 1777 11.3

April 3 2189 13.7

May 8 2105 38.0

June 10 1907 52.4

July 10 2301 43.5

August 18 2329 77.3

September 4 2002 20.0

October 5 1325 37.7

November 5 1054 47.4

December 7 1227 57.0

Total 83 22498 36.9

Table 2: Monthly cumulative incidence over 2007-2009.

2007(10727)

2008(4263)

2009(7508)

Total(22498)

HELLP syndromeFrequency 7 (58.3%) 17 (54.8%) 17(42.5%) 41

'Incidence 6.5 39.9 22.6 18.2

TTPFrequency 4 (33.3%) 4 (12.9%) 10(25.0%) 18

Incidence 3.7 9.4 13.3 8.0

ICPFrequency 0 (0.0%) 3 (9.7%) 4 (10.0%) 7

Incidence 0.0 7.0 5.3 3.1

HAVFrequency 0 (0.0%) 2 (6.5%) 1 (2.5%) 3

Incidence 0.0 4.7 1.3 1.3

AFLPFrequency 0 (0.0%) 1 (3.2%) 1 (2.5%) 2

Incidence 0.0 2.3 1.3 0.9

HUSFrequency 0 (0.0%) 0 (0.0%) 1 (2.5%) 1

Incidence 0.0 0.0 1.3 0.45

Undiagnosed casesFrequency 1 (8.3%) 3 (9.7%) 5 (12.5%) 9

Incidence 0.9 7.0 6.7 4.0

Focal hepatic lesionFrequency 0 (0.0%) 1 (3.2%) 0 (0.0%) 1

Incidence 0.0 2.3 0.0 0.45

Biliary obstructionFrequency 0 (0.0%) 0 (0.0%) 1 (2.5%) 1

Incidence 0.0 0.0 1.3 0.45

Total 12 31 40 83

Table 3: Frequency and incidence of different etiologies of pregnancy associated microangiopathies in late pregnancy among pregnant females admitted > 20 week/year.

* Incidence (Per ten thousands)




N %

Haemolysis, Low platelet, Elevated liver enzymes (HELLP) syndrome 41 49.4

Thrombotic Thrombocytopenic purpura (TTP) 18 21.7

Intrahepatic Cholestasis with Pregnancy (ICP) 7 8.4

Hepatitis A Virus (HAV) 3 3.6

Acute Fatty Liver with Pregnancy (AFLP) 2 2.4

Heamolytic Uremic Syndrome (HUS) 1 1.2

Undiagnosed cases 9 10.8

Focal hepatic lesion 1 1.2

Biliary obstruction 1 1.2

Total 83 100.0

Table 4: Frequency of different etiologies of acute liver disorder in late pregnancy cases among pregnant females admitted > 20 weeks.

HELLP syndrome (N=41) TTP (N=18) Undiagnosed (N=9) F/X

2 P

TLC 14.3 ± 3.2 14.3 ± 3.8 12.0 ± 2.6 1.920 0.155

HB 10.2 ± 1..2 9.311.7 10.0+1.2 2.654 0.078

PLT 88.7±22.9 65.7131.7 122.7±41.5 12.358 <0.001*

PT 14.0 ± 4.3 13.8±2.3 15.616.3 0.599 0.552

PIT 40.4±9.5 43.0±4.9 42.2 ± 11.5 0.622 0.540

ALT 120.0 (55.0-211.0) 53.0 (23.0-84.0) 81.0 (46.5-105.0) 11.948 0.003*

AST 99.0 (49.5-185.0) 56.0 (15.8-92.0) 85.0 (45.0-145.5) 8.234 0.016*

Total Billirubin 5.0 (1.9-12.0) 2.3 (1.0-4.7) 9.9 (5.0-14.3) 11.169 0.004*

Direct Billirubin 1.8(0.9-5.5) 1 .6 (0.6-3.0) 7.7 (2.4-9.7) 8.558 0.014*

Indirect Billirubin 2.0(1.0-4.1) 0.8(0.4-1.6) 2.0(1.2-3.9) 9.770 0.008*

Serum Creatinine 1.2(0.9-1.5) 1.0(0.9-1.2) 1.5(1.0-2.4) 1 .764 .0.414

SBP (mmHg) 164.4±17.0 124.4±17.6 127.8±21.1 39.20 <0.001*

DBP (mmHg) 103.9±10.2 82.8±12.3 80.0±11.2 33.446 <0.001*

Table 5: Comparison between HELLP syndrome, TTP and undiagnosed cases as regards Laboratory findings.

X2: Kruskal Wallis test, F: ANOVA test, * Significant The above table shows that thrombocytopenia was more significant in cases of HELLP syndrome and rarely found in undiagnosed cases; Total Bilirubin, Direct Bilirubin, and Indirect Bilirubin were significantly higher in undiagnosed cases followed by HELLP syndrome and was least in TTP. ALT and AST were significantly higher in HELLP syndrome followed by undiagnosed cases and least in TTP. SBP and DBP were significantly higher in HELLP syndrome than TTP and Undiagnosed cases.

frequent diagnosis being HELLP syndrome (49%). Table 5 shows a comparison between the 3 most commonly diagnosed cases HELLP syndrome, TTP and the undiagnosed cases as regards different laboratory findings and blood pressure values at time of diagnosis. In table 6 we describe adjuvant therapies used together with termination of pregnancy during management of the cases.

Tables 7 and 8 show the different maternal and neonatal complications and their frequencies among the 3 different etiologies. Unfortunately 12 of our cases died, 6 of them were diagnosed as HELLP syndrome, 2 of them were diagnosed as TTP and 4 cases were undiagnosed.

Discussion

As an obstetrician the first diagnosis to jump in mind for a patient presenting with evidence of haemolysis, DIC, elevated liver enzymes and renal impairment is HELLP$ which actually might not be the case. The distinction of HELLP$, AFLP and in our

opinion late cases of ICP (Intrahepatic cholestasis of pregnancy) from cases with TTP and HUS may not be possible in some cases. This retrospective study was conducted over a 3 years period to determine the incidence of pregnancy associated thrombotic microangiopathies at Ain Shams university maternity hospital. The calculated incidence of pregnancy associated microangiopathies in our study was found to be 36.9 per 10,000 pregnancies. In the study we found that the incidence of thrombotic microangiopathies during pregnancy had 2 peaks, a broad one over summer months and another narrower and smaller one over the early winter months. In the study the most frequent diagnosis was HELLP syndrome (49.9%) followed by TTP (21.7%) and then the undiagnosed cases (cases which we could not reach a final diagnosis) which represented 10.8%. The incidence of HELLP syndrome in the study was 18.2 per 10000 with a mean age of 33.8 +/- 4.7 years at the time of presentation which was in agreement with what Cappell 2008 reported in his study [6]. The incidence of TTP in the study was 8 per 10000 which was consistent with what Terrell et al 2005 reported [7],




HELLP syndrome (N=41) TTP (N=18) Undiagnosed (N=9) x2 P

Fresh blood transfusion 7 (17.1%) 4 (22.2%) 2 (22.2%) 0.279 0.870

FFP transfusion 6 (14.6%) 3 (16.7%) 2 (22.2%) 0.318 0.853

Platelet transfusion 0 (0.0%) 2(11.1%) 0 (0.0%) 5.724 0.057

Plasma-pharesis 0 (0.0%) 3 (16.6%) 1 (2.4%) 4.000 0.046

Hemo-dialysis 1(2.4%) 3(16.6%) 0(0.0%) 4.000 0.046

Pulsed steroid therapy 0(0.0%) 5(27%) 4(44.4%) 4.000 0.083

Icu admission 12(29.2%) 5(27.7%) 4(44.4%) 5.5 0.056

Table 6: Comparison between HELLP syndrome, TTP and Undiagnosed cases as regards various lines of treatment.

X2: Chi square test * insignificantThe above table shows that while the difference was statistically non-significant, but platelets transfusion and Plasmapheresis were more frequently required in TTP than HELLP syndrome and undiagnosed cases.

HELLP syndrome(N=41) TTP (N=18) Undiagnosed (N=9) x2 P

IUFD 6 (14.6%) 3(16.7%) 0 (0.0%) 1.627 0.443

IUGR 1 (2.4%) 2(11.1%) 0 (0.0%) 2.709 0.258

Still birth 2 (4.9%) 0 (0.0%) 0 (0.0%) 1.357 0.507

PT Labor 22 (53.7%) 4 (22.2%) 2 (22.2%) 6.642 0.036*

LBW 5(12.2%) 0 (0.0%) 0 (0.0%) 3.554 0.169

RD 4 (9.8%) 0 (0.0%) 0 (0.0%) 2.799 0.247

NICU 22 (53.7%) 5 (27.8%) 3 (33.3%) 3.888 0.143

Table 7: Comparison between undiagnosed cases HELLP syndrome, TTP and complications as regards neonatal outcome.

X2: Chi square test *SignificantThe above table shows that both preterm labor and NICU admission most frequently occurred in HELLP syndrome than TTP and Undiagnosed cases. Although stillbirth occurred in two cases of HELLP syndrome (4.9%), low birth weight occurred in five cases HELLP syndrome (12.2%)and respiratory distress occurred in four cases HELLP syndrome (9.8%) but all didn’t complicate any cases of TTP and Undiagnosed cases, IUFD most frequently occurred in TTP and HELLP syndrome but didn’t complicate any of the undiagnosed cases.

HELLP syndrome(N=41) TTP (N=18) Undiagnosed (N=9) x2 P

Eclampsia 3 (7.3%) 0 (0.0%) 0 (0.0%) 2.067 0.356

Abruptio placenta 3 (7.3%) 0 (0.0%) 0 (0.0%) 2.067 0.356

Renal failure 1 (2.4%) 3 (16.7%) 1 (11.1%) 3.932 0.140

Heamolytic crisis 1 (2.4%) 0 (0.0%) 0 (0.0%) 0.668 0.716

Death 6 (14.6%) 2(11.1%) 4 (44.4%) 0.176 0.916

Postpartum hemorrhage 6(14.6%) 4(22.2%) 2(22.2%) 0.296 0.812

Table 8: Comparison between HELLP syndrome, TTP and Undiagnosed cases as regards maternal complications.

X : Chi square test * SignificantThe above table shows that although the difference was insignificant but both eclampsia and abruptio placenta occurred in three cases of HELLP syndrome (7.3% of cases), but didn’t complicate any of the TTP or the Undiagnosed cases. Hemolytic crisis occurred only in one case of HELLP syndrome but didn’t complicate any of the TTP or the undiagnosed cases and unfortunately 12 of our cases died.

however the mean age of our patients at time of presentation was 25 +/- 4.3 years and that was in contrast to the same author who reported a mean age of 40 years at time of presentation.

The risks of pregnancy in thrombotic microangiopathies presenting in late pregnancy are real and involve both the mother and the fetus. Perinatal mortality and morbidity are considerably higher in HELLP syndrome than maternal mortality and morbidity, and are primarily dependent on the gestational age when the condition develops [8,9]. In our study there were 3 cases (3.6%) complicated by eclampsia, 3 cases (3.6%) complicated by accidental hemorrhage, 6 cases (7.2%)

complicated by renal failure and only one case (1.2%) complicated by hemolytic crisis. Eclampsia and accidental hemorrhage complicated cases of HELLP syndrome but didn’t complicate any of the other cases. This means that pregnant patients with HELLP syndrome had a greater risk of maternal complications than other cases. Our study showed that maternal death occurred in 12 cases (14.4%), 6 (7.2%) of them were HELLP syndrome, 2 cases (2.4%) were TTP, 4 cases (4.8%) were undiagnosed cases. In a large retrospective cohort study comprising 442 pregnancies complicated by the HELLP syndrome, the maternal mortality was 1.1 % [9]. However, higher maternal mortality up to 25% has




been reported [8]. From the above results it is clear that 4 (4.8%) of our cases died without even reaching a final diagnosis which represents a real trouble.

Regarding perinatal mortality and morbidity, IUFD complicated 10 cases (12.0%), 6 of them (7.2%) complicated HELLP syndrome, 3 cases (3.6%) complicated TTP and only one case complicated Hemolytic Uremic Syndrome(HUS). This is in agreement with the study of Cul et al. 2005 who reported that the perinatal mortality related to HELLP syndrome was between 7.4% and 34% [10].

In our study we also found that 28 cases (33.7%) were complicated by pre-term labor. 22 cases (26.5%) complicated HELLP syndrome, 4 cases (4.8%) complicated TTP and only 2 cases (2.4%) complicated the undiagnosed cases. Regarding NICU admission, 30 cases (36%) were admitted to the NICU, 22 of them (26.5%) complicated HELLP syndrome, 5 of them (6%) complicated TTP and the last 3cases (3.6%) complicated the undiagnosed cases. This means that HELLP syndrome has the highest perinatal morbidity and mortality rates among all cases.

Regarding the management of those cases, we found that termination of pregnancy after trial of correction of maternal general condition was done for all cases. 50 cases (60.2%) ended by caesarian section and the remaining 33 cases (39.8%) ended by successful vaginal delivery with cases of HELLP syndrome having the highest incidence of caesarian deliveries (26 cases i.e. 31%). Postpartum hemorrhage complicated 12 cases (14.4%). 6 (7.2%) of them complicated HELLP syndrome, 4 cases (4.8%) complicated TTP and the remaining 2 cases complicated the undiagnosed cases.

Fresh blood transfusion was needed in 13 cases (15.6%), fresh frozen plasma transfusion was needed in 11 cases (13.2%) and platelet transfusion was needed in 2 cases of the TTP cases (2.4%).

Pulsed steroid therapy was used in 9 cases (10.8%) of the cases, 5 of them were TTP and 4 of them were from the undiagnosed cases after hematological consultation. Hemodialysis was needed in one case of the HELLP syndrome and 3 cases of the TTP cases. Intensive care unit admission was needed in 21 cases (25.3%), 12 of them were HELLP syndrome, 5 were TTP and the last 4 cases were of the undiagnosed cases. To the best of our knowledge till the time of writing this paper no data in the literature were found to be compared with our results.

Comment

After revising the data collected we feel that there was no justification for the diagnosis of most of the cases as there was no definitive test for any of the diseases except for the eclamptic fits in some of the cases of the HELLP syndrome. Moreover in 9 cases (10.8%) of our cases we could not reach a final diagnosis and unfortunately almost half of them died.

The study raised some questions:

First, were all the cases diagnosed as HELLP syndrome really HELLP syndrome?

Second, what might be the diagnosis of the undiagnosed cases?

Third, could we save some of the lives lost if we considered other diagnoses and used other lines of treatment as pulsed steroid therapy or plasmapharesis?

We came to a conclusion that the name of the diagnosis does not matter but the important issue is whether improvement or deterioration following termination of pregnancy occurs.

We propose to introduce the term thrombotic microangiopathy overlap syndrome during pregnancy in the literature to describe this spectrum of diseases.

Since the date of the end of this study we began in our institute to change our policy in managing such cases. We constructed a team including an obstetrician, a hematologist, a nephrologist and an ICU specialist. We proposed a plan for management started by excluding acute viral hepatitis then termination of pregnancy after correction of the general condition and if no improvement of the general condition and laboratory abnormalities within 48 hours of termination, pulsed steroid therapy with or without plasmapharesis was started. We are now waiting to finish another 3 years with this policy to compare and publish our results.

Points of weakness and strength in the study:

A- Points of weakness:

1- The study is a retrospective study.

2- Insufficient data and poor registration in the files.

3- The data recruited represent only the magnitude of the problem in our hospital and this might not be representative to the real magnitude of the problem.

B- Points of strength:

1- The study highlights a clinically challenging situation of a thrombotic microangiopathy overlap syndrome in pregnancy.

2- The study forced our institute to adopt a policy for managing this case to avoid the high rates of maternal and perinatal mortality and morbidity related to these conditions.

CONCLUSIONThrombotic microangiopathies during pregnancy can hardly

be differentiated from case of HELLP$, AFLP and ICP. These disorders should be considered a continuum and a spectrum of a single disorder. Early termination of pregnancy with the start of plasma exchange, pulsed steroid therapy and plasmapharesis can result in marked reduction of maternal mortality in such cases.

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Mostafa FG, Ihab FS, Hassan AB, Wael S, Maha AS (2014) Pregnancy Associated Thrombotic Microangiopathies Overlap Syndrome: 3 Years Experience at a Tertiary Hospital. Med J Obstet Gynecol 2(1): 1034.

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Research Article Pregnancy Associated · pregnancy associated microangiopathies was 36.9 per 10000 in the 3 years studied (table 1) with monthly cumulative incidence showing two peaks;