Study design and participants

The study data were derived from a prospective screening study for adverse obstetrical outcomes in women attending routine pregnancy care at 19 0/7 to 23 6/7 weeks of gestation at King’s College Hospital and Medway Maritime Hospital in the United Kingdom between October 2011 and March 2020. The women gave written informed consent to participate in the study, which was approved by the National Health Service Research Ethics Committee.

In brief, at the routine hospital visit at 19 0/7 to 23 6/7 weeks of gestation, women underwent (1) recording of maternal demographic characteristics and medical history, (2) an ultrasound examination for fetal anatomy and growth, (3) measurement of the mean of the left and right uterine artery pulsatility indices (PIs) using transvaginal or transabdominal color Doppler ultrasound, ^, and (4) measurement of the mean arterial pressure using validated automated devices and a standardized protocol. The fetal head circumference, abdominal circumference, and femur length were measured, and the estimated fetal weight (EFW) was calculated using the Hadlock formula, identified as the most accurate model by systematic review. Serum placental growth factor (PlGF) was measured by BRAHMS Kryptor compact PLUS (Thermo Fisher Scientific, Hennigsdorf, Germany), DELFIA Xpress system (PerkinElmer Life and Analytical Sciences, Waltham, MA), or Cobas e411 (Roche Diagnostics, Penzberg, Germany). Gestational age was determined by the measurement of the fetal crown-rump length at 11 to 13 weeks of gestation or the fetal head circumference at 19 to 24 weeks of gestation. ^,

Data related to pregnancy outcomes were abstracted from electronic hospital maternity records or those of the women’s general medical practitioners. The obstetrical records of all women with chronic hypertension or pregnancy-associated hypertension were examined to determine the diagnosis of PE or gestational hypertension (GH).

The diagnosis of GH was based on the finding of new-onset hypertension developing after 20 weeks of gestation in previously normotensive women. The diagnosis of chronic hypertension was based on a prepregnancy history of such hypertension at <20 weeks of gestation. Hypertension was defined as a systolic blood pressure (BP) of ≥140 mm Hg or diastolic BP of ≥90 mm Hg, on at least 2 occasions, at least 4 hours apart.

The inclusion criteria for this analysis were singleton pregnancies delivering a nonmalformed live birth or stillbirth at ≥24 0/7 weeks of gestation. We excluded pregnancies with aneuploidy or major fetal abnormalities.

Diagnosis of preeclampsia

Here, 5 different definitions of PE were considered (Supplemental Table). The traditional definition of PE was based on new-onset proteinuria (ie, ≥300 mg per 24 hours, protein-to-creatinine ratio of ≥30 mg/mmol, or ≥2+ on urinary dipstick testing).

The broader definitions of PE, from both the ACOG and ISSHP definitions, ^, were based on evidence of maternal end-organ dysfunction (ACOG and ISSHP definitions) or uteroplacental dysfunction (ISSHP definition only). Neither broad definition requires the presence of proteinuria. In defining maternal end-organ dysfunction, we included only quantitative measures of renal, hepatic, or hematologic dysfunction, reliably documented in clinical care notes. The ACOG definition of PE was based on the development of at least 1 of the following: new-onset proteinuria, serum creatinine of >97 μmol/L (in the absence of underlying renal disease), serum transaminases more than twice the upper limit of normal (.e, ≥65 IU/L for our laboratory), platelet count of <100,000/μL, headache or visual symptoms, or pulmonary edema. The ISSHP definition of PE was examined according to its maternal (ISSHP-M) and uteroplacental (ISSHP-MF) components. The ISSHP-M definition was based on at least 1 of the following: new-onset proteinuria, serum creatinine of ≥90 μmol/L (in the absence of underlying renal disease), serum transaminases of >40 IU/L, platelet count of <150,000/μL, or neurologic complications (ie, altered mental status, blindness, stroke, clonus, severe headaches, or persistent visual scotomata); the criteria of altered mental status and clonus were not available. The ISSHP-MF definition included all criteria of ISSHP-M, with the addition of fetal death or FGR; FGR was defined according to ultrasound findings at 19 0/7 to 23 6/7 weeks of gestation, defined as an EFW of <3rd percentile or an EFW between the 3rd and 10th percentiles together with the uterine artery PI multiple of the median (MoM) of >95th percentile. The ISSHP-MF+PlGF definition included all criteria of the ISSHP-MF definition, with the addition of low serum PlGF MoM of <5th percentile at 19 to 23 weeks of gestation.

Outcome measures

The maternal and perinatal outcomes of interest were as follows: severe maternal hypertension, a composite of maternal death or major morbidity, a composite of perinatal death or major neonatal morbidity, neonatal intensive care unit (NICU) admission ≥48 hours, and birthweight (BW) of <3rd percentile.

Severe maternal hypertension was defined as systolic BP ≥160 mm Hg and/or diastolic BP ≥110 mm Hg. Major maternal morbidity was defined as one or more of the following: eclampsia, blindness, stroke, myocardial ischemia, pulmonary edema, elevated liver enzymes, hepatic hematoma, low platelet count, or acute kidney injury; these were based on the core maternal outcome set in PE, except for outcomes that were not available (ie, liver rupture, postpartum hemorrhage, ICU admission, and intubation and ventilation other than for childbirth), exclusion of placental abruption (which was defined clinically and underreported), and addition of myocardial ischemia (based on the Delphi-derived Preeclampsia Integrated Estimate of Risk score ^, ).

Perinatal death was defined as stillbirth or neonatal death prior to hospital discharge. Major neonatal morbidity was defined as one or more of the following, as indicated in the BadgerNet Neonatal discharge summary: ventilation (ie, need for continuous positive airway pressure or nasal continuous positive airway pressure or intubation), respiratory distress syndrome (ie, the need for surfactant and ventilation), brain injury (ie, hypoxic-ischemic encephalopathy, intraventricular hemorrhage grade ≥2, or periventricular leukomalacia), sepsis (based on positive blood cultures), anemia treated with blood transfusion, or necrotizing enterocolitis requiring surgical intervention. The BW percentile for gestational age was determined using the Fetal Medicine Foundation fetal and neonatal weight charts. Perinatal outcomes covered the core perinatal outcome set in PE, except for neonatal seizures.

Statistical analysis

Descriptive analysis was undertaken for (1) baseline data of assessment at 19 0/7 to 23 6/7 weeks of gestation and subsequent pregnancy outcomes for the study population overall, (2) the contribution of the components contributing to a diagnosis of PE among relevant women, and (3) pregnancy outcomes according to different definitions of PE (and the related impact on GH). Continuous variables were summarized by median and interquartile range, and categorical variables were summarized by number (percentage). The chi-squared test was used to compare the detection rate for adverse maternal and perinatal outcomes for each of the broad definitions of PE, relative to the traditional one; this was undertaken for PE overall and preterm (delivery at <37 weeks of gestation) and term PE. A P value of <.05 was considered statistically significant.

Study participants

There were 40,241 pregnancies evaluated at visits at 19 0/7 to 23 6/7 weeks of gestation and included in this analysis.

Table 1 shows that, on average, women were in their early 30s and overweight, with 25% of women considered obese. Most women were White, with a substantial minority of Black race. Few women (<10%) were cigarette smokers. Medical history was usually unremarkable, with few women reporting chronic hypertension (most of whom were treated with antihypertensive therapy), pregestational diabetes mellitus, or rheumatic disease. Just over half of women were parous, with 2.5% of parous women having had previous PE. Few women reported that their mothers had suffered from PE. Almost all conceptions were natural, following an interpregnancy interval of just under 3 years, when relevant. Few women were on aspirin for PE prevention, the prescription of which was guided entirely by routine clinical care.

The 19- to 23-week assessment occurred at a median of 21.6 weeks; at which point, approximately 5% of women had abnormal uterine artery Doppler readings or abnormal PlGF ( Table 1 ).

Birth occurred at a median of approximately 40 weeks, following induction for approximately 20% of women and by cesarean delivery for almost 30% of women ( Table 1 ). Perinatal mortality was mainly because of stillbirth, and neonatal morbidity was because of respiratory problems, for which just under 7% of neonates overall required prolonged NICU admission. Just under 5% of neonates were born with a BW of <3rd percentile.

Preeclampsia definitions

Table 2 presents the elements of the PE definitions, for women with new-onset hypertension (n=2188) or chronic hypertension (n=425). Most commonly, women with hypertension satisfied the maternal diagnostic criteria for PE based on proteinuria, particularly among women with new-onset hypertension (44.7%). Less often, abnormal routine laboratory tests defined PE in women with hypertension, particularly related to low platelet count of <150×10 ⁹ /L (10.6% of women) or elevated liver enzymes (11.4% of women). Almost 10% of women with new-onset hypertension had uteroplacental dysfunction based on low PlGF at 19 0/7 to 23 6/7 weeks of gestation, with about half that rate (approximately 5%) among women with chronic hypertension. More women satisfied the more liberal ISSHP (vs more conservative ACOG) criteria for thrombocytopenia (231 [10.6%] vs 38 [1.7%], respectively) and elevated liver enzymes (249 [11.4%] vs 141 [6.4%], respectively). Few women met the criteria for PE based on gestational or chronic hypertension with headache (77 [3.5%]) or visual symptoms (5 [1.2%]).

Table 2

The elements of the preeclampsia definitions for women with new-onset hypertension and those with a history of chronic hypertension

Characteristic	New-onset hypertension (n=2188)	Chronic hypertension (n=425)
Proteinuria a	979 (44.7)	81 (19.1)
Maternal symptoms b
Headache	77 (3.5)	5 (1.2)
Visual symptoms	42 (1.9)	2 (0.5)
Maternal signs c
Eclampsia	13 (0.6)	0 (0)
Myocardial ischemia	0 (0)	0 (0)
Pulmonary edema	4 (0.2)	0 (0)
Abnormal maternal laboratory tests d
Platelet count<150×10 9 /L	231 (10.6)	41 (9.6)
Platelet count<100×10 9 /L	38 (1.7)	2 (0.5)
Serum creatinine≥90 μmol/L	79 (3.6)	28 (6.6)
Serum creatinine>97 μmol/L	51 (2.3)	19 (4.5)
AST or ALT of >40 IU/L	249 (11.4)	45 (10.6)
AST or ALT of ≥65 IU/L	141 (6.4)	17 (4.0)
Uteroplacental dysfunction
Intrauterine fetal death	10 (0.5)	3 (0.7)
EFW<3rd percentile	58 (2.7)	16 (3.8)
EFW between the 3rd and 10th percentiles with uterine artery PI MoM>95th percentile	32 (1.5)	3 (0.7)
PlGF MoM <5th percentile	201 (9.2)	22 (5.2)

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