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Pregnancy Hypertension: An International Journal of Womens Cardiovascular Health xxx (2017) xxxxxx

Contents lists available at ScienceDirect

Pregnancy Hypertension: An International Journal of


Womens Cardiovascular Health
journal homepage: www.elsevier.com/locate/preghy

Clinical and laboratory markers in the recovery from severe


preeclampsia
Reut Rotem a, Avital Bilitzky a,1, Tamar Abady Nezer a,b, Igal Plakht b, Adi Y. Weintraub a,
a
Department of Obstetrics and Gynecology, Faculty of Health Sciences, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer Sheva, Israel
b
Department of Nursing, Recanati School for Community Health Professions, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer Sheva, Israel

a r t i c l e i n f o a b s t r a c t

Article history: Objective: To examine the recovery from severe Preeclampsia toxemia (PET) in women treated with mag-
Received 6 November 2016 nesium sulfate (MgSO4) during the first 24 h postpartum as reflected by the changes in various clinical
Received in revised form 17 January 2017 and laboratory markers.
Accepted 4 March 2017
Study design: The study population included all women diagnosed with severe PET that gave birth at the
Available online xxxx
Soroka University Medical center between 2013 and 2014, and were treated with MgSO4 in the first 24 h
postpartum. Data were collected from the institutional computerized records. The different parameters
Keywords:
were examined in 6 h intervals and were compared using appropriate statistical tests.
Severe preeclampsia
Hypertension
Main outcomes measures: Change in various postpartum laboratory and clinical parameters.
Urinary output Results: During the study period there were 132 singleton deliveries with severe PET treated with a 24-
Proteinuria hours postpartum MgSO4 regimen. Most of the women were primigravida and delivered vaginally. Both
Magnesium sulfate mean systolic and mean diastolic blood pressure values have shown recovery to normal values after the
Postpartum first 6 h of treatment (P < 0.001). Urine output and proteinuria have demonstrated later recovery (after
12 h).
Conclusions: When assessing the natural recovery of severe PET features, the earliest parameter to
recover during the first 24 h postpartum is hypertension followed by urine output and the proteinuria.
Further larger studies are needed in order to confirm these results. Moreover, the use of these parameters
may allow using shorter MgSO4 treatment regimens for appropriate women showing earlier recovery and
facilitating quicker mother-baby bonding and emotional recovery.
2017 Published by Elsevier B.V. on behalf of International Society for the Study of Hypertension in
Pregnancy.

1. Introduction edema, cerebral or visual symptoms) and that even in the absence
of proteinuria [3]. The management of women diagnosed with PET
Preeclampsia toxemia (PET) is a multi-system disorder preva- depends on various factors including the presence of maternal end
lent among 38% of pregnancies worldwide [1]. It has the potential organ dysfunction, gestational age and signs of fetal distress [4,5].
to pose great risks for morbidity and mortality for both the mother The Guidelines of ACOG support prompt delivery after maternal
and the fetus [2]. According to the American College of Obstetri- stabilization for any woman with severe PET past 34 0/7 weeks
cians and Gynecologists (ACOG), PET is defined as the onset of of gestation, or for any woman with maternal/fetal instability
hypertension (systolic 140 or diastolic 90) and proteinuria regardless to gestational age [3]. In addition to delivery, MgSO4
(300 mg in 24 h urinary collection, or 1+ in a urine dipstick) after prophylaxis is given to any woman diagnosed with severe PET, in
20 weeks of gestation in a previously healthy woman. PET with order to prevent deterioration to eclampsia (convulsive phase of
severe features is defined as either increased values of blood pres- the disorder) [6], and additional supportive care given to treat
sure (systolic 160 or diastolic 110) or hypertension as defined in hypertension and any preexisting complication. To date, there is
PET followed by any sign/symptoms of end organ failure (thrombo- no consensus regarding the treatment regimen of MgSO4 in terms
cytopenia, renal insufficiency, impaired liver function, pulmonary of loading dose, maintenance dose and maintenance duration as
well as route of administration. This is most probably due to the
fact that the precise maternal initial dose and continuous blood
Corresponding author. concentrations have never been established [7]. According to the
E-mail address: Adiyehud@bgu.ac.il (A.Y. Weintraub). World Health Organization (WHO), treatment with MgSO4 usually
1
The first two authors contributed equally to the manuscript.

http://dx.doi.org/10.1016/j.preghy.2017.03.003
2210-7789/ 2017 Published by Elsevier B.V. on behalf of International Society for the Study of Hypertension in Pregnancy.

Please cite this article in press as: R. Rotem et al., Clinical and laboratory markers in the recovery from severe preeclampsia, Preg. Hyper: An Int. J. Womens
Card. Health (2017), http://dx.doi.org/10.1016/j.preghy.2017.03.003
2 R. Rotem et al. / Pregnancy Hypertension: An International Journal of Womens Cardiovascular Health xxx (2017) xxxxxx

begins with the onset of labor or induction and is followed by 24 h 1st 2013 to January 1st 2014. All patients enrolled had completed
maintenance therapy postpartum (the time frame most suscepti- 24 h of postpartum treatment with MgSO4 in the delivery room.
ble for seizures) [8]. In past years, it has been suggested, that some Excluded from the study were: 1) Women who did not complete
women (with reduced risk of developing eclampsia) treated with a 24 h postpartum treatment, 2) Women in which the treatment
MgSO4 can benefit from shorter maintenance therapy regimens, with MgSO4was not directly continued after delivery (the treat-
given the great risk for magnesium toxicity and the need for close ment was given later, after discharge to the maternity ward), 3)
monitoring [9]. Few experimental studies were carried out [1016] Women with accompanying diseases (acute infectious disease,
using different regimens. Some were randomly assigned [11 liver disease and gestational thrombocytopenia) and 4) women
13,16] and others used different clinical and laboratory parameters with multiple gestations.
to assign women to shorter regimens, or in the case of mild PET, no
treatment at all. Among the parameters used were: blood pressure
2.4. Study design
[10,14,15] and urinary output [10,14]. To date, there is no one clear
clinical parameter known to predict the upcoming resolution of
A retrospective cohort study was conducted based on informa-
severe PET. Many challenges rise because mothers affected by sev-
tion collected from the computerized database of SUMC. The
ere PET who receive magnesium sulfate treatment are separated
potential candidates were detected using the diagnosis given by
from their infants in the immediate postpartum period, not only
the appropriate ICD-9 codes. The following characteristics were
physiological ones but mental and emotional ones as well. Early
collected from the computerized files of each woman fulfilling
maternal separation, reduced mother infant interaction and
inclusion criteria: A) Demographic and background characteristics:
reduced breastfeeding rates have been reported in patients with
maternal age, weight and height, and ethnicity (Jewish vs. Bedouin
severe PET [17].
Arabs), smoking (self - reported by the patient). B) Medical and
In light of the interest and need in shortening the use of main-
obstetrical history: chronic illnesses (e.g. hypertension, diabetes
tenance therapy for appropriate women with severe PET, we
mellitus), gravity and parity, previous cesarean section. C) Obstet-
decided to describe how certain clinical and laboratory parameters
rical outcomes: mode of current delivery (normal vaginal delivery
change during the first 24 h postpartum. Potential findings of sig-
vs. cesarean section), stillborn, fetal gender, birth weight, low
nificant early change in any of the parameters, may allow us to
Apgar scores (7 at 1 and 5 min). D) Laboratory parameters col-
use it as a predictor of resolution in future studies.
lected at the time of delivery and at 6 h interval in the 24 h post-
partum: blood count (hemoglobin and platelets), chemistry:
2. Materials and methods renal function test (urea and creatinine), liver function test (gluta-
mate oxaloacetate transaminase GOT, glutamate pyruvate
2.1. Setting transaminase GPT), lactate dhydrogenase LDH, and prothrom-
bin time - PT and H) Different measures taken at the time of deliv-
The study was conducted in the largest regional hospital in ery and at 6 h interval in the 24 h postpartum: systolic and
southern Israel Soroka University Medical Center (SUMC). SUMC diastolic blood pressures, urinary protein (every 6 h a urinary sam-
hosts roughly 98% of the deliveries that take place in the southern ple was taken from the catheter and checked for protein presence
region of Israel. The study has been approved by Institutional by a urine dipstick) and urinary output (average per hour calcu-
Review Broad (in accordance with Helsinki declaration). lated at 6 h intervals).

2.2. MgSO4 treatment regimen


2.5. Statistical analysis
According to the SUMC protocol, the loading dose of MgSO4 is
Statistical analysis was performed, using the SPSS software, ver-
given when the diagnosis of severe PET is made and maintained
sion 18. Parameters that distributed normally were evaluated
for 24 h following delivery, while the patient is closely monitored
using mean and standard deviation, while parameters that did
in the delivery room. The loading dose is 4 g over 2030 min, and
not distribute normally were evaluated using median and mode.
maintenance is 12 grams per hour given over 24 h. During that
We used the student paired t-test in order to determine statistical
period the patient is monitored in a darkened room, every hour.
significant differences in continuous variables that were normally
Vital signs including blood pressure and heart rate are taken and
distributed. For paired continuous variables that were not nor-
the urinary output as measured by foley catheter is recorded and
mally distributed, we used the Wilcoxon rank test. When we
documented. In addition, every six hours blood tests that include:
encountered missing values the percentages were calculated,
complete blood count, chemistry (including liver function test, cre-
excluding the missing values from the 100%. The P value set for sta-
atinine and urea and MgSO4 levels) and coagulation tests are
tistical significance was 0.05. Each of the measures taken at 6 h
drawn. The treatment with MgSO4 is stopped in case of the emer-
intervals was compared to the measure taken at the time of the
gence of any of the following: 1) MgSO4levels exceed 7.4 mg/dL
delivery that was set to be the reference point.
(therapeutic range is 4.77.4), 2) Loss of deep tendon reflexes, 3)
Respiratory depression (10 breaths per minute) and 4) oliguria
(30 cc of urine per hour) 5) 24 h from delivery if clinical improve- 3. Results
ment is noticed.
During the study period 132 deliveries met the inclusion crite-
2.3. Study population ria and were included in the study. The Maternal characteristics are
shown in Table 1. The mean maternal age was 29.55 6.97 years
The study population included patients with the diagnosis of and the majority (68.9%) of women in our study was Bedouin
severe PET who were traced by the international classifications of Arabs. While the average weight at conception was
diseases, 9th revision (ICD-9) as documented in the computerized 62.88 14.36 kg, the average weight at the time of delivery was
database of SUMC. The patients selected were given the ICD-9 76.71 16.37 kg, the difference between the weight values was
642.5 (Severe PET) and 642.7 (Eclampsia with pre-existing hyper- found to be statistically significant. Only 4.5% of the women
tension), and had a singleton delivery in SUMC between January smoked during the pregnancy.

Please cite this article in press as: R. Rotem et al., Clinical and laboratory markers in the recovery from severe preeclampsia, Preg. Hyper: An Int. J. Womens
Card. Health (2017), http://dx.doi.org/10.1016/j.preghy.2017.03.003
R. Rotem et al. / Pregnancy Hypertension: An International Journal of Womens Cardiovascular Health xxx (2017) xxxxxx 3

Table 1 Table 3
Demographic and background maternal characteristic of women with severe PET. Perinatal outcomes of pregnancies with
severe PET.
Maternal age (Mean SD) 29.55 6.97
Weight at conception (Mean SD) 62.88 14.36 pv < 0.001* Mode of current delivery% (N)
Weight at delivery (Mean SD) 76.71 16.37 Vaginal 52.3% (69)
Height (Mean SD) 1.60 0.08 VacuumVaccum 3% (4)
Ethnicity% (N) Ceasarian section 44.7% (59)
Jewish 31.1% (41) Stillborn% (N) 3.8% (5)
Bedouins 68.9% (91)
Fetal gender
Smokers% (N) 4.5% (6)
Male% (N) 2 52.3% (58)
*
The values were compared using paired t-test. Female% (N) 1 47.7% (53)
Birth weight
<2500 gr% (N) 51.4% (57)
Table 2 2,5004,000 gr% (N) 46.8% (52)
Medical and obstetrical characteristics of women >4000 gr% (N) 1.8% (2)
with severe PET. Apgar < 7 1 min% (N) 21.8% (24)
Apgar < 7 5 min% (N) 8.2% (9)
Chronic illnesses% (N)
Diabetes 9.8% (13)
Hypertension 0.8% (1)
Lupus 0.8% (1) of the measures recorded at later time intervals were higher, and
Obesity 2.3% (3) at 12 h and 18 h postpartum the median value exceeded 100 cc/
Gravidity% (N) HR. Yet, those differences were not found to be statistically signif-
1 38.6% (51) icant. However, when comparing the median taken at 6 h to the
24 26.5% (36)
median taken at 12 h and 18 h the difference was found to be sta-
5+ 34.8% (46)
tistically significant (<0.005 and <0.001, respectively). The median
Parity% (N)
urine protein measured at baseline was +2 (as measured by dip-
1 44.1% (49)
24 23.4% (26) stick), each of the measurements taken later was significantly
5+ 32.4% (36) lower, at 24 h the median was zero (no protein in urine). Mean cre-
Previous cesarian section% (N) 18.9% (25) atinine values were within normal range at all measurements, and
have not changed significantly. In contrast, mean urea levels taken
at baseline were slightly above normal (20.93 mg/dL), and were
The medical and obstetrical characteristics are presented in significantly lower at 12 h (18.44 mg/dL), 18 h (17.10 mg/dL) and
Table 2. Most of the patients in the study group were nulliparous 24 h (16.67 mg/dL).
(38.6%) and only 18.9% of the remaining had a previous cesarean
delivery. With regard to chronic illnesses, 9.8% of the women had
diabetes and only 0.8% had hypertension. 4. Discussion
Table 3 shows the perinatal outcomes of the study population.
While the majority of the women had a vaginal delivery (52.3%), In this cohort study we examined the 24-hours post-delivery
a substantial number of the women ended having a cesarean sec- trends in different clinical and laboratory features of patients com-
tion (47.7%). The rate of stillborn among the study group was plicated with severe PET among 132 women who delivered at the
3.8%. Most of the fetuses born were low birth weight <2500 g SUMC. Our observations have demonstrated that most of the
(51.4%) and only a small amount weighed over 4000 g (1.8%). women achieved statistically significant resolution of systolic and
While 21.8% of the fetuses were born with a low Apgar score diastolic hypertension during the first 6 h (Pv < 0.001), while urine
(<7) at 1 min after birth, only 8.2% had a low Apgar score at output exceeded 100 ml/h during the first 12 h. Urine protein
5 min after birth. tested by a dipstick test was the last to recover, below 1 at 12 h
The measures of central tendency and the comparisons and negative after 24 h (Pv < 0.001). We believe that the lack of sta-
between the different laboratory parameters and measures are tistical significance in the recovery of urine output may be due to
shown in Table 4 and Table 5. The mean systolic blood pressure multiple missing values at baseline and therefore small numbers
measured at the time of delivery was 160.32 mmHg, all mean mea- of comparisons.
surements taken later were lower. That difference was found to be In our sample, platelets, liver enzymes, creatinine and urea
statically significant when each time interval was compared to were within the normal range during the baseline measurements;
baseline (time of delivery; p < 0.001). Similarly, the mean diastolic therefore, we could not relate to resolution according to these
blood pressure measured at baseline was 96.61 mmHg and signif- parameters.
icantly lower at all later time points (p < 0.001). Although some When assessing the variability of different parameters along the
patients demonstrated thrombocytopenia, it should be noted that first 24 h postpartum, few things should be noted; the mean plate-
the mean values were within normal range limits. Yet, surprisingly let count significantly decreased during the first 24 h postpartum.
the mean baseline count (198.90  103/lL) was significantly higher This may be due to a delayed appearance of this feature of PET or it
when compared to each time interval later on. Likewise, liver func- may be related to serum dilution, given the amount of the fluids
tion test that were evaluated (GOT and GPT) were within normal that patients receive. Likewise, hydration can serve as an explana-
range limits in all time points. Compared with median baseline tion for the significant drop in urea levels. The changes seen in the
GOT (27.0 IU/L) those taken at 6 h and 18 h postpartum were found liver enzymes, though statistically significant are within normal
to be significantly higher (29.0 IU/L and 28.5 IU/L, respectively). limits and therefore may not have a true clinical significance.
Median GPT levels at baseline (14.5 IU/L) were significantly lower MgSO4 was shown to prevent eclamptic seizures among
when compared to the median value taken at 12 h postpartum women with severe PET [6,18]; yet the optimal duration of therapy
(15.5 IU/L). Median LDH levels at baseline was 554.5 IU/L, values needed to prevent seizures is still under debate. In accordance with
measured at all later time points were significantly higher. The the WHO guidelines, MgSO4 prophylaxis is traditionally given for
median urine output measured at baseline was 76.4 cc/HR. Each the first 24-hours postpartum, in which the greatest risk for
eclamptic seizures has been demonstrated [8]. In the last decade,

Please cite this article in press as: R. Rotem et al., Clinical and laboratory markers in the recovery from severe preeclampsia, Preg. Hyper: An Int. J. Womens
Card. Health (2017), http://dx.doi.org/10.1016/j.preghy.2017.03.003
4 R. Rotem et al. / Pregnancy Hypertension: An International Journal of Womens Cardiovascular Health xxx (2017) xxxxxx

Table 4
Laboratory parameters collected at the time of delivery and at 6 h interval in the 24 h postpartum.

Parameter N Time of delivery 6 h PP P 12 h PP P 18 h PP P 24 h PP P


Hemoglobin g/dL (mean SD) 114 11.83 1.61 11.03 1.65 <0.001 10.34 1.73 <0.001 10.00 2.00 <0.001 10.08 1.54 <0.001
Platelets 10^3/uL (mean SD) 114 198.90 83.78 191.81 77.45 <0.005 178.19 74.30 <0.001 168.25 73.19 <0.001 167.68 69.73 <0.001
Creatinine mg/dL (mean SD) 112 0.60 0.14 0.60 0.16 0.483 0.59 0.16 0.618 0.60 0.17 0.783 0.59 0.15 0.178
Urea mg/dL (mean SD) 112 20.93 8.05 20.38 8.18 0.006 18.44 8.37 <0.001 17.10 8.02 <0.001 16.67 6.82 <0.001
GOT IU/L (median, mode) 112 27.0, 16.0 29.0, 29.0 0.001 28.0, 24.0 0.090 28.5, 20.0 0.001 29.0, 22.0 0.080
GPT IU/L (median, mode) 112 14.5. 11.0 15.0, 8.0 0.822 15.5, 12.0 <0.05 14.0, 8.0 0.537 16.0, 8.0 0.584
LDH IU/L (median, mode) 74 554.5, 408.0 621.0, 466.0 <0.001 624.0, 488.0 <0.005 635.0, 551.0 <0.001 673.0, 614.0 <0.001
Prothrombin time (mean SD) 111 0.86 0.09 0.87 0.08 0.023 0.87 0.10 0.001 0.88 0.09 0.073 0.86 0.08 0.246

PP postpartum, SD - standard deviation.


The comparison was done to the parameter taken at the time of delivery.

Table 5
Clinical features of PET taken at the time of delivery and at 6 h interval in the 24 h postpartum.

Parameter N Time of 6 h PP P 12 h PP P 18 h PP P 24 h PP P
delivery
Systolic blood pressure mmHg 100 160.32 15.85 136.57 16.85 <0.001 135.69 15.60 <0.001 138.42 15.33 <0.001 139.26 13.15 <0.001
(mean SD)
Diastolic blood pressure mmHg 100 96.61 10.07 83.97 12.05 <0.001 84.82 11.10 <0.001 84.74 11.67 <0.001 86.03 9.67 <0.001
(mean SD)
Urine output cc/h(median, mode) 49 76.4, 54.5 79.65, 40.0 0.925 110.0, 14.8 0.132 150.65, 200 0.101 (&)
Urinary protein (median, mode) 89 2.0, 2.0 1.0, 1.0 <0.001 0.5, 1.0 <0.001 0.5, 0.0 <0.001 0.0, 0.0 <0.001

PET preeclampsia toxemia, PP postpartum, SD standard deviation.


The comparison was done to the parameter taken at the time of delivery.
(&) Multiple missing values.

concerns have emerged regarding MgSO4 safety and potential tox- patients complicated with severe PET. The main strength of the
icity. Severe side effects of MgSO4 include: the loss of patellar study lies in the fact that SUMC is the sole tertiary hospital serving
reflex, respiratory depression, cardiac depression and even mater- the entire obstetrical population in southern Israel and accommo-
nal death [9]. A 24-hours MgSO4 regimen may not be required for dates 98% of all deliveries in the region. Therefore, the study pop-
all women with severe PET. Previous studies demonstrated the effi- ulation represents a wide spectrum of the population, limiting the
cacy and safety of shorter regimens in women with early resolu- possibility of selection bias. In addition, the data was collected
tion [10,14,16]. In the current study we describe the 24-hours from computerized files which eliminate the risk of recall bias.
trends of several clinical and laboratory features of severe PET Our study has several limitations; the main limitation lies
and suggest that farther studies should focus on hypertension within the retrospective design and inherent faults of database
and urine output as parameters that can help determine the dura- studies. As a result, certain parameters had multiple missing val-
tion of MgSO4 therapy. ues, which in turn limited our ability to consolidate conclusions.
Treatment with MgSO4 necessitates intense monitoring which In conclusion, this study presents a detailed assessment of sev-
requires the new mothers to remain in the labor and delivery unit eral clinical and laboratory features in patients complicated with
until the completion of the therapy. Patient monitoring includes severe PET during the first 24-hours after delivery. According to
frequent assessment of vital signs, neurologic status and blood our results, hypertension, proteinuria and urine output normalize
tests. In addition, all women must have a Foley catheter for accu- during the first 12-hours. These observations suggest that ade-
rate assessment of urine output for at least 24 h post-delivery quate women with severe PET may benefit from a shorter regimen
[9]. This intense protocol of treatment has some major implications of MgSO4 therapy.
on both maternal welfare and newborn care. The delayed patient
ambulation increases the risk of thromboembolic disease [19],
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Please cite this article in press as: R. Rotem et al., Clinical and laboratory markers in the recovery from severe preeclampsia, Preg. Hyper: An Int. J. Womens
Card. Health (2017), http://dx.doi.org/10.1016/j.preghy.2017.03.003