Objective
We sought to evaluate whether clinical and laboratory variables differ between former patients who had HELLP syndrome and former patients who had preeclampsia (PE) without HELLP.
Study Design
We compared early-onset HELLP (n = 75) with early-onset PE (n = 40) with respect to clinical features during the hypertensive complication and to metabolic, hemodynamic, and hemostatic variables determined at least 6 months postpartum.
Results
HELLP differed from PE by a borderline higher frequency of eclampsia (13% vs 3%) during the complication, and by a lower prevalence of hypertension (19% vs 33%), proteinuria (2% vs 23%), thrombophilia (6% vs 27%), obesity (9% vs 33%), hypertriglyceridemia (1% vs 15%), hyperglycemia (0% vs 11%), and elevated levels of fasting homocysteine (6% vs 21%) at least 6 months postpartum.
Conclusion
Women with HELLP had fewer signs of abnormalities consistent with the metabolic syndrome and a 4-fold lower prevalence of thrombophilia as compared with PE women without HELLP.
Although preeclampsia (PE) and the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) are considered different clinical entities, the 2 syndromes are strongly related. In both (early-onset) syndromes, abnormal placental growth and development are thought to contribute to the initiation of a cascade of events that eventually leads to the well-known clinical symptoms of either. Together with the overlapping symptoms this has led to a comparable clinical management of both syndromes, consisting of symptomatic treatment followed by timely termination of pregnancy.
However, dissimilarities between PE and HELLP have also emerged. A recent study showed that the molecular signature of the placenta in early-onset HELLP differs from that in early-onset PE. Moreover, certain maternal features known as risk factors for PE, such as obesity, have not been associated with the HELLP syndrome. These observations provide support for the view that disentanglement of both syndromes may contribute to improvements in the current clinical management. Particularly in the perspective of the increased risk of recurrent disease in a next pregnancy, in which the main objective is to reduce risk factors before conception, the identification of possible differences in risk profile between PE and HELLP seems meaningful. Therefore, our objective was to evaluate clinical dissimilarities between the HELLP syndrome and PE without HELLP. To this end, we compared pregnancy outcome and the frequency of underlying disorders that had been assessed at least 6 months postpartum, between women who had their pregnancy complicated by HELLP and those whose pregnancy had been complicated by PE without HELLP.
Materials and Methods
We reviewed the medical records of women with early-onset HELLP syndrome and those of women with early-onset PE without any signs of the HELLP syndrome, who were admitted to Maastricht University Medical Center, The Netherlands (between March 1, 1996, and December 31, 2007), and who had been offered a set of tests to identify underlying disorders or abnormalities at least 6 months postpartum. All measurements reported in this prospective observational study were obtained as part of the usual care provided to high-risk obstetric patients in our tertiary referral center. We anonymized all data prior to statistical analysis. Women with twin pregnancies were excluded from the analysis. We only included women with early-onset disease, defined as diagnosis ≤34 weeks and delivery ≤37 weeks.
We applied the following diagnostic criteria for the HELLP syndrome: platelet count ≤100 × 10 9 /L, elevated liver enzymes (serum alanine aminotransferase >70 U/L and/or serum aspartate aminotransferase >70 U/L), and hemolysis characterized by serum lactic dehydrogenase level >600 U/L. PE was defined as de novo proteinuria (>300 mg/24 hours or >30 mg/mmol creatinine) in a pregnant patient with de novo hypertension (>140/90 mm Hg). Chronic hypertension was defined as hypertension already present before pregnancy, diagnosed <20th week of gestation or not resolving within 6 months postpartum. We used new-onset proteinuria as a diagnostic criterion for PE in these women. Epileptic seizures in women without history of epilepsy were considered to be eclamptic fits. All women who developed eclampsia received magnesium sulfate after their seizure to prevent recurrence. An infant was considered small for gestational age when birthweight was below the 10th percentile according to the most recent Dutch birthweight reference curves. Perinatal mortality was defined as infant mortality within 28 days after birth.
We determined the following metabolic variables between 6 and 10 months postpartum: circulating levels of fasting glucose, glycated hemoglobin (HbA1 C ), insulin, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides. We used the criteria stated by the National Cholesterol Education Program to define abnormalities related to the metabolic syndrome: fasting plasma glucose ≥ 5.6 mmol/L (101 mg/dL), high-density lipoprotein cholesterol ≤1.29 mmol/L (49.88 mg/dL), and triglycerides ≥1.7 mmol/L (150.6 mg/dL). Hypercholesterolemia was defined as total cholesterol >6.4 mmol/L (247.5 mg/dL) and increased low-density lipoprotein cholesterol was defined as a level ≥4.5 mmol/L (174.0 mg/dL) according to the laboratory reference values. We considered women hyperinsulinemic when fasting insulin exceeded 10 mmol/L. We defined obesity as a body mass index ≥30 kg/m 2 . Furthermore, we determined total protein excretion in a 24-hour urine collection and creatinine clearance (corrected for body surface area) was estimated by the ratio of urinary creatinine concentration to that in peripheral blood.
Echocardiography was performed in the semi-left lateral position by using a cross-sectional phased-array Doppler system (Agilent Sonos 5500; Philips Medical System, Eindhoven, The Netherlands). Aortic flow was measured across the aortic valves from an apical approach. The average area under the aortic velocity curve (aortic velocity integral) of 5 consecutive ejections was used to calculate stroke volume and cardiac output. Aortic valve diameter, necessary for the calculation of the aortic area, was measured offline at the orifice during systole using M-mode. Total peripheral vascular resistance was calculated by dividing mean arterial pressure by cardiac output. We obtained blood pressure and heart rate as the median of 11 measurements recorded at 3-minutes intervals under standardized conditions using a semiautomatic oscillometric device (Dinamap vital signs monitor 1846; Critikon, Tampa, FL). An estimate for global arterial compliance (mL/mm Hg) was obtained by dividing stroke volume by pulse pressure (systolic minus diastolic blood pressure).
Within the scope of the thrombophilic screening, all women were tested for cardiolipin antibodies (IgG/IgM >10 GPL [IgG per liter]/MPL [IgM per liter]) and lupus anticoagulant in peripheral blood, as detailed previously. We assessed the circulating level of fasting homocysteine and considered it elevated when the level exceeded 15 mmol/L. The factor V Leiden and prothrombin 20210A mutations were analyzed by routine polymerase chain reaction techniques after extraction of genomic DNA from peripheral leukocytes. Activity of antithrombin (Chromogenix, Mölndal, Sweden) and protein C (Behring, Marburg, Germany) was measured by chromogenic substrate assays, and protein S antigen levels by enzyme-linked immunosorbent assay (Dako, Glostrup, Denmark). We defined deficiency of each of these parameters as an activity level below 65% of normal.
In both subgroups, the type of management during pregnancy consisted of symptomatic treatment, stabilization of the maternal condition, and eventually pregnancy termination when the risks of pregnancy continuation outweighed the benefits for either mother or fetus. As part of the screening protocol, the participants discontinued breastfeeding and the use of oral contraceptives and antihypertensive medication at least 2 weeks prior to the measurements. We used SPSS, version 15.0 (SPSS, Chicago, IL) for statistical analysis. Data distribution was evaluated visually using histograms. Continuous variables were analyzed using independent samples t test and Mann-Whitney U test, and dichotomous variables using χ 2 and Fisher’s exact tests. A P value < .05 was considered statistically significant.
Results
In the postpartum screening database, we identified 40 former PE and 75 former HELLP patients with complete hospital records. The majority of HELLP patients also had hypertension and proteinuria (n = 70). Thirty-seven HELLP patients had class 1 and 38 class 2 HELLP syndrome. All women were white.
Table 1 lists clinical and obstetric characteristics of the women and their infants in the 2 patient groups. The groups were comparable with respect to maternal age, parity, family history of chronic hypertension, the proportion of women with delivery within 48 hours after diagnosis, gestational age at birth, infants’ birthweight, and intrauterine mortality. The prevalence of eclampsia, however, tended to be higher in women with the HELLP syndrome (13% vs 3%; P = .06).
| Characteristic | HELLP (n = 75) | PE without HELLP (n = 40) | P |
|---|---|---|---|
| Maternal age, y a | 29.8 ± 4.7 | 29.8 ± 4.7 | .97 |
| Family history (first degree) positive for: | |||
| PE/HELLP | 15 (20%) | 14 (35%) | .09 |
| Chronic hypertension | 44 (59%) | 23 (58%) | .71 |
| Multiparous, % | 8 (11%) | 8 (20%) | .17 |
| Interval between diagnosis and delivery ≤48 h | 6 (10%) | 4 (12%) | .73 |
| Eclampsia | 10 (13%) | 1 (3%) | .06 |
| Infant birthweight, g | 1150 (880–1545) | 1280 (810–2100) | .33 |
| Gestational age at birth, wk | 30.1 ± 2.6 | 30.2 ± 2.7 | .83 |
| IUFD | 7 (9%) | 5 (13%) | .59 |
| SGA infant (<10th percentile) | 15 (22%) | 13 (33%) | .19 |
| Extremely preterm birth (<32 wk) | 60 (81%) | 29 (74%) | .41 |
| Perinatal mortality | 7 (10%) | 1 (3%) | .17 |
| Interval between delivery and measurements, mo | 7.4 (6.0–9.6) | 7.0 (6.2–10.4) | .85 |
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