- Email: [email protected]
Serious Perinatal Complications of Non-Proteinuric Hypertension: An International, Multicentre, Retrospective Cohort Study
SERIOUS PERINATAL COMPLICATIONS OF NON-PROTEINURIC HYPERTENSION: AN INTERNATIONAL, MULTICENTRE, RETROSPECTIVE COHORT STUDY L.A. Magee, MD, FRCPC, MSc,1 P. von Dadelszen, MBChB, DPhil, FRCSC,2 C. M. Bohun, BA,3 E. Rey, MSc, MD, FRCPC,4 M. EI-Zibdeh, MD, FRCOG,s S. Stalker, BA,6 S. Ross, BSc, MPhil, PhD, MBA,7 S. Hewson, BA,s A.G. Logan, MD, FRCPC,9 A. Ohlsson, MSc, MD, FRCPC, 10 T. Naeem, MBBS, MRCOG, MRCPI, II
J. G. Thornton, MD, FRCOG,12 M.
Abdalla, MD, MRCOG, 13 S. Walkinshaw, MD, MRCOG, 14 M. Brown, MD, FRACp, IS
G. Davis, MD, FRANZCOG,16 M. E. Hannah, MD, MSc, FRCSCI7 IBCWomen's Hospital and Health Centre.Vancouver BC IDepartment of Medicine. University of British Columbia. Vancouver BC 1.2Department of Obstetrics and Gynaecology. University of British Columbia. Vancouver BC 3Faculty of Medicine. University College. Cork. Ireland 4Departments of Medicine and Obstetrics and Gynaecology. University of Montreal. Montreal QC 5Department of Obstetrics and Gynaecology.The Islamic Hospital.Amman.Jordan 6.7.8.17University of Toronto Maternal Infant and Reproductive Health Research Unit, Centre for Research in Women's Health. Toronto ON 7. 17Department of Health Policy and Evaluation. University of Toronto. Toronto ON 17Department of Obstetrics and Gynaecology. Sunnybrook and Women's College Health Sciences Centre. University of Toronto. Toronto ON 9Samuel Lunenfeld Research Institute and Department of Medicine. Mount Sinai Hospital. University of Toronto. Toronto ON IODepartment of Pediatrics. Mount Sinai Hospital. University of Toronto. Toronto ON II Department of Obstetrics and Gynaecology. University of Leeds. Leeds. UK 12Department of Obstetrics and Gynaecology. University of Nottingham, Nottingham. UK 13. I4liverpool Women's Hospital. University of liverpool. liverpool, UK 15Departments of Renal Medicine and Medicine, St. George Hospital and Hurstville Community Hospital, University of New South Wales, Sydney. Australia 16Department of Obstetrics. St. George Hospital and Hurstville Community Hospital. University of New South Wales, Sydney, Australia Abstract Objective: To determine the proportion of births complicated by either a pre-existing or a gestational non-proteinuric hypertension, presenting at <34 weeks' gestation, and the associated incidence with I or more serious perinatal complications or birth weight <3rd centile for gestational age. Methods: A retrospective chart review was conducted in 5 international centres, from 1998 to 2002, where "tight" control (normalization) of blood pressure (BP) is the norm. International Classification of Diseases (ICD) codes were used to identify women who delivered at ::::20 weeks' gestation, with any hypertensive disorder of pregnancy. Women were included if they had a diastolic blood pressure (dBP) of 90 to 109 mm Hg, due to either a pre-existing or a gestational non-proteinuric hypertension, presenting at <34 weeks' gestation. Women were excluded if they had ongoing severe hypertension, or if at presentation with dBP of 90 to 109 mm Hg, they had I or more of the following: proteinuria, an indication for "tight" control of BP or
KeyWords
imminent delivery, or a known intrauterine fetal death or lethal fetal anomaly. Data were collected on paper forms, scanned into an electronic database, and summarized descriptively by type of hypertension. Results: There were 305 eligible women (0.7% deliveries, 12.8% hypertensive deliveries) identified with non-proteinuric hypertension that was either pre-existing (133 [43.6%]) or gestational (172 [56.4%]). Regardless of hypertension type, 16.4% (n = 50) of pregnancies were complicated by birth weight <3rd centile or I or more serious perinatal complications, 34.3% (n = 100) by preterm birth, 30.8% (n = 94) by preeclampsia, and 2.0% (n = 6) by serious maternal complications. Conclusion: Non-proteinuric pre-existing or gestational hypertension, presenting before 34 weeks' gestation, identifies a subpopulation of hypertensive pregnant women at both substantial perinatal risk and maternal risk. The CHIPS (Control of Hypertension In Pregnancy Study) trial is designed to determine how best to manage the hypertension of such women in order to optimize perinatal outcome. Resume Objectif : Determiner la proportion de naissances compliquees par une hypertension de nature non proteinurique, soit preexistante, so it gestationnelle, avant la 34" semaine de gestation, ainsi que I'incidence connexe d'une ou de plusieurs complications perinatales graves ou d'un poids de naissance (en fonction de I'age gestationnel) inferieur au 3" centile.
Hypertension, pregnancy, pregnancy complications, small for gestational age infants Competing interests: None declared. Received on September 18. 2002 Revised and accepted on December 20, 2002 JOGe
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Methodes : On a mene une etude retrospective des dossiers des patientes, pour la peri ode de 1998 a 2002, dans 5 centres de pays differents Oll iI existait des normes strictes sur la normalisation de la pression arterielle (PA). Le recours aux codes de classification internationale des maladies, traumatismes et causes de deces a permis de savoir quelles femmes, ayant accouche apres 20 semaines ou plus de gestation, etaient atteintes de troubles d'hypertension gestationnelle. On a choisi les femmes ayant une PA diastolique (PAd) de 90 a 109 mm Hg, attribuable a une hypertension non proteinurique gestationnelle ou preexistante, se presentant avant la 34 e semaine de gestation. On a exclu les femmes atteintes d'une hypertension grave continue ou celles qui, au moment oll elles presentaient une PAd de 90 a 109 mm Hg, revelaient une ou plusieurs des caracteristiques suivantes : une proteinurie, une indication laissant entendre qu'iI fallait une « etroite )} surveillance de la PA ou que Ie travail etait imminent, ou une mort fcetale intra-uterine ou une anomalie fcetale letale connues. On a recueilli les donnees sur papier, puis on les a transmises a une base de donnees et on les a classifiees sommairement par type d'hypertension. Resultats : On a identifie 305 femmes admissibles a I'etude (0,7 % des accouchements, 12,8 % des accouchements en presence d'hypertension) en raison d'une hypertension arterielle non proteinurique, soit preexistante (133 [43,6 %]), soit gestationnelle (172 [56,4 %]). Quel qu'ait ete Ie type d'hypertension, 16,4 % (n = 50) des grossesses ont eu des complications en raison d'un poids de naissance inferieur au 3e centile ou d'une complication perinatale grave ou plus; 34,3 % (n = 100), en raison d'une naissance prematuree; 30,8 % (n = 94), en raison d'une preeclampsie et 2,0 % (n = 6), en raison de complications maternelles graves. Conclusion : Avant la 34e semaine de gestation, I'hypertension arterielle non proteinurique, preexistante ou gestationnelle, caracterise une sous-population de femmes enceintes atteintes d'hypertension qui presentent un risque perinatal ou maternel important. L'essai CHIPS (Control of Hypertension In Pregnancy Study) est con<;u pour determiner la meilleure fa<;on de traiter I'hypertension que presentent ces femmes, de maniere a assurer les meilleures issues perinatales possibles.
J Obstet
Gynaecol Can 2003;25(5):372-82.
INTRODUCTION
Hypertensive disorders of pregnancy are leading causes of maternal and perinatal mortality and morbidity worldwide. 1 There is general agreement that treatment of severe pregnancy hypertension, usually defined as a sustained blood pressure (BP) measurement of ~ 170/ 11 0 mm Hg, is necessary to reduce the risk of maternal mortality and serious morbidity, such as stroke. 2-4 However, how best to manage mild to moderately elevated BP in pregnancy is controversial. Serious maternal complications are rare; no deaths or strokes were reported among 26 trials enrolling 2280 women. 5-IO The perinatal risks are uncertain as indicated by the results of randomized clinical trials (RCTs) for management of mild to moderate pre-existing or gestational hypertension, in which normalization of BP may be hannfol as it could JOGC
increase the risk of small for gestational age (SGA) infants. 9,11-13 However, normalization ofBP may be beneficial in decreasing the risk of maternal BP measurements of 160/100-110 mm Hg, antenatal hospitalization, proteinuria at delivery, and respiratory distress syndrome (RDS).9 Unfortunately, sufficient confidence cannot be placed in these results because of reporting bias and uncertainty about the clinical relevance of the outcomes as defined. 12 Not surprisingly, international guidelines differ. 2-4 The literature describing maternal or perinatal outcomes associated with mild to moderate hypertension is problematic due to variability in definitions of maternal or perinatal outcomes, failure to account for factors (including antihypertensive therapy) that may confound the BP-fetal growth relationship, and remote publication dates associating outcomes with now outdated methods of perinatal care. 14 Therefore, among women with non-protein uric hypertension, it is difficult to estimate reliably the incidence of serious perinatal complications or birth weight <3rd centile for gestational age and gender. Despite these problems, for women with pre-existing hypertension, estimates of perinatal mortality, SGA infants, and some complications of preterm delivery are available. 15-24 However, very little information about these outcomes is available for women with non-protein uric gestational hypertension, who present at less than 34 weeks' gestation and who are thought to be at increased risk. 25-29 To examine the incidence of these clinically relevant outcomes, we conducted an international, multicentre, retrospective cohort study, designed to estimate the proportion of births complicated by either a pre-existing or a gestational non-proteinuric hypertension presenting at <34 weeks' gestation, and the associated incidence of serious perinatal complications or birth weight <3rd centile for gestational age and gender. This is also the primary outcome for CHIPS (Control of Hypertension In Pregnancy Study), a protocol describing an RCT to determine if "less tight" control (aiming for a diastolic BP [dBP] of 100 mm Hg) of mild to moderate maternal hypertension, presenting before 34 weeks' gestation, improves perinatal outcome compared to "tight" control (aiming for a dBP of85 mm Hg). METHODS
This chart review of hypertensive pregnancies was conducted from September 1, 1998, to January 10, 2002, in 5 institutions: BC Women's Hospital and Health Centre, Vancouver, BC; Ste. Justine Hospital, Montreal, QC; The Islamic Hospital, Amman, Jordan; Leeds General Infirmary, Leeds, UK; and Liverpool Women's Hospital, Liverpool, UK. In all centres, normalization of dBP in pregnancy (i.e., "tight" control) was the standard of care by informal policy. Computerized records and International Classification of Diseases (lCD) codes (Table 1) were used to identify the charts of consecutive women who delivered at ~o weeks' gestation, with a diagnosis of pregnancy hypertension. MAY 2003
Women were eligible if they had non-protein uric, mild to moderately elevated dBP (90 to 109 mm Hg, measured twice at the same visit or on 2 consecutive outpatient visits) due to a preexisting or a gestational hypertension, and were at <34 weeks' gestation at first presentation with hypertension. Pre-existing hypertension was defined as hypertension diagnosed before pregnancy or in the first 20 weeks' gestation, and gestational hypertension as that diagnosed at :220 weeks' gestation. 13,30 Women were eligible only if hypertensive before 34 weeks' gestation, in order to identifY fetuses who were more likely to remain in utero longer and thus have greater opportunity to be affected by the type ofBP control and the underlying pathology. Women were enrolled whether or not they were on antihypertensive medication when they met the inclusion criteria. Women were excluded if they had severe systolic hypertension (defined as a systolic blood pressure [sBP] :2170 mm Hg); proteinuria (defined as :20.3 g/d by 24-hour urine collection, or by urinary dipstick testing of:21+, unless 24-hour urinary protein was shown to be <0.3 gld)13,30; a prepregnancy condition that mandated normalization ofBP in pregnancy (e.g., renal disease)31; an indication for imminent delivery for maternal or fetal reasons (e.g., suspected preeclampsia); therapy with atenolo!, angiotensin converting enzyme inhibitors, or angiotensin-II receptor antagonists throughout pregnancy; known intrauterine fetal death; or lethal fetal anomaly.
The inpatient charts of eligible women and their babies were reviewed. Outpatient charts were reviewed only for data on antihypertensive or non-drug management of hypertension. The following baseline information was recorded at the time of eligibility: type of maternal hypertension; maternal age; gestational age; multiple pregnancy; parity; smoking during pregnancy; severity of hypertension (by dBP at enrolment: mild [dBP 90-99 mm Hgl or moderate [dBP 100-109 mm Hgl); whether there was any severe hypertension (sBP :2170 mm Hg or dBP :2110 mm Hg) in the index pregnancy prior to eligibility; and for women enrolled at >24 weeks' gestation, whether the estimated fetal weight was <10th centile for gestational age and gender. 13,32 Data were collected on the development of severe hypertension; preeclampsia (defined as new or worsening hypertension with 1 or more of the following: proteinuria, thrombocytopenia, elevated liver enzymes, severe headache, or epigastric pain)3,13,30; and the subsequent use of non-pharmacological therapy specifically to lower BP (e.g., advice to quit work) and pharmacological antihypertensive therapies. Data were also abstracted on use of other medications in labour, maternal transfers to the intensive care unit (lCU), timing and method of delivery, type of analgesia or anaesthesia for delivery, and the type of neonatal resuscitation and care. The proportion of births complicated by a pre-existing or a
TABLE I INTERNATIONAL CLASSIFICATION OF DISEASES (ICD) CODES FOR CHART SELECTION ICD-9 Code Definition
642.0
Benign essential hypertension complicating pregnancy, childbirth, and the puerperium ("A pregnancy-induced hypertensive condition characterized by albuminuria and edema, specified as mild or unspecified:')
642.2
Other pre-existing hypertension complicating pregnancy, childbirth, and the puerperium ("PerSistently high arterial blood pressure resulting in [either] heart and kidney functional abnormalities, functional cardiac abnormalities, [or] functional kidney abnormalities, [or] an accelerated, severe form of persistently high arterial blood pressure.")
642.3
Transient hypertension of pregnancy (''Temporary elevated arterial blood pressure noted during pregnancy.")
642.4
Mild or unspecified preeclampsia ("A pregnancy-induced hypertensive condition characterized by albuminuria [not defined] and edema, specified as mild or unspecified.")
642.5
Severe preeclampsia ("A pregnancy-induced hypertensive condition characterized by albuminuria and edema, specified as severe:' This includes HELLP [hemolysis, elevated liver enzymes, low platelets] syndrome, which is 642.5.)
642.6
Eclampsia ("A pregnancy-induced hypertensive state characterized by convulsions and coma in a previously preeclamptic patient.")
642.7
Preeclampsia or eclampsia superimposed on pre-existing hypertension ("Conditions classifiable to 642.4-642.6, with conditions classifiable to 642.0-642.2 [or] either 642.4 or 642.5 and [either] 642.0 or 642.1.")
642.9
Unspecified hypertension complicating pregnancy, childbirth, or the puerperium ("Use this code when the diagnosis is identified as 'hypertension complicating pregnancy, childbirth, or the puerperium: but is not specified as to type.")
646.2
Proteinuria without hypertension
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gestational non-protein uric hypertension presenting before 34 weeks' gestation and, among these women, the incidence of serious perinatal complications (up to 28 days oflife) or birth weight <3rd centile32 were recorded. 13 Serious perinatal complications were defined as 1 or more of the following: complications of intrauterine growth restriction or preterm birth: stillbirth (death of a fetus ;:::500 g or at ;:::20 weeks' gestation); neonatal death of a newborn at <28 days of age; RDS requiring assisted ventilation and supplemental oxygen within the first 24 hours oflife; broncho-pulmonary dysplasia (BPD), requiring oxygen at a postnatal gestational age of36 completed weeks and X-ray compatible with BPD33; intraventricular hemorrhage (IVH) grade 3 or 4 (by cranial ultrasound, using categorization ofPapile et aL,34 or at autopsy); cystic periventricular leukomalacia (PVL - periventricular cystic changes in the white matter, excluding subependymal and choroid plexus cysts, by cranial ultrasound or at autopsy); signs of retinopathy of prematurity stage 3 to 5 in one or both eyes including intraretinal ridge with extraretinal fibrovascular proliferation, or retinal detachment, by the worst stage in the most severely affected eye; or signs of necrotizing enterocolitis (NEC) including perforation of the intestine, pneumatosis intestinalis, or air in the portal vein, diagnosed by X-ray, surgery, or at autopsy.35 Other outcomes recorded were the incidence of serious maternal complications and birth weight dOth centile. Serious maternal complications were defined, up to 6 weeks postpartum, as death or 1 or more of stroke, eclampsia, or end-organ failure. Endorgan failure included 1 or more (as recorded in the chart) of the following: pulmonary edema; acute RDS; respiratory arrest; cardiovascular failure (the absence of hemorrhage, an arterial sBP <70 mm Hg for at least 1 hour despite adequate fluid resuscitation, adequate intravascular volume, or the use of vasopressors to maintain sBP >90 mm Hg or mean arterial BP >70 mm Hg)36; severe HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome requiring administration of blood products; hepatic failure (increased liver enzymes, conjugated hyperbilirubinemia and either hypoglycemia or international normalized ratio [INR] > 1.5); renal failure (serum creatinine >200 f1M); or coagulopathy (decreased fibrinogen below normal reported by local laboratory). Also of interest were preterm birth, other measures of neonatal morbidity, Caesarean section, placental abruption, induction oflabour, sustained severe hypertension (sBP ;:::170 mm Hg, or dBP ;:::110mm Hg),37 and preeclampsia (e.g., proteinuria, thrombocytopenia, elevated serum aspartate aminotransferase [AST], worsening hypertension, severe headaches, or epigastric pain). Data were collected on paper forms and mailed to the Maternal, Infant, and Reproductive Health Research Unit (MIRU) at the Centre for Research in Women's Health, Toronto, where they were scanned into an electronic database. Logic and range checks verified the accuracy of the data, and forms with errors or missing data were returned to participating centres for correction or completion. Data were summarized according to type of hypertension, by mean (±SD) JOGC
or median (interquartile range [IQR]), as appropriate for continuous variables, and by proportions for categorical variables. Prior to the study, we estimated a probability of 5% for our primary outcome: 1 or more serious perinatal complications or birth weight <3rd centile. Each of the 5 participating centres had at least 4000 deliveries per year over the study period. We assumed that 5% of pregnancies would be complicated by non-protein uric hypertension that was either preexisting or gestational, and that 25% of these women would be eligible for inclusion in the study, giving us 250 women in total on which to base the primary outcome, with a 95% confidence interval of [0.025, 0.082]. RESULTS
Between September 1, 1998, and January 10, 2002, there were 2380 hypertensive cases (5.5% of all deliveries) identified for review in the 5 centres. Of these, 305 women were eligible for this study, representing 0.70% of all deliveries and 12.8% of hypertensive deliveries. Based on the data from Vancouver, the most frequent reasons for exclusion were gestational age at diagnosis ;:::34 weeks (77.8%) and/or proteinuria at first presentation with hypertension (9.4%); 18.0% of women presented both at ;:::34 weeks' gestation and with proteinuria. Table 2 presents, by type of hypertension, the characteristics of eligible women and their pregnancies when they first met eligibility criteria. Similar proportions of women had non-protein uric hypertension that was either pre-existing (n = 133 women, 42.6%) or gestational (n = 172 women, 56.4%). Mean maternal age was 32.3 ± 6.0 years at presentation with nonprotein uric hypertension. Similar proportions of women were nulliparous (48.2%) or parous (51.5%) and there were only 15 twin gestations (4.9%). Few (3.3%) of the women were smokers. Predictably, mean gestational age at eligibility was lower in the preexisting hypertension group (I8.5 ± 8.0 weeks) than in the gestational hypertension group (29.5 ± 3.5). At eligibility, dBP was usually in the 90 to 99 mm Hg range, but apparently more frequently for women with pre-existing hypertension (81.2%) compared to those with gestational hypertension (71.5%). Few women (3.6%) had experienced an episode of severe hypertension, prior to eligibility. Of the women who presented at ;:::24 weeks' gestation, estimated fetal weight was available for 192 (63.0%) and, among these, was dOth centile for 8 (4.2%). Table 3 shows the use of non-pharmacological and pharmacological therapies for management of hypertension among the eligible women. Non-pharmacological therapy was prescribed to 78.7% of the women, but there were apparent differences by type of hypertension. Women with gestational (vs. pre-existing) hypertension appeared to more commonly be prescribed any non-pharmacological therapy (84.3% vs. 71.4%), and particularly put on bedrest at home (54.1 % vs. 35.3%) or hospitalized (37.8% vs. 27.1 %), but less frequently advised to quit work MAY 2003
existing hypertension (71.4%) than to those with gestational hypertension (43.0%). Most commonly, women received methyldopa (36.7%), labetalol (26.2%), or a calcium channel blocker (20.3%). Use of other beta-blockers occurred only in women with pre-existing hypertension (7.5%). Table 4 shows that 16.4% (n = 50) of pregnancies, regardless of hypertension type, achieved the primary outcome for CHIPS: 1 or more serious perinatal complications or birth
(16.3% vs. 32.3%). A minority of women were enrolled in an antepartum homecare (APHC) program (10.8%), or asked to attend a day assessment unit (DAU) (6.6%) or perform home BP monitoring (2.6%). Three women, all with pre-existing hypertension, were advised to either reduce their working hours, swim, or present for more frequent hospital visits. Also indicated in Table 3, antihypertensive drug therapy appeared to be more frequently prescribed to women with pre-
TABLE 2 BASELINE INFORMATION AT PRESENTATION WITH NON-PROTEINURIC MILD TO MODERATE HYPERTENSION, BY TYPE OF HYPERTENSION Pre-existing Hypertension wlo Proteinuria (n 133)
=
Gestational Hypertension wlo Proteinuria (n 172)
=
Total N (%) (N
= 30S)
Maternal age at eligibility (y) (mean ± SD)
33.7 ± 5.9
31.2 ± 5.8
32.3 ± 6.0
Gestational age at eligibility (wk) (mean ± SD)
18.5 ± 8.0
29.5 ± 3.5
24.7 ± 8.0
122 (91.7) 4 (3.0) 7 (5.3)
161 (93.6) II (6.4) 0 (0)
283 (92.8) 15 (4.9) 7 (2.3)
54 (40.6) 78 (58.7) I (0.8)
93 (54.1) 79 (45.9) 0
147 (48.2) 157 (51.5) I (0.3)
Smoking history during pregnancy (%) Smoker Nonsmoker Not stated
4 (3.0) 128 (96.2) I (0.8)
6 (3.5) 162 (94.2) 4 (2.3)
10 (3.3) 290 (95.1) 5 ( 1.6)
dBP at eligibility* (%) 90-99 mm Hg (mild hypertension) 100-109 mm Hg (moderate hypertension)
108 (81.2) 25 (18.8)
123 (71.5) 49 (28.5)
231 (75.7) 74 (24.3)
Previous severe hypertension during the pregnancy (%) Yes No Not stated
7 (5.3) 122 (91.7) 4 (3.0)
4 (2.3) 167 (97.1) I (0.6)
II (3.6) 289 (94.8) 5 ( 1.6)
Multiple pregnancy (%) Singleton Twin Missing Parity (%) Nulliparous Multi~arous
Missing
For only those women at eligibility
~24
weeks' gestation
n
Estimated fetal weight < 10th centile t Yes No Not stated Missing
= 37
0 13 (35.1) 20 (54.1) 4 (10.8)
n
= 155
N
= 192
8 75 58 14
(5.2) (48.4) (37.4) (9.0)
8 88 78 18
(4.2) (45.8) (40.6) (9.4)
dBP: diastolic blood pressure.
* Medical records do not usually state whether BP was measured in the sitting position; therefore, all recordings were accepted unless they were stated to have been taken with the woman in the left lateral position. t By ultrasound, done at the time nearest to eligibility.
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37.2 ± 3.2 weeks and the incidence of preterm birth was 34.3%. Apgar scores <7 at 5 minutes were infrequent (4.0%), but 15.0% of babies required admission to a neonatal intensive care unit (NICU), and 8.7% of babies remained there for more than 7 days. Most records did not have information about umbilical arterial blood pH (n = 201, 67% missing) or base deficit (n = 216, 72% missing). In addition to the 30 babies with RDS, another 34 babies received supplemental oxygen in the first 24 hours of life, without assisted ventilation or surfactant, presumably for a diagnosis of transient tachypnea of the newborn. Table 6 shows that 6 women (2.0%) had serious maternal complications, 2 with pre-existing hypertension and 4 with gestational hypertension. The complications (which are not mutually exclusive) were severe HELLP syndrome (0.7%), pulmonary edema (0.7%), eclampsia (0.3%), and/or coagulopathy (0.3%). Preeclampsia developed in 30.8% of women, at a mean gestational age of33.2 ± 4.4 weeks. The incidence was similar among women who received non-pharmacological therapy (80/240 [33.3%]),
weight <3rd centile for gestational age and gender. One or more serious perinatal complications occurred in 11.7% (n = 36) of pregnancies. There were 9 (2.9%) perinatal deaths, 2 of which were neonates with congenital heart disease that was unrecognized at eligibility. The most common serious perinatal morbidity was RDS (n = 30,10%), which occurred with similar frequency in all centres. Of these 30 babies, 13 (43.3%) received surfactant, 20 (66.7%) were born at ::;32 weeks' gestation, and 300.0%) were born at term (37 to 42 weeks' gestation). Overall, 4.7% (n = 14) of babies had birth weight <3rd centile. In all, 68.0% (n = 34) of babies with either 1 or more serious perinatal complication(s) or birth weight <3rd centile for gestational age and gender were born at <34 weeks' gestation. Table 5 shows that 52 babies 07.3%) were born with birth weight < 10th centile, possibly more frequently in the setting of gestational (19.9%) rather than pre-existing (14.0%) hypertension. Other perinatal outcomes did not appear to differ by type of hypertension. Mean gestational age at delivery was
TABLE 3 TREATMENT OF HYPERTENSION DURING PREGNANCY, BY TYPE OF HYPERTENSION
Pre-existing Hypertension w/o Proteinuria (n 133)
Gestational Hypertension w/o Proteinuria (n 172)
(N
Non-pharmacological therapy for hypertension (as indicated in the medical record)*t Advised to quit work Put on bed rest at home Hospitalized Other (as stated): Antepartum home care Day assessment unit Home BP monitoring Other therapies
95 (71.4)
145 (84.3)
240 (78.7)
43 47 36 30 14 7 6 3
(32.3) (35.3) (27.1) (22.6) (10.5) (5.3) (4.5) (2.3)
28 93 65 34 19 13 2 0
(16.3) (54.1) (37.8) (19.8) (11.1) (7.6) ( 1.2)
71 140 101 64 33 20 8 3
(23.3) (45.9) (33.1) (21.0) (10.8) (6.6) (2.6) ( 1.0)
Antihypertensive drug therapy * Methyldopa Labetalol Beta-blockers other than labetalol Calcium channel blockers (e.g .• nifedipine XL) Other (as stated): Hydrochlorothiazide Clonidine Hydralazine Hydralazine & clonidine Magnesium sulfate Nadolol
99 63 50 10 27 9 0 I 2 I 4 I
(74.4) (47.4) (37.6) (7.5) (20.3) (6.8)
84 49 30 0 22 12 I 0 I 0 10 0
(48.8) (28.5) (17.4)
183 I 12 80 10 49 21 1 1 3 I 14 I
(60.0) (36.7) (26.2) (3.3) (16.1) (6.9) (0.3) (0.3) ( 1.0) (0.3) (4.6) (0.3)
=
(0.8) ( 1.5) (0.8) (3.0) (0.8)
=
(12.8) (7.0) (0.6) (0.6) (5.8)
*Responses are not mutually exclusive. All missing answers were recorded as "no." tThese were used specifically to treat hypertension. and not other obstetric complications (e.g .• IUGR). BP: blood pressure; IUGR: intrauterine growth restriction.
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Total N (%)
=305)
pharmacological therapy (68/183 [37.2%]), and/or had a previous episode of severe hypertension in the index pregnancy (4/11 [36.4%]). After presenting with mild to moderate hypertension (dBP 90--109 mm Hg), 114 women (37.4%) subsequently developed severe hypertension, despite "tight" control ofBP being the norm in the participating centres. The incidence of severe hypertension was greatest among women who had already had an
episode of severe hypertension in the index pregnancy (10/11 [90.9%]), compared with those on either pharmacological (with or without non-pharmacological) therapy (85/183 [46.4%]) or non-pharmacological therapy (921240 [38.3%]). Regardless of hypertension type, almost half of the women underwent induction oflabour (45.9%), or were delivered by Caesarean section (43.3%) as indicated in Table 6. Placental
TABLE 4 PRIMARY OUTCOME FOR CHIPS (BIRTH WEIGHT <3RD CENTILE OR I OR MORE SERIOUS PERINATAL COMPLICATIONS) BY TYPE OF HYPERTENSION Pre-existing Hypertension w/o Proteinuria (n = 133)
Primary outcome (one or more of the following)' Fetal death Due to congenital anomalies
23 (17.3) 4 (3.0) 0
For the following outcomes, the 5 stillbirths have been excluded: Birth weight <3rd centile for gestational age and gendert Neonatal death Congenital heart disease Multiple cardiac anomalies Adequate ventilation not achieved Prematurity Respiratory distress syndrome (RDS) Received surfactant Bronchopulmonary dysplasia (BPD) Intraventricular hemorrhage (IVH) (grade 3 or 4 or at autopsy) Cystic periventricular leukomalacia (PVL) Retinopathy of prematurity (ROP) (stage 3 or 4) Necrotizing enterocolitis (NEC)
(n
= 129)
5 2 0 I I 0 14 6 I I
(3.9) ( 1.6) (0.8) (0.8) (10.9) (4.7) (0.8) (0.8)
0 I (0.8) I (0.8)
Gestational Hypertension w/o Proteinuria (n = 172)
27 (15.7) I (0.6) 0 (n 9 2 I 0 0 I 16 7 0 I
= 171) (5.3) ( 1.2) (0.6)
(0.6) (9.4) (4.1) (0.6)
0 0 I (0.6)
Total N (%) (N = 30S)
50 (16.4) 5 ( 1.6) 0 (N 14 4 I I I I 30 13 I 2
= 300) (4.7) ( 1.3) (0.3) (0.3) (0.3) (0.3) (10.0) (4.3) (0.3) (0.7)
0 I (0.3) 2 (0.7)
*Definitions: Fetal death (stillbirth): death of a fetus
~500
g or at
~20
weeks' gestation
Neonatal death: death of a newborn at <28 days of age Respiratory distress: after initial resuscitation, the requirement for assisted ventilation and supplemental oxygen within the first 24 hours of life BPD: requiring oxygen at a postnatal gestational age of 36 completed weeks and X-ray compatible with BPD IVH grade 3 or 4: diagnosed on or before day 28 of life. by the most severe grade on cranial ultrasound. using categorization of Papile et 0/.,34 or at autopsy Cystic PVL: periventricular cystic changes in the white matter, excluding subependymal and choroid plexus cysts. diagnosed on or before day 28 of life. by cranial ultrasound or at autopsy ROP stages 3 to 5 in one or both eyes: intraretinal ridge with extraretinal fibrovascular proliferation. or retinal detachment. respectively. by the worst stage in the most severely affected eye NEC: perforation of the intestine. pneumatosis intestinalis. or air in the portal vein, diagnosed by X-ray. surgery. or at autopsy tTwo birth weights are missing. one in each group.
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abruption was rare (1.6%). The maternal stay in hospital was usually brief: only 1 day (IQR, 0-4) before delivery, and 3 days (IQR, 2-4) postpartum. DISCUSSION
Hypertension complicates 7% to 9% of pregnancies,38 and is associated with an increased maternal and perinatal risk, even in the absence of proteinuria. 15-25,39 However, there is very little information about the presumably higher risk population of women who present with either a pre-existing or a gestational non-protein uric hypertension, at <34 weeks' gestation. 25 -29 In this international retrospective cohort study, such women represented 12.8% of hypertensive pregnancies, but had a high risk of associated perinatal and maternal adverse outcomes, regardless of whether the non-proteinuric hypertension was pre-existing or gestational. Clearly, these results are important from a population health perspective, as these women represent approximately 45 000 deliveries per year in Canada. In this study, non-proteinuric hypertension, with onset before 34 weeks' gestation, was associated with a 16.4% incidence of one or more serious perinatal complications 01.7%) or birth weight <3rd centile (4.7%). Of the babies, 32% were born at ~34 weeks' gestation, although overall the incidence of indicated preterm birth was high (34%) and 9% of babies stayed in the NICU for more than 7 days. Also,
17% of babies had birth weight dOth centile, the more traditional definition of SGA. Being SGA, even across the normal range of birth weight,40 is a risk factor for short-term neonatal complications, adverse neurological outcomes and cognitive function in childhood, and cardiovascular and endocrine complications in adulthood, possibly because of irreversible in utero metabolic adaptations (the Barker Hypothesis).41,42 Our population of women with non-protein uric hypertension with onset before 34 weeks' gestation also had a clinically important risk of maternal complications. One-third (most of whom were nonsmokers) developed preeclampsia and 2% end-organ failure and/or eclampsia. At least 1 episode of severe hypertension (after presentation with mild to moderate hypertension) occurred in 40% of cases, despite few (5%) having had it earlier in the pregnancy and the fact that the study was conducted in centres where "tight" control of BP is the norm. Also, there was a high incidence of obstetric intervention, even compared with hypertensive pregnancies. 11,43 Almost half of the women underwent induction of labour because of hypertension, and over 40% had a Caesarean section. There are limitations to our study. Although retrospective and not population-based, the study was performed in centres providing tertiary care in a variety of health-care systems, including those with different levels of resources. All centres contributed to the outcomes reported; however, the relatively small sample
TABLE 5
OTHER PERINATAL OUTCOMES, BY TYPE OF HYPERTENSION* Pre-existing Hypertension w/o Proteinuria (n = 129) Birth weight < 10th centile t Birth weight <2500 g Birth weight < 1250 g Birth weight (g) (mean ± SD) Gestational age at delivery (wk) (mean ± SD) Birth at <37 wk Birth at <34 wk Apgar score 5 mint <4 at 5 min <7 at 5 min Admission to NICU (Level III nursery) Stay in NICU >24 hours Stay in NICU >7 d On oxygen at 2S d of life
Gestational Hypertension w/o Proteinuria (n = 171)
Total N (%)
(N = 300)
18 (14.0) 38 (28.6) 12 (9.0%) 2785.9 ± 883.5 37.1 ± 3.5 40 (31.0) 22 (17.1)
34 ( 19.9) 53 (30.8) 10 (5.8%) 2797.9 ± 802.1 37.2 ± 2.9 63 (36.S) 24 ( 14.0)
52(17.3) 91 (29.8) 22 (7.2%) 2792.7 ± 837.0 37.2 ± 3.2 103 (34.3) 46 (15.3)
I (O.S) 3 (2.3) IS (14.0) 14 (10.9) II (S.5) 6 (4.7)
I (0.6) 9 (5.3) 27 (15.S) 26 ( 15.2) 15 (S.S) 0
2 (0.7) 12 (4.0) 45 (15.0) 40 (13.3) 26 (S.7) 6 (2.0)
*The total N reflects the exclusion of 5 stillborn babies. tTwo birth weights are missing, one in each group. +A 5-minute Apgar is missing from the pre-existing hypertension group. NICU: neonatal intensive care unit.
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TABLE 6
MATERNAL OUTCOMES, BY TYPE OF HYPERTENSION Pre-existing Hypertension w/o Proteinuria (n 133)
=
Serious maternal complications' (one or more of the following)
Gestational Hypertension w/o Proteinuria (n 172)
Total N (%)
6 (2.0)
=
(N
=30S)
2 ( 1.5)
4 (2.3)
Death
0
0
0
Stroke
0
0
Eclampsia
0
I (0.6)
0 I (0.3)
Multiple organ dysfunction - one or more of:
2 ( 1.5)
3 ( 1.7)
5 ( 1.6)
Pulmonary edema
I (0.8)
I (0.6)
2 (0.7)
ARDS
0
0
0
Respiratory arrest
0
0
0
Cardiovascular failure
0
0
0
Severe HELLP syndrome
0
2 ( 1.2)11
2 (0.7)11
Hepatic failure
0
0
0
Renal failure
0
0
0
Coagulopathy
I (0.8)
0
39 (29.3)
I (0.3)
32.0 ± 5.2
55 (32.0) 34.2 ± 3.411
33.2 ± 4.4
Sustained severe hypertension+
54 (40.6)
60 (34.9)
I 14 (37.4)
Induction of labour
63 (47.4)
77 (44.8)
140 (45.9)
Caesarean section
54 (40.6)
78 (45.4)
132 (43.3)
4 (3.0)
I (0.6)
5 ( 1.6)
Preeclampsia t Gestational age at presentation (wk) (mean ± SD)
Placental abruption§
Median (IQR) n 13211
n
4 (2. 7)
5 (2.8)
4 (2.8)
I (0. 3.5) 3 (2.4)
I (0.4) 3 (1.4)
I (0.4) 3 (2.4)
=
No. maternal days in hospital II Before delivery After delivery
Median (IQR)
94 (30.8)
= 172
Median (IQR) N 304
=
* Serious maternal complications (up to 6 weeks postpartum): death or I or more life-threatening maternal complications defined as:
I. Stroke: acute neurological event with deficits lasting >24 hours. not due to a post-ictal state 2. Eclampsia: a generalized convulsion in the absence of a history of epilepsy 3. Multiple organ dysfunction. one or more (as recorded in the chart) of the following: pulmonary edema; ARDS (acute respiratory distress syndrome); respiratory arrest; cardiovascular failure in the absence of hemorrhage (e.g .• arterial sBP <::;70 mm Hg for at least I hour despite adequate fluid resuscitation. adequate intravascular volume. or the use of vasopressors to maintain sBP >90 mm Hg or mean arterial BP >70 mm Hg); severe HELLP (hemolysis. elevated liver enzymes. low platelets) syndrome requiring blood products; hepatic failure (e.g .• increased liver enzymes. conjugated hyperbilirubinemia and either hypoglycemia or INR > 1.2); renal failure (e.g .• serum creatinine >200 IJM); coagulopathy (e.g .• decreased fibrinogen below normal reported by local laboratory). t Development of proteinuria (~0.3 g/d by 24-hour urine collection. or 2 dipstick results of ~2+ in the event that 24-hour
urinary protein was not completed); or thrombocytopenia (platelets < I 00 000 x 109/L). + sBP > 170 mm Hg or dBP > I 10 mm Hg. §
Diagnosed clinically by abdominal pain or uterine contractions. with I or more of vaginal bleeding, intrauterine fetal death. and/or disseminated intravascular coagulation.
II One response is missing. IQR: interquartile range; sBP: systolic blood pressure; dBP: diastolic blood pressure; INR: international normalized ratio. JOGe
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size from any given centre did not allow for between-centre comparisons in outcome event rates. We showed that the outcomes were easily abstracted from the medical record, with very little missing data. The prevalence of hypertensive pregnancies identified was low at 5.5%. We could have missed some cases miscoded by the ICD system. Also, we identified only births at ;:::20 weeks' gestation, and therefore, would have missed women with pre-existing non-protein uric hypertension who suffered a miscarriage. Unfortunately, there was minimal information about the proportion of eligible pregnancies complicated by fetal growth restriction at presentation with maternal hypertension. We do not know how best to manage the hypertension of women who present at <34 weeks' gestation with either preexisting or gestational non-protein uric hypertension. This study focused on centres where "tight" control of BP is the norm, achieved by non-pharmacological means in 79% of cases, and/or antihypertensive therapy in 60% of cases. A large RCT is needed to assess whether "less tight" control, aiming for a higher dBp, could reduce the risk of perinatal complications. We are planning to have CHIPS determine whether "less tight" control (aiming for a dBP of 100 mm Hg) of mild to moderate maternal hypertension improves perinatal outcome (decreases the incidence of 1 or more serious perinatal complication[sl or birth weight <3rd centile for gestational age and gender) compared to "tight" control (aiming for a dBP of 85 mm Hg). CHIPS will enrol women with either pre-existing or gestational non-protein uric hypertension, presenting at <34 weeks' gestation. Based on the findings of this study, the CHIPS trial will need to enrol 1200 women/group to find a clinically important reduction in the incidence of serious perinatal complications or birth weight <3rd centile, from 16% to 12% (2-tailed, ex = 0.05, power of80%). This sample size would have 80% power of finding a 5.5% increase in the incidence of severe hypertension, or a 1.6% increase in serious maternal complications, associated with "less tight" control.
receives salary support and Establishment Funding from the BC Research Institute for Children's and Women's Health. M.E.H. has a Senior Scientist award from the Canadian Institutes of Health Research. Special thanks to the CHIPS Steering Committee. Also, we wish ro thank Darren McKay of MIRU for programming, Parvinder Birdi for assisting with data collection in Vancouver, and the Medical Records and Data Coding Departments of all participating institutions without whose assistance this study could not have been completed. REFERENCES I.
2.
3.
4.
5.
6.
7.
8.
9.
10.
CONCLUSION
Women who present with non-protein uric hypertension before 34 weeks' gestation represent a high-risk subpopulation of hypertensive pregnancies. It is imperative that we know how to manage their hypertension in order to optimize perinatal outcomes and minimize maternal risks. The CHIPS trial is designed to answer this important question for women in Canada and abroad.
I I.
12.
13.
ACKNOWLEDGEMENTS
The Maternal Infant and Reproductive Health Research Unit (MIRU) graciously provided support for this study. L.M. receives salary support from the BC Women's Hospital Foundation, and received an Establishment Grant from the BC Research Institute for Children's and Women's Health. P.vD. JOGC
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Wittmann BK, Murphy KJ, King JF,Yuen BH, Shaw D, Wittmann AG. Maternal mortality in British Columbia in 1971--86. Can Med Assoc J 1988; 139:37-40. Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol 2000; 183:S I-S22. Brown MA, Hague WM, Higgins J, Lowe S, McCowan L, Oats J, et al. The detection, investigation and management of hypertension in pregnancy: executive summary [review]. Aust N Z J Obstet Gynaecol 2000;40: 133--8. Rey E, LeLorier J, Burgess E, Lange IR, Leduc L. Report of the Canadian Hypertension Society Consensus Conference: 3. Pharmacologic treatment of hypertensive disorders in pregnancy. Can Med Assoc J 1997;157:1245-54. Blake S, MacDonald D.The prevention of the maternal manifestations of pre-eclampsia by intensive antihypertensive treatment. Br J Obstet Gynaecol 1991 ;98:244--8. Bortolus R, Ricci E, Chatenoud L, Parazzini F. Nifedipine administered in pregnancy: effect on the development of children at 18 months. Br J Obstet Gynaecol 2000; I07:792-4. Catalano D, Ercolano S, Pollio F, Ascione L, Russo C, DeSanti B, et al. Valuazione della monoterapia con nifedipina nel management della gestosi EPH [Evaluation of nifedipine monotherapy in the management of pregnancy hypertension]. Giorn It Ost Gin 1997;6:373-5. Gruppo di Studio Ipertensione in Gravidanza. Nifedipine versus expectant management in mild to moderate hypertension in pregnancy. Br J Obstet Gynaecol 1998; I05(7):718-22. Magee LA, Ornstein MP, von Dadelszen P. Fortnightly review: management of hypertension in pregnancy [review]. BMJ 1999;318(7194): 1332-6. Odendaal HJ, Schabort I, Pattinson RC. Prazosin for the treatment of hypertension in pregnancy: a randomized control trial [database on CD-ROM].Version 1.2 (Disk Issue 6). Oxford Database of Perinatal Trials 1991. Abalos E, Duley L, Steyn DW, Henderson-Smart DJ. Antihypertensive drug therapy for mild to moderate hypertension during pregnancy (Cochrane Review).ln:The Cochrane Library, Issue I 2003. Oxford: Update Software. Magee LA, Duley L. Oral beta-blockers for mild to moderate hypertension during pregnancy (Cochrane Review).ln:The Cochrane Library, Issue I 2003. Oxford: Update Software. von Dadelszen P, Ornstein MP, Bull SB, Logan AG, Koren G, Magee LA. Fall in mean arterial pressure and fetal growth restriction in pregnancy hypertension: a meta-analysis. Lancet 2000;355(9198):87-92. Misra DP. The effect of the pregnancy-induced hypertension on fetal growth: a review of the literature [review]. Paediatr Perinat Epidemiol 1996; I0:244-63. Ferrazzani S, Caruso A, De Carolis S, Martino IV, Mancuso S. Proteinuria and outcome of 444 pregnancies complicated by hypertension. Am J Obstet Gynecol 1990; 162:366-71.
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16. McCowan LM. Buist RG. North RA. Gamble G. Perinatal morbidity in chronic hypertension. Br J Obstet Gynaecol 1996; 103: 123-9. 17. Lydakis C. Beevers DG. Beevers M. Lip GY. Obstetric and neonatal outcome following chronic hypertension in pregnancy among different ethnic groups. Q J Med 1998;91 (12):837-44. 18. Mabie WC. Pernoll ML. Biswas MK. Chronic hypertension in pregnancy. Obstet Gynecol 1986;67: 197-205. 19. Ray JG. Burrows RF, Burrows EA. Vermeulen MJ. MOS HIP: McMaster Outcome Study of Hypertension In Pregnancy. Early Hum Dev 200 I ;64: 129-43. 20. Ray JG.Vermeulen MJ. Burrows EA, Burrows RF. Use of antihypertensive medications in pregnancy and the risk of adverse perinatal outcomes: McMaster Outcome Study of Hypertension In Pregnancy 2 (MOS HIP 2). BMC Pregnancy Childbirth 200 I; I:6. 21. Rey E. Couturier A. The prognosis of pregnancy in women with chronic hypertension. Am J Obstet Gynecol 1994; 171 :41 ~. 22. Sibai BM. Abdella TN. Anderson GD. Pregnancy outcome in 21 I patients with mild chronic hypertension. Obstet Gynecol 1983;61 (5):571-6. 23. Sibai BM. Anderson GD. Pregnancy outcome of intensive therapy in severe hypertension in first trimester. Obstet Gynecol 1986;67:517-22. 24. Sibai BM. Lindheimer MD. Hauth J. Caritis S. VanDorsten P, Klebanoff M. et al.. for the National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. Risk factors for preeclampsia. abruptio placentae. and adverse neonatal outcomes among women with chronic hypertension. N Engl J Med I998;339( I0):667-71. 25. Barton JR. O'Brien JM. Bergauer NK.Jacques DL. Sibai BM. Mild gestational hypertension remote from term: progression and outcome. Am J Obstet Gynecol 200 I; 184(5):979~3. 26. Brown MA, Buddie ML. The importance of nonproteinuric hypertension in pregnancy. Hypertens Pregn 2002; 14:57-65. 27. Horsager R. Adams M. Richey S. Leveno KJ. Cunningham FG. Outpatient management of mild pregnancy induced hypertension. 15th Annual Meeting of the Society of Perinatal Obstetricians; 1995; Atlanta. Georgia. 28. Saudan P, Brown MA, Buddie ML.Jones M. Does gestational hypertension become pre-eclampsia? Br J Obstet Gynaecol 1998; I05( II): I 177--84. 29. Scott A. MoarV, Ounsted M.The relative contributions of different maternal factors in small-for-gestational-age pregnancies. Eur J Obstet Gynecol Reprod Bioi 1981; 12: 157-65. 30. Helewa ME. Burrows RF. Smith J. Williams K. Brain P, Rabkin SW Report of the Canadian Hypertension Society Consensus Conference: I. Definitions. evaluation and classification of hypertensive disorders in pregnancy. Can Med Assoc J 1997; 157:715-25. 31. Feldman RD. Campbell N. Larochelle P, Bolli P, Burgess ED. Carruthers SG. et al. 1999 Canadian recommendations for the management of hypertension. Task Force for the Development of the 1999 Canadian Recommendations for the Management of Hypertension. Can MedAssocJ 1999;161(SuppI12):SI-17. 32. Kramer MS. Platt RW,Wen SW,Joseph KS. Allen A, Abrahamowicz M. et al. A new and improved population-based Canadian reference for birth weight for gestational age. Pediatrics 200 I; 108:E35. 33. Shennan AT. Dunn MS. Ohlsson A. Lennox K. Hoskins EM. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 1988;82:527-32. 34. Papile LA. Burstein J. Burstein R. Koffler H.lncidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1.500 gm.J Pediatr 1978;92(4):529-34. 35. Walsh MC. Kliegman RM. Fanaroff AA. Necrotizing enterocolitis: a practitioner's perspective. Pediatr Rev 1988;9:219-26. 36. Bone RC. Balk RA. Cerra FB. Dellinger RP, Fein AM. Knaus WA, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992; I0 I: 1644-55.
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37. Davey DA. MacGillivray I.The classification and definition of the hypertensive disorders of pregnancy. Am J Obstet Gynecol 1988; 158(4):892~. 38. Lindberg BS. Epidemiology of hypertension during pregnancy. Int J Technol Assess Health Care I992;8(Suppl 1):57-62. 39. Allen VM.The effect of hypertensive disorders in pregnancy on perinatal outcomes: a population-based cohort study. Ottawa: National Library of Canada; 2002. 40. Godfrey KM. Barker DJ. Fetal programming and adult health [review]. Public Health Nutr 200 1;4:61 1-24. 41. Barker DJ.The long-term outcome of retarded fetal growth. Clin Obstet Gynecol 1997;40:853-63. 42. Strauss RS. Adult functional outcome of those born small for gestational age: twenty-six-year follow-up of the 1970 British Birth Cohort. JAm Med Assoc 2000;283(5):625-32. 43. Hjertberg R. Belfrage P, Hanson U. Conservative treatment of mild and moderate hypertension in pregnancy. Acta Obstet Gynecol Scand 1992;71 (6):439-46.
The Management of Uterine Leiomyomas This issue of the IOGC includes a Self-Directed Learning Module on The Management of Uterine Leiomyomas. This module qualifies for credits under Section 2 of the Maintenance of Certification Program of the Royal College ofPhysicians and Surgeons of Canada. Don't miss this valuable self-directed learning module on The Management of Uterine Leiomyomas. Supported by an unrestricted educational grant from
Wyeth" 2003 Wyeth Canada Montreal, Canada H4R U6
~
MAY 2003
J. G. Thornton, MD, FRCOG,12 M.
Abdalla, MD, MRCOG, 13 S. Walkinshaw, MD, MRCOG, 14 M. Brown, MD, FRACp, IS
G. Davis, MD, FRANZCOG,16 M. E. Hannah, MD, MSc, FRCSCI7 IBCWomen's Hospital and Health Centre.Vancouver BC IDepartment of Medicine. University of British Columbia. Vancouver BC 1.2Department of Obstetrics and Gynaecology. University of British Columbia. Vancouver BC 3Faculty of Medicine. University College. Cork. Ireland 4Departments of Medicine and Obstetrics and Gynaecology. University of Montreal. Montreal QC 5Department of Obstetrics and Gynaecology.The Islamic Hospital.Amman.Jordan 6.7.8.17University of Toronto Maternal Infant and Reproductive Health Research Unit, Centre for Research in Women's Health. Toronto ON 7. 17Department of Health Policy and Evaluation. University of Toronto. Toronto ON 17Department of Obstetrics and Gynaecology. Sunnybrook and Women's College Health Sciences Centre. University of Toronto. Toronto ON 9Samuel Lunenfeld Research Institute and Department of Medicine. Mount Sinai Hospital. University of Toronto. Toronto ON IODepartment of Pediatrics. Mount Sinai Hospital. University of Toronto. Toronto ON II Department of Obstetrics and Gynaecology. University of Leeds. Leeds. UK 12Department of Obstetrics and Gynaecology. University of Nottingham, Nottingham. UK 13. I4liverpool Women's Hospital. University of liverpool. liverpool, UK 15Departments of Renal Medicine and Medicine, St. George Hospital and Hurstville Community Hospital, University of New South Wales, Sydney. Australia 16Department of Obstetrics. St. George Hospital and Hurstville Community Hospital. University of New South Wales, Sydney, Australia Abstract Objective: To determine the proportion of births complicated by either a pre-existing or a gestational non-proteinuric hypertension, presenting at <34 weeks' gestation, and the associated incidence with I or more serious perinatal complications or birth weight <3rd centile for gestational age. Methods: A retrospective chart review was conducted in 5 international centres, from 1998 to 2002, where "tight" control (normalization) of blood pressure (BP) is the norm. International Classification of Diseases (ICD) codes were used to identify women who delivered at ::::20 weeks' gestation, with any hypertensive disorder of pregnancy. Women were included if they had a diastolic blood pressure (dBP) of 90 to 109 mm Hg, due to either a pre-existing or a gestational non-proteinuric hypertension, presenting at <34 weeks' gestation. Women were excluded if they had ongoing severe hypertension, or if at presentation with dBP of 90 to 109 mm Hg, they had I or more of the following: proteinuria, an indication for "tight" control of BP or
KeyWords
imminent delivery, or a known intrauterine fetal death or lethal fetal anomaly. Data were collected on paper forms, scanned into an electronic database, and summarized descriptively by type of hypertension. Results: There were 305 eligible women (0.7% deliveries, 12.8% hypertensive deliveries) identified with non-proteinuric hypertension that was either pre-existing (133 [43.6%]) or gestational (172 [56.4%]). Regardless of hypertension type, 16.4% (n = 50) of pregnancies were complicated by birth weight <3rd centile or I or more serious perinatal complications, 34.3% (n = 100) by preterm birth, 30.8% (n = 94) by preeclampsia, and 2.0% (n = 6) by serious maternal complications. Conclusion: Non-proteinuric pre-existing or gestational hypertension, presenting before 34 weeks' gestation, identifies a subpopulation of hypertensive pregnant women at both substantial perinatal risk and maternal risk. The CHIPS (Control of Hypertension In Pregnancy Study) trial is designed to determine how best to manage the hypertension of such women in order to optimize perinatal outcome. Resume Objectif : Determiner la proportion de naissances compliquees par une hypertension de nature non proteinurique, soit preexistante, so it gestationnelle, avant la 34" semaine de gestation, ainsi que I'incidence connexe d'une ou de plusieurs complications perinatales graves ou d'un poids de naissance (en fonction de I'age gestationnel) inferieur au 3" centile.
Hypertension, pregnancy, pregnancy complications, small for gestational age infants Competing interests: None declared. Received on September 18. 2002 Revised and accepted on December 20, 2002 JOGe
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Methodes : On a mene une etude retrospective des dossiers des patientes, pour la peri ode de 1998 a 2002, dans 5 centres de pays differents Oll iI existait des normes strictes sur la normalisation de la pression arterielle (PA). Le recours aux codes de classification internationale des maladies, traumatismes et causes de deces a permis de savoir quelles femmes, ayant accouche apres 20 semaines ou plus de gestation, etaient atteintes de troubles d'hypertension gestationnelle. On a choisi les femmes ayant une PA diastolique (PAd) de 90 a 109 mm Hg, attribuable a une hypertension non proteinurique gestationnelle ou preexistante, se presentant avant la 34 e semaine de gestation. On a exclu les femmes atteintes d'une hypertension grave continue ou celles qui, au moment oll elles presentaient une PAd de 90 a 109 mm Hg, revelaient une ou plusieurs des caracteristiques suivantes : une proteinurie, une indication laissant entendre qu'iI fallait une « etroite )} surveillance de la PA ou que Ie travail etait imminent, ou une mort fcetale intra-uterine ou une anomalie fcetale letale connues. On a recueilli les donnees sur papier, puis on les a transmises a une base de donnees et on les a classifiees sommairement par type d'hypertension. Resultats : On a identifie 305 femmes admissibles a I'etude (0,7 % des accouchements, 12,8 % des accouchements en presence d'hypertension) en raison d'une hypertension arterielle non proteinurique, soit preexistante (133 [43,6 %]), soit gestationnelle (172 [56,4 %]). Quel qu'ait ete Ie type d'hypertension, 16,4 % (n = 50) des grossesses ont eu des complications en raison d'un poids de naissance inferieur au 3e centile ou d'une complication perinatale grave ou plus; 34,3 % (n = 100), en raison d'une naissance prematuree; 30,8 % (n = 94), en raison d'une preeclampsie et 2,0 % (n = 6), en raison de complications maternelles graves. Conclusion : Avant la 34e semaine de gestation, I'hypertension arterielle non proteinurique, preexistante ou gestationnelle, caracterise une sous-population de femmes enceintes atteintes d'hypertension qui presentent un risque perinatal ou maternel important. L'essai CHIPS (Control of Hypertension In Pregnancy Study) est con<;u pour determiner la meilleure fa<;on de traiter I'hypertension que presentent ces femmes, de maniere a assurer les meilleures issues perinatales possibles.
J Obstet
Gynaecol Can 2003;25(5):372-82.
INTRODUCTION
Hypertensive disorders of pregnancy are leading causes of maternal and perinatal mortality and morbidity worldwide. 1 There is general agreement that treatment of severe pregnancy hypertension, usually defined as a sustained blood pressure (BP) measurement of ~ 170/ 11 0 mm Hg, is necessary to reduce the risk of maternal mortality and serious morbidity, such as stroke. 2-4 However, how best to manage mild to moderately elevated BP in pregnancy is controversial. Serious maternal complications are rare; no deaths or strokes were reported among 26 trials enrolling 2280 women. 5-IO The perinatal risks are uncertain as indicated by the results of randomized clinical trials (RCTs) for management of mild to moderate pre-existing or gestational hypertension, in which normalization of BP may be hannfol as it could JOGC
increase the risk of small for gestational age (SGA) infants. 9,11-13 However, normalization ofBP may be beneficial in decreasing the risk of maternal BP measurements of 160/100-110 mm Hg, antenatal hospitalization, proteinuria at delivery, and respiratory distress syndrome (RDS).9 Unfortunately, sufficient confidence cannot be placed in these results because of reporting bias and uncertainty about the clinical relevance of the outcomes as defined. 12 Not surprisingly, international guidelines differ. 2-4 The literature describing maternal or perinatal outcomes associated with mild to moderate hypertension is problematic due to variability in definitions of maternal or perinatal outcomes, failure to account for factors (including antihypertensive therapy) that may confound the BP-fetal growth relationship, and remote publication dates associating outcomes with now outdated methods of perinatal care. 14 Therefore, among women with non-protein uric hypertension, it is difficult to estimate reliably the incidence of serious perinatal complications or birth weight <3rd centile for gestational age and gender. Despite these problems, for women with pre-existing hypertension, estimates of perinatal mortality, SGA infants, and some complications of preterm delivery are available. 15-24 However, very little information about these outcomes is available for women with non-protein uric gestational hypertension, who present at less than 34 weeks' gestation and who are thought to be at increased risk. 25-29 To examine the incidence of these clinically relevant outcomes, we conducted an international, multicentre, retrospective cohort study, designed to estimate the proportion of births complicated by either a pre-existing or a gestational non-proteinuric hypertension presenting at <34 weeks' gestation, and the associated incidence of serious perinatal complications or birth weight <3rd centile for gestational age and gender. This is also the primary outcome for CHIPS (Control of Hypertension In Pregnancy Study), a protocol describing an RCT to determine if "less tight" control (aiming for a diastolic BP [dBP] of 100 mm Hg) of mild to moderate maternal hypertension, presenting before 34 weeks' gestation, improves perinatal outcome compared to "tight" control (aiming for a dBP of85 mm Hg). METHODS
This chart review of hypertensive pregnancies was conducted from September 1, 1998, to January 10, 2002, in 5 institutions: BC Women's Hospital and Health Centre, Vancouver, BC; Ste. Justine Hospital, Montreal, QC; The Islamic Hospital, Amman, Jordan; Leeds General Infirmary, Leeds, UK; and Liverpool Women's Hospital, Liverpool, UK. In all centres, normalization of dBP in pregnancy (i.e., "tight" control) was the standard of care by informal policy. Computerized records and International Classification of Diseases (lCD) codes (Table 1) were used to identify the charts of consecutive women who delivered at ~o weeks' gestation, with a diagnosis of pregnancy hypertension. MAY 2003
Women were eligible if they had non-protein uric, mild to moderately elevated dBP (90 to 109 mm Hg, measured twice at the same visit or on 2 consecutive outpatient visits) due to a preexisting or a gestational hypertension, and were at <34 weeks' gestation at first presentation with hypertension. Pre-existing hypertension was defined as hypertension diagnosed before pregnancy or in the first 20 weeks' gestation, and gestational hypertension as that diagnosed at :220 weeks' gestation. 13,30 Women were eligible only if hypertensive before 34 weeks' gestation, in order to identifY fetuses who were more likely to remain in utero longer and thus have greater opportunity to be affected by the type ofBP control and the underlying pathology. Women were enrolled whether or not they were on antihypertensive medication when they met the inclusion criteria. Women were excluded if they had severe systolic hypertension (defined as a systolic blood pressure [sBP] :2170 mm Hg); proteinuria (defined as :20.3 g/d by 24-hour urine collection, or by urinary dipstick testing of:21+, unless 24-hour urinary protein was shown to be <0.3 gld)13,30; a prepregnancy condition that mandated normalization ofBP in pregnancy (e.g., renal disease)31; an indication for imminent delivery for maternal or fetal reasons (e.g., suspected preeclampsia); therapy with atenolo!, angiotensin converting enzyme inhibitors, or angiotensin-II receptor antagonists throughout pregnancy; known intrauterine fetal death; or lethal fetal anomaly.
The inpatient charts of eligible women and their babies were reviewed. Outpatient charts were reviewed only for data on antihypertensive or non-drug management of hypertension. The following baseline information was recorded at the time of eligibility: type of maternal hypertension; maternal age; gestational age; multiple pregnancy; parity; smoking during pregnancy; severity of hypertension (by dBP at enrolment: mild [dBP 90-99 mm Hgl or moderate [dBP 100-109 mm Hgl); whether there was any severe hypertension (sBP :2170 mm Hg or dBP :2110 mm Hg) in the index pregnancy prior to eligibility; and for women enrolled at >24 weeks' gestation, whether the estimated fetal weight was <10th centile for gestational age and gender. 13,32 Data were collected on the development of severe hypertension; preeclampsia (defined as new or worsening hypertension with 1 or more of the following: proteinuria, thrombocytopenia, elevated liver enzymes, severe headache, or epigastric pain)3,13,30; and the subsequent use of non-pharmacological therapy specifically to lower BP (e.g., advice to quit work) and pharmacological antihypertensive therapies. Data were also abstracted on use of other medications in labour, maternal transfers to the intensive care unit (lCU), timing and method of delivery, type of analgesia or anaesthesia for delivery, and the type of neonatal resuscitation and care. The proportion of births complicated by a pre-existing or a
TABLE I INTERNATIONAL CLASSIFICATION OF DISEASES (ICD) CODES FOR CHART SELECTION ICD-9 Code Definition
642.0
Benign essential hypertension complicating pregnancy, childbirth, and the puerperium ("A pregnancy-induced hypertensive condition characterized by albuminuria and edema, specified as mild or unspecified:')
642.2
Other pre-existing hypertension complicating pregnancy, childbirth, and the puerperium ("PerSistently high arterial blood pressure resulting in [either] heart and kidney functional abnormalities, functional cardiac abnormalities, [or] functional kidney abnormalities, [or] an accelerated, severe form of persistently high arterial blood pressure.")
642.3
Transient hypertension of pregnancy (''Temporary elevated arterial blood pressure noted during pregnancy.")
642.4
Mild or unspecified preeclampsia ("A pregnancy-induced hypertensive condition characterized by albuminuria [not defined] and edema, specified as mild or unspecified.")
642.5
Severe preeclampsia ("A pregnancy-induced hypertensive condition characterized by albuminuria and edema, specified as severe:' This includes HELLP [hemolysis, elevated liver enzymes, low platelets] syndrome, which is 642.5.)
642.6
Eclampsia ("A pregnancy-induced hypertensive state characterized by convulsions and coma in a previously preeclamptic patient.")
642.7
Preeclampsia or eclampsia superimposed on pre-existing hypertension ("Conditions classifiable to 642.4-642.6, with conditions classifiable to 642.0-642.2 [or] either 642.4 or 642.5 and [either] 642.0 or 642.1.")
642.9
Unspecified hypertension complicating pregnancy, childbirth, or the puerperium ("Use this code when the diagnosis is identified as 'hypertension complicating pregnancy, childbirth, or the puerperium: but is not specified as to type.")
646.2
Proteinuria without hypertension
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gestational non-protein uric hypertension presenting before 34 weeks' gestation and, among these women, the incidence of serious perinatal complications (up to 28 days oflife) or birth weight <3rd centile32 were recorded. 13 Serious perinatal complications were defined as 1 or more of the following: complications of intrauterine growth restriction or preterm birth: stillbirth (death of a fetus ;:::500 g or at ;:::20 weeks' gestation); neonatal death of a newborn at <28 days of age; RDS requiring assisted ventilation and supplemental oxygen within the first 24 hours oflife; broncho-pulmonary dysplasia (BPD), requiring oxygen at a postnatal gestational age of36 completed weeks and X-ray compatible with BPD33; intraventricular hemorrhage (IVH) grade 3 or 4 (by cranial ultrasound, using categorization ofPapile et aL,34 or at autopsy); cystic periventricular leukomalacia (PVL - periventricular cystic changes in the white matter, excluding subependymal and choroid plexus cysts, by cranial ultrasound or at autopsy); signs of retinopathy of prematurity stage 3 to 5 in one or both eyes including intraretinal ridge with extraretinal fibrovascular proliferation, or retinal detachment, by the worst stage in the most severely affected eye; or signs of necrotizing enterocolitis (NEC) including perforation of the intestine, pneumatosis intestinalis, or air in the portal vein, diagnosed by X-ray, surgery, or at autopsy.35 Other outcomes recorded were the incidence of serious maternal complications and birth weight dOth centile. Serious maternal complications were defined, up to 6 weeks postpartum, as death or 1 or more of stroke, eclampsia, or end-organ failure. Endorgan failure included 1 or more (as recorded in the chart) of the following: pulmonary edema; acute RDS; respiratory arrest; cardiovascular failure (the absence of hemorrhage, an arterial sBP <70 mm Hg for at least 1 hour despite adequate fluid resuscitation, adequate intravascular volume, or the use of vasopressors to maintain sBP >90 mm Hg or mean arterial BP >70 mm Hg)36; severe HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome requiring administration of blood products; hepatic failure (increased liver enzymes, conjugated hyperbilirubinemia and either hypoglycemia or international normalized ratio [INR] > 1.5); renal failure (serum creatinine >200 f1M); or coagulopathy (decreased fibrinogen below normal reported by local laboratory). Also of interest were preterm birth, other measures of neonatal morbidity, Caesarean section, placental abruption, induction oflabour, sustained severe hypertension (sBP ;:::170 mm Hg, or dBP ;:::110mm Hg),37 and preeclampsia (e.g., proteinuria, thrombocytopenia, elevated serum aspartate aminotransferase [AST], worsening hypertension, severe headaches, or epigastric pain). Data were collected on paper forms and mailed to the Maternal, Infant, and Reproductive Health Research Unit (MIRU) at the Centre for Research in Women's Health, Toronto, where they were scanned into an electronic database. Logic and range checks verified the accuracy of the data, and forms with errors or missing data were returned to participating centres for correction or completion. Data were summarized according to type of hypertension, by mean (±SD) JOGC
or median (interquartile range [IQR]), as appropriate for continuous variables, and by proportions for categorical variables. Prior to the study, we estimated a probability of 5% for our primary outcome: 1 or more serious perinatal complications or birth weight <3rd centile. Each of the 5 participating centres had at least 4000 deliveries per year over the study period. We assumed that 5% of pregnancies would be complicated by non-protein uric hypertension that was either preexisting or gestational, and that 25% of these women would be eligible for inclusion in the study, giving us 250 women in total on which to base the primary outcome, with a 95% confidence interval of [0.025, 0.082]. RESULTS
Between September 1, 1998, and January 10, 2002, there were 2380 hypertensive cases (5.5% of all deliveries) identified for review in the 5 centres. Of these, 305 women were eligible for this study, representing 0.70% of all deliveries and 12.8% of hypertensive deliveries. Based on the data from Vancouver, the most frequent reasons for exclusion were gestational age at diagnosis ;:::34 weeks (77.8%) and/or proteinuria at first presentation with hypertension (9.4%); 18.0% of women presented both at ;:::34 weeks' gestation and with proteinuria. Table 2 presents, by type of hypertension, the characteristics of eligible women and their pregnancies when they first met eligibility criteria. Similar proportions of women had non-protein uric hypertension that was either pre-existing (n = 133 women, 42.6%) or gestational (n = 172 women, 56.4%). Mean maternal age was 32.3 ± 6.0 years at presentation with nonprotein uric hypertension. Similar proportions of women were nulliparous (48.2%) or parous (51.5%) and there were only 15 twin gestations (4.9%). Few (3.3%) of the women were smokers. Predictably, mean gestational age at eligibility was lower in the preexisting hypertension group (I8.5 ± 8.0 weeks) than in the gestational hypertension group (29.5 ± 3.5). At eligibility, dBP was usually in the 90 to 99 mm Hg range, but apparently more frequently for women with pre-existing hypertension (81.2%) compared to those with gestational hypertension (71.5%). Few women (3.6%) had experienced an episode of severe hypertension, prior to eligibility. Of the women who presented at ;:::24 weeks' gestation, estimated fetal weight was available for 192 (63.0%) and, among these, was dOth centile for 8 (4.2%). Table 3 shows the use of non-pharmacological and pharmacological therapies for management of hypertension among the eligible women. Non-pharmacological therapy was prescribed to 78.7% of the women, but there were apparent differences by type of hypertension. Women with gestational (vs. pre-existing) hypertension appeared to more commonly be prescribed any non-pharmacological therapy (84.3% vs. 71.4%), and particularly put on bedrest at home (54.1 % vs. 35.3%) or hospitalized (37.8% vs. 27.1 %), but less frequently advised to quit work MAY 2003
existing hypertension (71.4%) than to those with gestational hypertension (43.0%). Most commonly, women received methyldopa (36.7%), labetalol (26.2%), or a calcium channel blocker (20.3%). Use of other beta-blockers occurred only in women with pre-existing hypertension (7.5%). Table 4 shows that 16.4% (n = 50) of pregnancies, regardless of hypertension type, achieved the primary outcome for CHIPS: 1 or more serious perinatal complications or birth
(16.3% vs. 32.3%). A minority of women were enrolled in an antepartum homecare (APHC) program (10.8%), or asked to attend a day assessment unit (DAU) (6.6%) or perform home BP monitoring (2.6%). Three women, all with pre-existing hypertension, were advised to either reduce their working hours, swim, or present for more frequent hospital visits. Also indicated in Table 3, antihypertensive drug therapy appeared to be more frequently prescribed to women with pre-
TABLE 2 BASELINE INFORMATION AT PRESENTATION WITH NON-PROTEINURIC MILD TO MODERATE HYPERTENSION, BY TYPE OF HYPERTENSION Pre-existing Hypertension wlo Proteinuria (n 133)
=
Gestational Hypertension wlo Proteinuria (n 172)
=
Total N (%) (N
= 30S)
Maternal age at eligibility (y) (mean ± SD)
33.7 ± 5.9
31.2 ± 5.8
32.3 ± 6.0
Gestational age at eligibility (wk) (mean ± SD)
18.5 ± 8.0
29.5 ± 3.5
24.7 ± 8.0
122 (91.7) 4 (3.0) 7 (5.3)
161 (93.6) II (6.4) 0 (0)
283 (92.8) 15 (4.9) 7 (2.3)
54 (40.6) 78 (58.7) I (0.8)
93 (54.1) 79 (45.9) 0
147 (48.2) 157 (51.5) I (0.3)
Smoking history during pregnancy (%) Smoker Nonsmoker Not stated
4 (3.0) 128 (96.2) I (0.8)
6 (3.5) 162 (94.2) 4 (2.3)
10 (3.3) 290 (95.1) 5 ( 1.6)
dBP at eligibility* (%) 90-99 mm Hg (mild hypertension) 100-109 mm Hg (moderate hypertension)
108 (81.2) 25 (18.8)
123 (71.5) 49 (28.5)
231 (75.7) 74 (24.3)
Previous severe hypertension during the pregnancy (%) Yes No Not stated
7 (5.3) 122 (91.7) 4 (3.0)
4 (2.3) 167 (97.1) I (0.6)
II (3.6) 289 (94.8) 5 ( 1.6)
Multiple pregnancy (%) Singleton Twin Missing Parity (%) Nulliparous Multi~arous
Missing
For only those women at eligibility
~24
weeks' gestation
n
Estimated fetal weight < 10th centile t Yes No Not stated Missing
= 37
0 13 (35.1) 20 (54.1) 4 (10.8)
n
= 155
N
= 192
8 75 58 14
(5.2) (48.4) (37.4) (9.0)
8 88 78 18
(4.2) (45.8) (40.6) (9.4)
dBP: diastolic blood pressure.
* Medical records do not usually state whether BP was measured in the sitting position; therefore, all recordings were accepted unless they were stated to have been taken with the woman in the left lateral position. t By ultrasound, done at the time nearest to eligibility.
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37.2 ± 3.2 weeks and the incidence of preterm birth was 34.3%. Apgar scores <7 at 5 minutes were infrequent (4.0%), but 15.0% of babies required admission to a neonatal intensive care unit (NICU), and 8.7% of babies remained there for more than 7 days. Most records did not have information about umbilical arterial blood pH (n = 201, 67% missing) or base deficit (n = 216, 72% missing). In addition to the 30 babies with RDS, another 34 babies received supplemental oxygen in the first 24 hours of life, without assisted ventilation or surfactant, presumably for a diagnosis of transient tachypnea of the newborn. Table 6 shows that 6 women (2.0%) had serious maternal complications, 2 with pre-existing hypertension and 4 with gestational hypertension. The complications (which are not mutually exclusive) were severe HELLP syndrome (0.7%), pulmonary edema (0.7%), eclampsia (0.3%), and/or coagulopathy (0.3%). Preeclampsia developed in 30.8% of women, at a mean gestational age of33.2 ± 4.4 weeks. The incidence was similar among women who received non-pharmacological therapy (80/240 [33.3%]),
weight <3rd centile for gestational age and gender. One or more serious perinatal complications occurred in 11.7% (n = 36) of pregnancies. There were 9 (2.9%) perinatal deaths, 2 of which were neonates with congenital heart disease that was unrecognized at eligibility. The most common serious perinatal morbidity was RDS (n = 30,10%), which occurred with similar frequency in all centres. Of these 30 babies, 13 (43.3%) received surfactant, 20 (66.7%) were born at ::;32 weeks' gestation, and 300.0%) were born at term (37 to 42 weeks' gestation). Overall, 4.7% (n = 14) of babies had birth weight <3rd centile. In all, 68.0% (n = 34) of babies with either 1 or more serious perinatal complication(s) or birth weight <3rd centile for gestational age and gender were born at <34 weeks' gestation. Table 5 shows that 52 babies 07.3%) were born with birth weight < 10th centile, possibly more frequently in the setting of gestational (19.9%) rather than pre-existing (14.0%) hypertension. Other perinatal outcomes did not appear to differ by type of hypertension. Mean gestational age at delivery was
TABLE 3 TREATMENT OF HYPERTENSION DURING PREGNANCY, BY TYPE OF HYPERTENSION
Pre-existing Hypertension w/o Proteinuria (n 133)
Gestational Hypertension w/o Proteinuria (n 172)
(N
Non-pharmacological therapy for hypertension (as indicated in the medical record)*t Advised to quit work Put on bed rest at home Hospitalized Other (as stated): Antepartum home care Day assessment unit Home BP monitoring Other therapies
95 (71.4)
145 (84.3)
240 (78.7)
43 47 36 30 14 7 6 3
(32.3) (35.3) (27.1) (22.6) (10.5) (5.3) (4.5) (2.3)
28 93 65 34 19 13 2 0
(16.3) (54.1) (37.8) (19.8) (11.1) (7.6) ( 1.2)
71 140 101 64 33 20 8 3
(23.3) (45.9) (33.1) (21.0) (10.8) (6.6) (2.6) ( 1.0)
Antihypertensive drug therapy * Methyldopa Labetalol Beta-blockers other than labetalol Calcium channel blockers (e.g .• nifedipine XL) Other (as stated): Hydrochlorothiazide Clonidine Hydralazine Hydralazine & clonidine Magnesium sulfate Nadolol
99 63 50 10 27 9 0 I 2 I 4 I
(74.4) (47.4) (37.6) (7.5) (20.3) (6.8)
84 49 30 0 22 12 I 0 I 0 10 0
(48.8) (28.5) (17.4)
183 I 12 80 10 49 21 1 1 3 I 14 I
(60.0) (36.7) (26.2) (3.3) (16.1) (6.9) (0.3) (0.3) ( 1.0) (0.3) (4.6) (0.3)
=
(0.8) ( 1.5) (0.8) (3.0) (0.8)
=
(12.8) (7.0) (0.6) (0.6) (5.8)
*Responses are not mutually exclusive. All missing answers were recorded as "no." tThese were used specifically to treat hypertension. and not other obstetric complications (e.g .• IUGR). BP: blood pressure; IUGR: intrauterine growth restriction.
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Total N (%)
=305)
pharmacological therapy (68/183 [37.2%]), and/or had a previous episode of severe hypertension in the index pregnancy (4/11 [36.4%]). After presenting with mild to moderate hypertension (dBP 90--109 mm Hg), 114 women (37.4%) subsequently developed severe hypertension, despite "tight" control ofBP being the norm in the participating centres. The incidence of severe hypertension was greatest among women who had already had an
episode of severe hypertension in the index pregnancy (10/11 [90.9%]), compared with those on either pharmacological (with or without non-pharmacological) therapy (85/183 [46.4%]) or non-pharmacological therapy (921240 [38.3%]). Regardless of hypertension type, almost half of the women underwent induction oflabour (45.9%), or were delivered by Caesarean section (43.3%) as indicated in Table 6. Placental
TABLE 4 PRIMARY OUTCOME FOR CHIPS (BIRTH WEIGHT <3RD CENTILE OR I OR MORE SERIOUS PERINATAL COMPLICATIONS) BY TYPE OF HYPERTENSION Pre-existing Hypertension w/o Proteinuria (n = 133)
Primary outcome (one or more of the following)' Fetal death Due to congenital anomalies
23 (17.3) 4 (3.0) 0
For the following outcomes, the 5 stillbirths have been excluded: Birth weight <3rd centile for gestational age and gendert Neonatal death Congenital heart disease Multiple cardiac anomalies Adequate ventilation not achieved Prematurity Respiratory distress syndrome (RDS) Received surfactant Bronchopulmonary dysplasia (BPD) Intraventricular hemorrhage (IVH) (grade 3 or 4 or at autopsy) Cystic periventricular leukomalacia (PVL) Retinopathy of prematurity (ROP) (stage 3 or 4) Necrotizing enterocolitis (NEC)
(n
= 129)
5 2 0 I I 0 14 6 I I
(3.9) ( 1.6) (0.8) (0.8) (10.9) (4.7) (0.8) (0.8)
0 I (0.8) I (0.8)
Gestational Hypertension w/o Proteinuria (n = 172)
27 (15.7) I (0.6) 0 (n 9 2 I 0 0 I 16 7 0 I
= 171) (5.3) ( 1.2) (0.6)
(0.6) (9.4) (4.1) (0.6)
0 0 I (0.6)
Total N (%) (N = 30S)
50 (16.4) 5 ( 1.6) 0 (N 14 4 I I I I 30 13 I 2
= 300) (4.7) ( 1.3) (0.3) (0.3) (0.3) (0.3) (10.0) (4.3) (0.3) (0.7)
0 I (0.3) 2 (0.7)
*Definitions: Fetal death (stillbirth): death of a fetus
~500
g or at
~20
weeks' gestation
Neonatal death: death of a newborn at <28 days of age Respiratory distress: after initial resuscitation, the requirement for assisted ventilation and supplemental oxygen within the first 24 hours of life BPD: requiring oxygen at a postnatal gestational age of 36 completed weeks and X-ray compatible with BPD IVH grade 3 or 4: diagnosed on or before day 28 of life. by the most severe grade on cranial ultrasound. using categorization of Papile et 0/.,34 or at autopsy Cystic PVL: periventricular cystic changes in the white matter, excluding subependymal and choroid plexus cysts. diagnosed on or before day 28 of life. by cranial ultrasound or at autopsy ROP stages 3 to 5 in one or both eyes: intraretinal ridge with extraretinal fibrovascular proliferation. or retinal detachment. respectively. by the worst stage in the most severely affected eye NEC: perforation of the intestine. pneumatosis intestinalis. or air in the portal vein, diagnosed by X-ray. surgery. or at autopsy tTwo birth weights are missing. one in each group.
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abruption was rare (1.6%). The maternal stay in hospital was usually brief: only 1 day (IQR, 0-4) before delivery, and 3 days (IQR, 2-4) postpartum. DISCUSSION
Hypertension complicates 7% to 9% of pregnancies,38 and is associated with an increased maternal and perinatal risk, even in the absence of proteinuria. 15-25,39 However, there is very little information about the presumably higher risk population of women who present with either a pre-existing or a gestational non-protein uric hypertension, at <34 weeks' gestation. 25 -29 In this international retrospective cohort study, such women represented 12.8% of hypertensive pregnancies, but had a high risk of associated perinatal and maternal adverse outcomes, regardless of whether the non-proteinuric hypertension was pre-existing or gestational. Clearly, these results are important from a population health perspective, as these women represent approximately 45 000 deliveries per year in Canada. In this study, non-proteinuric hypertension, with onset before 34 weeks' gestation, was associated with a 16.4% incidence of one or more serious perinatal complications 01.7%) or birth weight <3rd centile (4.7%). Of the babies, 32% were born at ~34 weeks' gestation, although overall the incidence of indicated preterm birth was high (34%) and 9% of babies stayed in the NICU for more than 7 days. Also,
17% of babies had birth weight dOth centile, the more traditional definition of SGA. Being SGA, even across the normal range of birth weight,40 is a risk factor for short-term neonatal complications, adverse neurological outcomes and cognitive function in childhood, and cardiovascular and endocrine complications in adulthood, possibly because of irreversible in utero metabolic adaptations (the Barker Hypothesis).41,42 Our population of women with non-protein uric hypertension with onset before 34 weeks' gestation also had a clinically important risk of maternal complications. One-third (most of whom were nonsmokers) developed preeclampsia and 2% end-organ failure and/or eclampsia. At least 1 episode of severe hypertension (after presentation with mild to moderate hypertension) occurred in 40% of cases, despite few (5%) having had it earlier in the pregnancy and the fact that the study was conducted in centres where "tight" control of BP is the norm. Also, there was a high incidence of obstetric intervention, even compared with hypertensive pregnancies. 11,43 Almost half of the women underwent induction of labour because of hypertension, and over 40% had a Caesarean section. There are limitations to our study. Although retrospective and not population-based, the study was performed in centres providing tertiary care in a variety of health-care systems, including those with different levels of resources. All centres contributed to the outcomes reported; however, the relatively small sample
TABLE 5
OTHER PERINATAL OUTCOMES, BY TYPE OF HYPERTENSION* Pre-existing Hypertension w/o Proteinuria (n = 129) Birth weight < 10th centile t Birth weight <2500 g Birth weight < 1250 g Birth weight (g) (mean ± SD) Gestational age at delivery (wk) (mean ± SD) Birth at <37 wk Birth at <34 wk Apgar score 5 mint <4 at 5 min <7 at 5 min Admission to NICU (Level III nursery) Stay in NICU >24 hours Stay in NICU >7 d On oxygen at 2S d of life
Gestational Hypertension w/o Proteinuria (n = 171)
Total N (%)
(N = 300)
18 (14.0) 38 (28.6) 12 (9.0%) 2785.9 ± 883.5 37.1 ± 3.5 40 (31.0) 22 (17.1)
34 ( 19.9) 53 (30.8) 10 (5.8%) 2797.9 ± 802.1 37.2 ± 2.9 63 (36.S) 24 ( 14.0)
52(17.3) 91 (29.8) 22 (7.2%) 2792.7 ± 837.0 37.2 ± 3.2 103 (34.3) 46 (15.3)
I (O.S) 3 (2.3) IS (14.0) 14 (10.9) II (S.5) 6 (4.7)
I (0.6) 9 (5.3) 27 (15.S) 26 ( 15.2) 15 (S.S) 0
2 (0.7) 12 (4.0) 45 (15.0) 40 (13.3) 26 (S.7) 6 (2.0)
*The total N reflects the exclusion of 5 stillborn babies. tTwo birth weights are missing, one in each group. +A 5-minute Apgar is missing from the pre-existing hypertension group. NICU: neonatal intensive care unit.
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TABLE 6
MATERNAL OUTCOMES, BY TYPE OF HYPERTENSION Pre-existing Hypertension w/o Proteinuria (n 133)
=
Serious maternal complications' (one or more of the following)
Gestational Hypertension w/o Proteinuria (n 172)
Total N (%)
6 (2.0)
=
(N
=30S)
2 ( 1.5)
4 (2.3)
Death
0
0
0
Stroke
0
0
Eclampsia
0
I (0.6)
0 I (0.3)
Multiple organ dysfunction - one or more of:
2 ( 1.5)
3 ( 1.7)
5 ( 1.6)
Pulmonary edema
I (0.8)
I (0.6)
2 (0.7)
ARDS
0
0
0
Respiratory arrest
0
0
0
Cardiovascular failure
0
0
0
Severe HELLP syndrome
0
2 ( 1.2)11
2 (0.7)11
Hepatic failure
0
0
0
Renal failure
0
0
0
Coagulopathy
I (0.8)
0
39 (29.3)
I (0.3)
32.0 ± 5.2
55 (32.0) 34.2 ± 3.411
33.2 ± 4.4
Sustained severe hypertension+
54 (40.6)
60 (34.9)
I 14 (37.4)
Induction of labour
63 (47.4)
77 (44.8)
140 (45.9)
Caesarean section
54 (40.6)
78 (45.4)
132 (43.3)
4 (3.0)
I (0.6)
5 ( 1.6)
Preeclampsia t Gestational age at presentation (wk) (mean ± SD)
Placental abruption§
Median (IQR) n 13211
n
4 (2. 7)
5 (2.8)
4 (2.8)
I (0. 3.5) 3 (2.4)
I (0.4) 3 (1.4)
I (0.4) 3 (2.4)
=
No. maternal days in hospital II Before delivery After delivery
Median (IQR)
94 (30.8)
= 172
Median (IQR) N 304
=
* Serious maternal complications (up to 6 weeks postpartum): death or I or more life-threatening maternal complications defined as:
I. Stroke: acute neurological event with deficits lasting >24 hours. not due to a post-ictal state 2. Eclampsia: a generalized convulsion in the absence of a history of epilepsy 3. Multiple organ dysfunction. one or more (as recorded in the chart) of the following: pulmonary edema; ARDS (acute respiratory distress syndrome); respiratory arrest; cardiovascular failure in the absence of hemorrhage (e.g .• arterial sBP <::;70 mm Hg for at least I hour despite adequate fluid resuscitation. adequate intravascular volume. or the use of vasopressors to maintain sBP >90 mm Hg or mean arterial BP >70 mm Hg); severe HELLP (hemolysis. elevated liver enzymes. low platelets) syndrome requiring blood products; hepatic failure (e.g .• increased liver enzymes. conjugated hyperbilirubinemia and either hypoglycemia or INR > 1.2); renal failure (e.g .• serum creatinine >200 IJM); coagulopathy (e.g .• decreased fibrinogen below normal reported by local laboratory). t Development of proteinuria (~0.3 g/d by 24-hour urine collection. or 2 dipstick results of ~2+ in the event that 24-hour
urinary protein was not completed); or thrombocytopenia (platelets < I 00 000 x 109/L). + sBP > 170 mm Hg or dBP > I 10 mm Hg. §
Diagnosed clinically by abdominal pain or uterine contractions. with I or more of vaginal bleeding, intrauterine fetal death. and/or disseminated intravascular coagulation.
II One response is missing. IQR: interquartile range; sBP: systolic blood pressure; dBP: diastolic blood pressure; INR: international normalized ratio. JOGe
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size from any given centre did not allow for between-centre comparisons in outcome event rates. We showed that the outcomes were easily abstracted from the medical record, with very little missing data. The prevalence of hypertensive pregnancies identified was low at 5.5%. We could have missed some cases miscoded by the ICD system. Also, we identified only births at ;:::20 weeks' gestation, and therefore, would have missed women with pre-existing non-protein uric hypertension who suffered a miscarriage. Unfortunately, there was minimal information about the proportion of eligible pregnancies complicated by fetal growth restriction at presentation with maternal hypertension. We do not know how best to manage the hypertension of women who present at <34 weeks' gestation with either preexisting or gestational non-protein uric hypertension. This study focused on centres where "tight" control of BP is the norm, achieved by non-pharmacological means in 79% of cases, and/or antihypertensive therapy in 60% of cases. A large RCT is needed to assess whether "less tight" control, aiming for a higher dBp, could reduce the risk of perinatal complications. We are planning to have CHIPS determine whether "less tight" control (aiming for a dBP of 100 mm Hg) of mild to moderate maternal hypertension improves perinatal outcome (decreases the incidence of 1 or more serious perinatal complication[sl or birth weight <3rd centile for gestational age and gender) compared to "tight" control (aiming for a dBP of 85 mm Hg). CHIPS will enrol women with either pre-existing or gestational non-protein uric hypertension, presenting at <34 weeks' gestation. Based on the findings of this study, the CHIPS trial will need to enrol 1200 women/group to find a clinically important reduction in the incidence of serious perinatal complications or birth weight <3rd centile, from 16% to 12% (2-tailed, ex = 0.05, power of80%). This sample size would have 80% power of finding a 5.5% increase in the incidence of severe hypertension, or a 1.6% increase in serious maternal complications, associated with "less tight" control.
receives salary support and Establishment Funding from the BC Research Institute for Children's and Women's Health. M.E.H. has a Senior Scientist award from the Canadian Institutes of Health Research. Special thanks to the CHIPS Steering Committee. Also, we wish ro thank Darren McKay of MIRU for programming, Parvinder Birdi for assisting with data collection in Vancouver, and the Medical Records and Data Coding Departments of all participating institutions without whose assistance this study could not have been completed. REFERENCES I.
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CONCLUSION
Women who present with non-protein uric hypertension before 34 weeks' gestation represent a high-risk subpopulation of hypertensive pregnancies. It is imperative that we know how to manage their hypertension in order to optimize perinatal outcomes and minimize maternal risks. The CHIPS trial is designed to answer this important question for women in Canada and abroad.
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ACKNOWLEDGEMENTS
The Maternal Infant and Reproductive Health Research Unit (MIRU) graciously provided support for this study. L.M. receives salary support from the BC Women's Hospital Foundation, and received an Establishment Grant from the BC Research Institute for Children's and Women's Health. P.vD. JOGC
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The Management of Uterine Leiomyomas This issue of the IOGC includes a Self-Directed Learning Module on The Management of Uterine Leiomyomas. This module qualifies for credits under Section 2 of the Maintenance of Certification Program of the Royal College ofPhysicians and Surgeons of Canada. Don't miss this valuable self-directed learning module on The Management of Uterine Leiomyomas. Supported by an unrestricted educational grant from
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