Study design and context
We conducted a hospital-based prospective, cross-sectional study included a cohort of childbearing women ≥ 34 weeks of gestation with severe PE (case group) and group of matched healthy childbearing females (control group) between September, 2018 and March, 2019. All study participants were recruited from Obstetrics and Gynecology Department, Kasr Al Aini Hospital that serves as a tertiary referral center for more than 220 thousand women across Egypt and Middle East region annually. The department incorporates six inpatient units, surgery, antenatal care and fetal medicine with 297 bed capacity [9]. The sample size was obtained to yield a 95 % confidence level, 5 % margin of error with anticipated response rate 80 %.
Study Population
All childbearing women who presented to the Labor and Delivery triage unit at Kasr Al Aini hospital during a six- month study period were screened for eligibility. The case group (Group I) was comprised of sixty women with a viable singleton pregnancy ≥ 34 weeks, complicated by LOP with severe features and delivered by caesarean section (CS) who consented to participate. All childbearing women with <34 weeks’ gestation, non- severe PE, eclampsia, existing comorbidities (e.g., diabetes, renal disorders etc.), vaginal birth and those who declined to participate were excluded from the study. Moreover, twin and multifetal pregnancy diagnosed by ultrasound scan and those complicated by intrauterine fetal death and fetal anomalies were also excluded. A comparison group of 60 healthy, non-preeclamptic, parity-, maternal age- and gestational age- matched women with uncomplicated singleton pregnancies were recruited during the same calendar period (Group II).
Operational definitions
Based on criteria set by International Society for the Study of Hypertension in Pregnancy (ISSHP) [10], preeclampsia was defined if the patient has gestational hypertension in the form of sustained systolic blood pressure (SBP) ≥ 160 mmHg or diastolic blood pressure (DBP) ≥ 110 mmHg, accompanied by one or more of new onset conditions ≥ 20 weeks’ gestation as illustrated in Table 1.
Table 1
Diagnostic criteria of pre-eclampsia and severe pre-eclampsia [10, 11]
Preecalmpsia
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Proteinuria of ≥ 0.3 grams in a 24-hour urine specimen, protein (mg/dL) /creatinine (mg/dl) ratio of 0.3 or higher, or a urine dipstick protein of 1
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Other maternal organ dysfunctions, including:
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Acute kidney injury (AKI) (creatinine ≥ 90 µmol/L; 1 mg/dL)
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liver involvement (elevated transaminases e.g., ALT or AST > 40 IU/L) with or without right upper quadrant or epigastric abdominal pain)
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Neurological complications e.g., altered mental status, blindness, stroke
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Hematological complications (thrombocytopenia – platelet count below 150,000/µL, DIC, hemolysis)
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Uteroplacental dysfunction e.g., fetal growth restriction.
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Severe features of preeclampsia
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Elevated blood pressure (systolic ≥ 160 mm Hg, diastolic ≥ 110 mm Hg)
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Elevated creatinine level (> 1.1 mg per dL [97 µmol per L] or ≥ 2 times baseline)
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Hepatic dysfunction (transaminase levels ≥ 2 times upper limit of normal) or right upper-quadrant or epigastric pain
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New-onset headache or visual disturbances
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Platelet count < 100 × 103 per µL (100 × 109 per L)
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Pulmonary edema
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Pre-eclampsia with severe features diagnosed based on the presence of severe uncontrolled hypertension and any severe renal, hepatic, neurological, hematological, or cardiorespiratory complications (Table 1)
Gestational age was estimated based on maternal recall of the first day of last menstrual period (LMP) and/or the ultrasound measurement of the crown-rump length in first trimester, if available.
For purpose of this study, adverse neonatal outcomes were defined as occurrence of one or more of the following: 1- and / 5- minutes Apgar score < 7, metabolic acidosis at birth (pH < 7.20), low birth weight (LBW) (defined as birth weight of less than 2500 grams) [12], intrauterine growth retardation (IUGR) (defined as fetal abdominal circumference or estimated fetal weight < 10th percentile and umbilical Doppler PI > 95th percentile on ultrasound scan) [13] and admission to NICU.
Study measurements
To assure consistency and minimize interpersonal biases, all participating physicians were instructed regarding selection and exclusion criteria, definitions and procedures prior to the study. In addition, the neonatologists were evaluated in the delivery room for adequate Apgar score interpretation.
All study population were subjected to full history taking including demographic data (age, parity, and gestational age), current health status and occurrence of any chronic illnesses. Two well-trained nurses were assigned to measure the blood pressure for all study population using automated well-calibrated device validated to be used in pregnancy following guidelines for measuring blood pressure in the clinic setting. Mercury sphygmomanometer was used concurrently with respect to National Institute for Health and Care Excellence (NICE) antenatal Care guidance steps [14].
Immediately, after birth, the clinical status of newborn infants was evaluated by the attending neonatologist using Apgar score at 1 and 5 minutes of life. Other data included gestational age and birth weight were assessed by New Ballard scoring system [15] and Niklasson percentile growth curves, consecutively [16].
Samples for blood gas analysis were collected from pulsating unclamped umbilical cords of all neonates in sterilized heparinized syringes labelled with patient identifier. After collection, samples were immediately placed in ice and transferred to the laboratory and results were obtained within 30 minutes from collection.
Doppler ultrasonography
Doppler analysis was performed for all study participants using the same ultrasound machine (SAMSUNG Model: SONOACE R3) and by the same physician (AMA) with over 10 years of antenatal Doppler ultrasound experience. Doppler indices of fetal UA and MCA were measured including:
Pulsatility index (PI) = Peak systolic velocity – End diastolic velocity / Time-averaged maximum velocity
Rresistance index (RI) = systolic velocity - diastolic velocity / Peak systolic velocity
Systolic/diastolic ratio (S/D) ratio = Peak systolic velocity/End- diastolic ratio, calculated from blood flow velocities.
These Doppler indices were recorded automatically from consecutive waveforms with the angle of insinuation below 30°. The UA Doppler waveform was produced by sampling a free-floating portion of the umbilical cord using colour Doppler and UA PI, RI and S/D ratio were calculated according to the standard protocol [17]. A transverse section of the fetal head was obtained and MCA was identified, using colour Doppler, at the level of its origin from the circle of Willis. The MCA was sampled using pulsed Doppler with the vessel passing the sphenoid wing and PI, RI, S/D ratio were calculated according to the standard protocol [18]. Cerebroplacental ratio is calculated by dividing the MCA PI/ UA PI (i.e., MCA S/D to UA S/D) [18].
In the current study, reference values for fetal Doppler indices were based on the study conducted by Ciobanu et al [19]. All measured Doppler values were plotted on the appropriate reference range for the corresponding centile charts [19]. Umbilical artery, MCA and CPR indices were defined as being abnormal if values > 95th percentiles, < 5th percentiles and ˂ 1, respectively.
Data management and statistical analysis
Data were statistically described in terms of mean, standard deviation (± SD), median and range for qualitative data or frequencies (number of cases) and percentages for categorical data. Comparison of numerical variables between the study groups was done using the Student t test for independent samples when normally distributed and Mann Whitney U test for independent samples when not normally distributed. For comparing categorical data, Chi square (χ2) test was performed. When the expected frequency is < 5, Fisher’s exact test was used instead. The test of sensitivity, specificity, positive and negative predictive values (PPV and NPV) were also used. P-values less than 0.05 were considered statistically significant. All statistical calculations were coded and entered using the statistical package SPSS (Statistical Package for the Social Sciences) version 25.