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The classification and definition of the hypertensive disorders of pregnancy
CLINICAL SECTION Clinical Opinion The classification and definition of the hypertensive disorders of pregnancy Dennis A. Davey, PhD, and Ian MacGillivray, MD Cape Town, South Africa Hypertension and proteinuria in pregnancy may be the result of a number of different disorders with different etiologies and pathologic characteristics. As the causes of hypertension and proteinuria in pregnancy are largely unknown, a new clinical classification of the hypertensive disorders is proposed and is based solely on the physical signs of hypertension and proteinuria. The classification is intended to define meaningful clinical categories by which all cases of hypertension and proteinuria occurring in pregnancy, labor, or the puerperium may be classified. New definitions of hypertension and proteinuria are also proposed; they are based on standardized methods of measurement and simple criteria of abnormality. It is hoped that this clinical classification and associated definitions will find general acceptance so that the incidence and outcome of the hypertensive disorders of pregnancy and the results of research in different centers may be compared and mutual understanding achieved. (AM J OSSTET GVNECOL 1988;158:892-8.)
Key words: Hypertension, proteinuria, pregnancy, classification, definition
Hypertension and proteinuria have long been recognized to be important complications of pregnancy, but agreement on their classification and definition is still lacking. The failure to achieve an agreed classification results from a lack of knowledge of the precise nature and cause of the disorders, the absence of clinical or pathologic features or tests by which they can be clearly separated, and the want of an agreed nomenclature. Because the causes of hypertension and proteinuria in pregnancy are largely unknown, a new clinical classification is proposed; it is based solely on the physical signs of hypertension and proteinuria (Table I). New definitions of hypertension are also proposed; they are based on standardized methods of measurement with simple criteria of abnormality that are readily applicable in virtually all clinical situations (Table II). For the sake of brevity and euphony the term hypertensive disorders of pregnancy is taken to include all conditions of disorders that present with hypertension and/or proteinuria in pregnancy.
From the UCT Reproductive Medicine Research Unit, Department of Obstetrics and Gynaecology, University of Cape Town Medical School. Reprint requests:Professor D. A. Davey, UCT Reproductive Medicine Research Unit, Department of Obstetrics and Gynaecology, University of Cape Town Medical School, Observatory, Cape, South Africa 7925.
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Clinical features of the hypertensive disorders of pregnancy A number of differing combinations of symptoms and signs have been used in the classification of the hypertensive disorders of pregnancy. Symptoms, however, are usually absent or late in appearing, and the definition and significance of some signs are disputed. Edema that occurs in 80% of all pregnancies is generally a favorable sign' and is of no prognostic significance even when associated with hypertension and proteinuria." Therefore reliance has to be placed solely on hypertension and proteinuria. Definition of hypertension in pregnancy Hypertension is a physical sign, not a disease entity, and may be due'to a number of different underlying causes. Its definition depends on the technique and conditions of measurement of the blood pressure, an appreciation of the changes in blood pressure in normal pregnancy, and the precise criteria adopted to define hypertension. Technique and conditions of blood pressure measurement. In obstetric practice the arterial blood pressure is nearly always measured by sphygmomanometry. The systolic blood pressure is more variable than the diastolic blood pressure and, though valuable in management, it does not add to the diagnostic or prognostic significance of the hypertensive disorders of preg-
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Table I. Clinical classification of hypertensive disorders of pregnancy A.
B.
C.
D.
A.
B.
C.
Gestational hypertension and /or proteinuria Hypertension and/or proteinuria developing during pregnancy, labor, or the puerperium in a previously normotensive nonproteinuric woman subdivided into I. Gestational hypertension (without proteinuria) a. Developing antenatally b. Developing for first time in labor c. Developing for first time in the puerperium 2. Gestational proteinuria (without hypertension) a. Developing antenatally b. Developing for the first time in labor c. Developing for first time in puerperium 3. Gestational proteinuric hypertension (preeclampsia) a. Developing antenatally b. Developing for first time in labor c. Developing for first time in puerperium Chronic hypertension and chronic renal disease Hypertension and/or proteinuria in pregnancy in a woman with chronic hypertension or chronic renal disease diagnosed before, during, or after pregnancy subdivided into I. Chronic hypertension (without proteinuria) 2. Chronic renal disease (proteinuria with or without hypertension) 3. Chronic hypertension with superimposed preeclampsia Proteinuria developing for first time during pregnancy in a woman with known chronic hypertension Unclassified hypertension and/or proteinuria Hypertension and/or proteinuria found either I. At first examination after twentieth week of pregnancy (140 days) in a woman without known chronic hypertension or chronic renal disease or 2. During pregnancy, labor, or the puerperium where information is insufficient to permit classification is regarded as unclassified during pregnancy and is subdivided into I. Unclassified hypertension (without proteinuria) 2. Unclassified proteinuria (without hypertension) 3. Unclassified proteinuric hypertension Eclampsia The occurrence of generalized convulsions during pregnancy, during labor, or within 7 days of delivery and not caused by epilepsy or other convulsive disorders Notes on classification: Hypertension and/or proteinuria at the first visit before the twentieth week of pregnancy (in the absence of trophoblastic disease) is presumed to be caused by either I. Chronic hypertension (hypertension only) or 2. Chronic renal disease (proteinuria with or without hypertension) Unclassified hypertension and/or proteinuria may be reclassified after delivery I. If the hypertension and/or proteinuria disappears into a. Gestational hypertension (without proteinuria) or b. Gestational proteinuria (without hypertension) or c. Gestational proteinuric hypertension (preeclampsia) 2. If the hypertension and/or proteinuria persists after delivery or other tests confirm the diagnosis into a. Chronic hypertension (without proteinuria) or b. Chronic renal disease (proteinuria with or without hypertension) or 3. Chronic hypertension with superimposed preeclampsia Gestational proteinuric hypertension may be regarded as synonymous with "preeclampsia." "Gestational hypertension" is often regarded as synonymous with "pregnancy-induced hypertension," but the term "pregnancyinduced hypertension" is reserved in this classification for that form of hypertension that commonly but not exclusively occurs in primigravid women and is primarily caused by an abnormality of pregnancy, which if it is severe or progresses is associated with the development of proteinuria and other features of "preeclampsia."
nancy! The definition of hypertension is therefore based solely on the diastolic blood pressure as it has the advantage of being both simple and unequivocal. To minimize variations caused by exercise and posture it is recommended that the blood pressure should be measured with the patient lying on a bed or couch on
the right side at 30 degrees of lateral tilt and with the sphygmomanometer cuff at the same level as the heart. The blood pressure should normally be taken in the right arm, as most observers stand on the right side of the patient when taking the blood pressure and the right arm is more convenient. Taking the blood pres-
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Table II. Definitions Hypertension in pregnancy A. Diastolic blood pressure of ~ 110 mm Hg on any one occasion or B. A diastolic blood pressure of ~90 mm Hg on two or more consecutive occasions ~4 hours apart Proteinuria in pregnancy A. One 24-hour urine collection with a total protein excretion of ~300 mg per 24 hours or B. Two "clean-catch-midstream" or catheter specimens of urine collected ~4 hours apart with I. 1 gm albumin per liter or 2 + more on reagent strip or sulfosalicylic acid "cold" test or 2. 0.3 gm albumin per liter or 1 + on reagent strip if specific gravity < 1.030 and pH < 8
sure when standing on the customary right side of the patient with the patient lying on the left side at a 30degree lateral tilt is more difficult and the blood pressure measurements will be fallacious if the sphygmomanometer cuff is not at the same level as the heart. The diastolic blood pressure is taken as the "point of muffling" (phase IV) of the Korotkoff sounds because this measurement corresponds most closely to the true diastolic blood pressure in pregnancy. If the point of muffling is uncertain, the point of disappe.arance (phase V) is used and a special note made in the patient's records. Changes in blood pressure in normal pregnancy. The blood pressure normally falls in pregnancy and reaches its lowest level in the second trimester when the diastolic blood pressure is, on average, 15 mm Hg lower than before pregnancy." The fall occurs in both normotensive women and in women with chronic hypertension who may appear normotensive in early pregnancy. The blood pressure also normally rises in the third trimester and reaches prepregnancy levels by term." A rise in blood pressure has been used in previous definitions of hypertension in pregnancy, but this may cause considerable difficulties. A rise of up to 30 or 40 mm Hg may thus fall within the normal statistical range. Furthermore the use of a rise in blood pressure involves at least two observations, which increases the variability and may result in misdiagnosis if the blood pressure is abnormally low at any time in early pregnancy. The absolute level of blood pressure provides the best guide to fetal and maternal prognosis and the development of proteinuria. Including a rise of blood pressure does not increase precision of diagnosis. I Definition of hypertension in pregnancy. Any definition of hypertension that is based on a particular level of blood pressure is inevitably arbitrary, but the use of a diastolic blood pressure (phase IV) of ;,,90
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mm Hg on two or more occasions during pregnancy as the diagnostic criterion, as suggested by Nelson,' has the advantages of: (1) simplicity, precision, and convenience; (2) correspondence with defined statistical limits (a diastolic blood pressure of 90 mm Hg corresponds approximately to three SD above the mean in early and mid pregnancy to 2 SD above the mean between 34 and 38 weeks' gestation, and to 1.5 SD above the mean at term"); (3) a defined relationship to perinatal mortality (in gross overall terms, a diastolic blood pressure of 90 mm Hg corresponds to the points of inflexion of the curve relating diastolic blood pressure to perinatal mortality; above this point perinatal mortality is significantly increased"). Anxiety, excitement, and stress, may cause transient elevations of blood pressure in normal healthy women and single, isolated readings of blood pressure may lead to an erroneous diagnosis of "hypertension." The number of readings required to justify a diagnosis of "hypertension" is unknown but two consecutive readings of at least 4 hours apart accords with clinical experience and the practice of taking the blood pressure at intervals of 4 to 6 hours. Measurement of"4 hours or more" includes "6 hours or more," but the converse does not apply. If hypertension is severe, it may not be possible to wait 4 hours to make a diagnosis and to commence antihypertensive therapy. If treatment is given, the blood pressure may then fall and remain within the normal range for the rest of the pregnancy. To meet this contingency it is proposed that hypertension in pregnancy should be defined as either (I) one measurement of diastolic blood pressure ;,,110 mm Hg or (2) two consecutive measurements of a diastolic blood pressure of 90 mm Hg 4 or more hours apart. It has been suggested that different levels of diastolic blood pressure should be used for the diagnosis of hypertension in the different stages of pregnancy and in different communities. The use of different criteria at different stages of pregnancy, however, would cause confusion, particularly if the duration of pregnancy is unknown or wrong or if the criterion for diagnosis is changed during management. The use of different criteria in different populations and different centers would similarly lead to confusion and vitiate any comparison of results. It is better to have one agreed criterion for the diagnosis of hypertension and to recognize that "hypertension" may have a different significance in different populations, different stages in pregnancy, and different clinical circumstances.
Definition of proteinuria The definition of proteinuria in pregnancy depends on: (I) the nature and the normal range of the proteins excreted in the urine in pregnancy; (2) the methods
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used for their detection and measurement; (3) the period and timing of the urine collection, the urinary volume and concentration, and the activity and posture of the patient during the period of collection. Normal ranges of urinary protein excretion in pregnancy. A small amount of protein is normally present in the urine, and the average 24-hour urinary excretion of protein in healthy nonpregnant subjects is: total protein, 18 mg; albumin, 10 mg; and ~2-microglobulin, 1 to 2 mg." In pregnancy protein excretion may be considerably increased, and up to 300 mg of total protein per 24 hours is accepted as normal. The Committee of Terminology of the American College of Obstetricians and Gynecologists recommended that a concentration of ;;.300 mg of protein in a 24-hour urine collection or ;;.1 gm/L in a random urine sample should be regarded as abnormal but did not specify an upper limit in terms of excretion per 24 hours. The concentration of protein in the urine, however, is dependent on several factors, including the volume of urine excreted and the degree of concentration of any particular urine specimen. The total amount of protein excreted is affected by exercise and posture, and there may be up to a fivefold variation in urinary protein concentration in successive 4-hour periods." It is generally agreed that the total amount of protein excreted in a 24-hour urine collection provides the most reliable measure of the degree of proteinuria. However, there have been no adequate studies of 24-hour urinary protein excretion in healthy women in pregnancy and the normal range of protein excretion has not as yet been defined. In the absence of better information it is generally accepted that the finding of ;;.300 mg of total protein in a 24-hour urine collection, when measured by a reliable quantitative method, should be regarded as abnormal or as "significant" proteinuria. Detection and diagnosis of proteinuria. In practice proteinuria is detected most commonly by the use of reagent strips or "dipsticks" (such as Multistix, Ames Co., Elkhart, Ind.) or less commonly by the use of the sulfosalicylic acid "cold" test. Reagent strips may give false-negative results if the urine is dilute and falsepositive results if the urine is highly alkaline or contaminated with quaternary ammonia compounds, chlorhexidine, or vaginal discharge. The incidence of false-positive results in random urine specimens may be up to 25% in trace reactions and 6% with 1 + reactions in women with normal 24-hour urinary protein excretion." The diagnosis of "significant" proteinuria in pregnancy on the basis of tests of random urine specimens presents considerable problems, and although dipsticks provide a useful screening test for proteinuria, it is recommended that a 24-hour urinary protein measurement should be performed, wherever
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possible, as a confirmatory test in all patients in whom proteinuria is detected in a random urine specimen. The use of24-hour urine collections also presents problems because they are inconvenient, are often incomplete, and require storage at 4° C or the use of a preservative. Clinical circumstances may also require immediate action without a wait of ;;.24 hours to complete a collection and make a diagnosis. Where 24-hour urine collections are not available, alternative approaches to the diagnosis of "significant proteinuria" with random urine specimens can be used: (1) Measure specific gravity and pH to exclude very dilute or very concentrated and- very alkaline urine specimens. This may be done conveniently with multiple reagent strips such as Multistix SG (Ames). Very dilute urine specimens (specific gravity <1.010) may give false-negative results, and very concentrated (specific gravity ;;'1.030) and also very alkaline urine specimens may give false-positive results and may then be disregarded. (2) Set a high limit for diagnosis of "significant" proteinuria such as 2 + (1 gm albumin/L) or more, as proposed by the American Committee on Terminology. This definition will eliminate most false positive results but may lead to a significant number of women with "significant proteinuria" being diagnosed as "nonproteinuric" and is not ideal.
Classification and nomenclature The present classification follows that of the American Committee on Maternal Welfare as modified by the Committee on Terminology and by Gant and WorleylO but with some differences in nomenclature. Gestational hypertension, proteinuria, and proteinuric hypertension. The term "gestational hypertension," meaning pertaining to pregnancy, labor, or the puerperium, is applied to all hypertensive and/or proteinuric conditions that develop during pregnancy or labor in a previously normotensive, nonproteinuric woman. It is preferred to "pregnancy-induced hypertension," which may be taken to imply that pregnancy is the sole cause of the condition, whereas in some instances the hypertension is primarily caused by an underlying latent tendency to essential hypertension which becomes overt during pregnancy. It is also preferred to the term "pregnancy-associated hypertension," which tends to imply that the development of hypertension or proteinuria is purely coincidental, whereas in other cases the hypertension may be caused entirely by pregnancy. The term "gestational" in this classification is not intended to have any etiologic or pathologic implication but is intended simply to mean that hypertension and/or proteinuria developed during pregnancy and disappeared after delivery. Gestational hypertension may be caused by a number
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of different causes or underlying conditions including latent essential hypertension, "pregnancy-induced hypertension,"* or "supranormal" or "physiologic" hypertension. In individual patients it is not possible to distinguish reliably between these conditions by clinical or any other means, although groups of patients may have certain characteristics. Latent essential hypertension thus tends to occur in older, multigravid women with a family history of essential hypertension, whereas "pregnancy-induced" hypertension tends to occur in younger, primigravid women. "Supranormal hypertension" may occur later in pregnancy in women with "hyperplacentosis," as, for example, in multiple pregnancy. Gestational proteinuria may also be caused by a number of different conditions, including postural (orthostatic) proteinuria, pyuria, "pregnancy-induced proreinuria,"t exacerbation of undiagnosed chronic renal disease, acute renal disease, or renal tuberculosis. In many cases a definitive diagnosis is not possible and "gestational proteinuria" includes all proteinuric conditions of known or unknown origin that develop during pregnancy in the absence of hypertension and disappear either on treatment or after delivery. Gestational proteinuric hypertension may be regarded as synonymous with "preeclampsia" because the development of proteinuria and hypertension in pregnancy is closely correlated with the finding of specific "preeclamptic" changes in the renal glomeruli." Gestational proteinuric hypertension also includes acute nephritis and an exacerbation of chronic nephritis, but these conditions are so rare that the occurrence of gestational proteinuric hypertension may be presumed to be "preeclampsia" until proved otherwise. Gestational hypertension, proteinuria, and proteinuric hypertension are further subdivided according to whether the hypertension and/or proteinuria develop antenatally, for the first time in labor, or for the first time after delivery. This recommendation is important because the clinical, pathologic, and prognostic significance of hypertension and/or proteinuria occurring antenatally may be entirely different from that of hy-
*"Pregnancy-induced hypertension" in this context is defined as that form of hypertensivedisorder of pregnancycommonly but not exclusively found in primigravid women and primarily if not solely caused by an abnormality of the pregnancy that may initially present with hypertension alone but, if it issevereor progresses, isassociated withthe development of proteinuria and other features of "preeclampsia." t"Pregnancy-induced proteinuria" in this context is similarly defined as that form of proteinuria in pregnancy commonly but not exclusively, found in primigravid women and is primarily if not solely caused by an abnormality of pregnancy that may initially present with proteinuria but, if it is severe or progresses, is associated with the development of hypertension and other features of "preeclampsia."
April 1988 Am J Obstet Gynecol
pertension and/or proteinuria developing in labor or the puerperium. The subdivision of patients who develop hypertension antenatally from those who develop hypertension for the first time in labor is also important because it greatly affects the reported incidence of gestational hypertension and preeclampsia, which increases from approximately 10% in antenatal patients to approximately 30% when patients who develop hypertension for the first time in labor are included." A rise in blood pressure in labor may be a normal physiologic response to anxiety, effort, or stress and may not constitute any abnormality or disease state. A rise in blood pressure after delivery may similarly be a normal physiologic occurrence as the result of the acute hemodynamic changes that occur postpartum or of the administration of drugs such as ergonovine. Thus the finding of hypertension for the first time in labor or in the puerperium may have an entirely different clinical and prognostic significance from that of hypertension developing antenatally. The subdivision of gestational hypertension, proteinuria, and proteinuric hypertension by the time of first occurrence antenatally, in labor, or in the puerperium also overcomes the difficulties in previous classifications where terms such as "transient" or "transitory" hypertension were used to describe a temporary rise in blood pressure, particularly during labor. Chronic hypertension, chronic renal disease, and chronic hypertension with superimposed preeclampsia. Chronic hypertension is diagnosed as the finding of hypertension (1) at the first booking visit before the twentieth week of pregnancy in the absence of trophoblastic disease, (2) at any stage of pregnancy in women with known chronic hypertension, or (2) at >6 weeks after delivery. Chronic hypertension may be due to essential hypertension or to other, rarer causes such as pheochromocytoma. Some patients with known essential hypertension may have a fall in blood pressure to normotensive levels in pregnancy. Should the blood pressure rise later in pregnancy in such patients, a diagnosis of chronic rather than gestational hypertension should be made. Chronic renal disease may be diagnosed by a number of criteria including renal biopsy and other specific clinical or pathologic findings. In the absence of such findings the occurrence of "significant proteinuria" (with or without hypertension) (I) at the first booking visit before the twentieth week of pregnancy in the absence of trophoblastic disease, (2) at any stage in pregnancy in a woman with known chronic renal disease, or (3) at any stage in pregnancy and persisting >6 weeks after delivery is sufficient to justify a provisional diagnosis of chronic renal disease in pregnancy. Proteinuria in pregnancy may be intermittent and may be benign, but
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the occurrence of previously undiagnosed chronic renal disease in cases of intermittent proteinuria is sufficiently common to merit a provisional diagnosis of chronic renal disease in pregnancy pending further investigation post partum. The development of proteinuria in a patient with known chronic hypertension in pregnancy is a significant event, and on renal biopsy such patients have histologic changes specific to both chronic hypertension and "preeclampsia.'?" The preeclamptic changes ref verse after delivery while the hypertensive changes persist. The development of proteinuria in a patient with chronic hypertension indicates the development of preeclampsia as a new, additional disease and merits separate classification on both clinical and pathological grounds. Unclassified hypertension and/or proteinuria in pregnancy. A significant number of women present for the first time relatively late in pregnancy and are found to have hypertension and/or proteinuria at the first examination. If no information is available about the presence of hypertension or proteinuria either earlier in pregnancy or before pregnancy, it is impossible to say whether the condition preceded the pregnancy and is therefore "chronic" or developed during pregnancy and is "gestational." If the hypertension and proteinuria are found before the twentieth week, it is generally conceded that the condition should be regarded as "chronic" because the development of these signs in a previously normotensive, nonproteinuric patient in the absence of trophoblastic disease at this stage of pregnancy is so rare. However, if the patient is found to have hypertension and/or proteinuria at the first visit after the twentieth week or if the gestational age is uncertain, such patients are then allocated to a separate "unclassified" category. The category of "unclassified" is also used to include all cases where essential clinical information is lacking or where the diagnosis is uncertain. This category is useful and ensures that the "chronic" and "gestational" categories of the hypertensive disorders of pregnancy are not confused by the inclusion of equivocal cases. Although patients with hypertension and/or proteinuria may be "unclassified" during pregnancy they may be reclassified into appropriate diagnostic categories after delivery. Thus, if the hypertension and proteinuria disappear after delivery, the classification may be revised from "unclassified" to "gestational." On the other hand, if the hypertension and/or proteinuria persist and are still present 6 weeks after delivery, the diagnosis may be revised from "unclassified" to "chronic." The time limit up to which reclassification may be carried out is arbitrary. The traditional 6-week postnatal examination is a practical limit, and review of
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Table III. Suggested definition of "severe" hypertension A. A diastolic blood pressure 2:120 mm Hg on any one occasion or
B. A diastolic blood pressure 2:110 mm Hg on two or more consecutive occasions 2:4 hours apart
the diagnosis at this time should enable the majority of women with unclassified hypertension and/or proteinuria.to be reallocated to their correct "chronic" or "gestational" categories. In any epidemiologic studies of hypertension and proteinuria in pregnancy it will be essential to specify what proportion, if any, of "unclassified" patients were classified after delivery and at what stage in the puerperium. Eclampsia. Eclampsia is included as a separate category of hypertensive disorders of pregnancy, although it may be debated whether it represents a continuum or a complication of the hypertensive disorders of pregnancy. It is such a clear-cut entity with major clinical and prognostic implications that it merits inclusion as a separate condition. No attempt has been made to include other complications or degrees of severity in the present classification and definitions of the hypertensive disorders of pregnancy. It is recommended that complications should be classified according to a separate additional classification and that "severe hypertension" and "severe proteinuria" should be defined according to separate additional definitions. A suggested definition of "severe" hypertension is included (Table III) as it may serve to indicate a "high-risk" category of patients requiring immediate antihypertensive therapy. The proposed classification and definitions have been approved by the International Society for the Study of Hypertension in Pregnancy, and the International Committee of the society at its meeting in Nottingham, England in 1986 recommended their general adoption by all countries. They were also approved in principle at the meeting on classification at the International Federation of Obstetrics and Gynecology in West Berlin in 1985 and have been incorporated in a World Health Organization report on hypertension in pregnancy. A full motivation for these proposals including detailed methods for taking the blood pressure and testing the urine for protein have been published" and are available on request. All systems of classification, definitions, and terminology have their defects and deficiencies. Until such time as the causes of the hypertensive disorders of pregnancy are better understood, a classification that is based on simple clinical criteria may have considerable advantages, and it is hoped that
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these proposals will meet with general approval and acceptance and will be a step forward in mutual understanding. REFERENCES 1. Robertson RR. The natural history of oedema during pregnancy. J Obstet Gynaecol Br Commonw 1971;78:520. 2. Friedman EA, Neff RK. Pregnancy hypertension: a systematic evaluation of clinical diagnostic criteria. Littleton, Massachusetts: PSG Publishing, 1977:238. 3. MacGillivray I, Rose GA, Rowe D. Blood pressure survey in pregnancy. Clin Sci 1969;37:395. 4. MacGillivray I. Hypertension in pregnancy and its consequences. J Obstet Gynaecol Br Commonw 1961;557: 569. 5. Nelson TR. A clinical study of pre-eclampsia. J Obstet Gynaecol Br Emp 1955;62:48. 6. Friedman EA. Blood pressure, edema and proteinuria in pregnancy. Amsterdam: Elsevier, 1976:279. 7. Peterson PA, Evrin P, Berggard I. Differentiation of glo-
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8. 9. 10. II. 12. 13. 14.
merular tubular and normal proteinuria: determinations of urinary excretion of ~2 microglobulin, albumin and total protein. J Clin Invest 1969;48:1189. Chesley LC. The variability of proteinuria in the hypertensive complications of pregnancy. J Clin Invest 1939;18:617. Rennie IDB, Keen H, Cohwig J, Field M, Quartey E. Evaluation of clinical methods for detecting proteinuria. Lancet 1967;2:489. Gant N, Worley R. Hypertension in pregnancy. New York: Appleton-Century-Crofts, 1980: 101. Sheehan HL, Lynch JB. Pathology of toxaemia of pregnancy. Edinburgh: Churchill Livingston, 1973:2. Knutzen VK, Davey DA. Hypertension in pregnancy: perinatal mortality and causes of fetal death. S Afr Med J 1977;51:675. Pollak VE, Nettles JB. The kidney in toxaemia of pregnancy: a clinical and pathological study based on renal biopsies. Medicine 1960;39:469. Davey DA, MacGillivray I. The classification and definition of the hypertensive disorders of pregnancy. Clin Exp Hypertens [B] 1986; B5(1):97.
The relationship between calcium intake and pregnancy-induced hypertension: Up-to-date evidence Jose M. Belizan, MD,. Jose Villar, MD:' c and John Repke, MDc Rosario, Argentina, and Bethesda and Baltimore, Maryland In 1980 we pointed to a relationship between calcium intake and pregnancy-induced hypertension. The original epidemiologic observations showed an inverse association between calcium intake and incidence of eclampsia after adjusting by several confounding factors. A series of recent randomized clinical trials have demonstrated a reduction in blood pressure with calcium supplementation in animals, in healthy and mildly hypertensive subjects, and in pregnant women. It is hypothesized that parathyroid hormone plays a role since it is affected by calcium intake and can partially regulate the concentration of free cytosolic ionized calcium, thus triggering smooth muscle contraction. Randomized clinical trials showing a reduction in the incidence of pregnancy-induced hypertension with calcium supplementation have not as yet been published. However, preliminary observations appear to support this hypothesis. (AM J OBSTET GVNECOL 1988;158:898-902.)
Key words: Calcium intake, pregnancy-induced hypertension, parathyroid hormone In 1980 we published the first evidence pointing to a relationship between calcium intake and pregnancyinduced hypertension. I In this article we concluded that From the Centro Rosarino de Estudios Perinatales, Rosario: the Prevention Research Program, National Institute of Child Health and Human Development, National Institutes ofHealth, Bethesda,' and the Department of Gynecology and Obstetrics, The Johns Hopkins University School of Medicine, Baltimore.' Partially supported by grants from the National Dairy Board, the National Dairy Council and the International Development Research Center, Ottawa, Ontario, Canada. Reprint requests: Dr. Jose M. Belizan, Centro Rosarino de Estudios Perinatales, Bv. Orono 500,2000 Rosario, Argentina.
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further studies were needed to reject or confirm this hypothesis and that "such studies are warranted since a confirmation of the association between calcium deficit and EPH-gestosis could have significant public health implications in that the administration of calcium to pregnant women in early stages of pregnancy could prevent the development of this disease." Since the original report, several publications have given support to a negative relationship between high calcium intake and blood pressure! Presented here is a summary of the published data since 1980 on this subject, as well as a discussion of areas for future research.
Key words: Hypertension, proteinuria, pregnancy, classification, definition
Hypertension and proteinuria have long been recognized to be important complications of pregnancy, but agreement on their classification and definition is still lacking. The failure to achieve an agreed classification results from a lack of knowledge of the precise nature and cause of the disorders, the absence of clinical or pathologic features or tests by which they can be clearly separated, and the want of an agreed nomenclature. Because the causes of hypertension and proteinuria in pregnancy are largely unknown, a new clinical classification is proposed; it is based solely on the physical signs of hypertension and proteinuria (Table I). New definitions of hypertension are also proposed; they are based on standardized methods of measurement with simple criteria of abnormality that are readily applicable in virtually all clinical situations (Table II). For the sake of brevity and euphony the term hypertensive disorders of pregnancy is taken to include all conditions of disorders that present with hypertension and/or proteinuria in pregnancy.
From the UCT Reproductive Medicine Research Unit, Department of Obstetrics and Gynaecology, University of Cape Town Medical School. Reprint requests:Professor D. A. Davey, UCT Reproductive Medicine Research Unit, Department of Obstetrics and Gynaecology, University of Cape Town Medical School, Observatory, Cape, South Africa 7925.
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Clinical features of the hypertensive disorders of pregnancy A number of differing combinations of symptoms and signs have been used in the classification of the hypertensive disorders of pregnancy. Symptoms, however, are usually absent or late in appearing, and the definition and significance of some signs are disputed. Edema that occurs in 80% of all pregnancies is generally a favorable sign' and is of no prognostic significance even when associated with hypertension and proteinuria." Therefore reliance has to be placed solely on hypertension and proteinuria. Definition of hypertension in pregnancy Hypertension is a physical sign, not a disease entity, and may be due'to a number of different underlying causes. Its definition depends on the technique and conditions of measurement of the blood pressure, an appreciation of the changes in blood pressure in normal pregnancy, and the precise criteria adopted to define hypertension. Technique and conditions of blood pressure measurement. In obstetric practice the arterial blood pressure is nearly always measured by sphygmomanometry. The systolic blood pressure is more variable than the diastolic blood pressure and, though valuable in management, it does not add to the diagnostic or prognostic significance of the hypertensive disorders of preg-
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Table I. Clinical classification of hypertensive disorders of pregnancy A.
B.
C.
D.
A.
B.
C.
Gestational hypertension and /or proteinuria Hypertension and/or proteinuria developing during pregnancy, labor, or the puerperium in a previously normotensive nonproteinuric woman subdivided into I. Gestational hypertension (without proteinuria) a. Developing antenatally b. Developing for first time in labor c. Developing for first time in the puerperium 2. Gestational proteinuria (without hypertension) a. Developing antenatally b. Developing for the first time in labor c. Developing for first time in puerperium 3. Gestational proteinuric hypertension (preeclampsia) a. Developing antenatally b. Developing for first time in labor c. Developing for first time in puerperium Chronic hypertension and chronic renal disease Hypertension and/or proteinuria in pregnancy in a woman with chronic hypertension or chronic renal disease diagnosed before, during, or after pregnancy subdivided into I. Chronic hypertension (without proteinuria) 2. Chronic renal disease (proteinuria with or without hypertension) 3. Chronic hypertension with superimposed preeclampsia Proteinuria developing for first time during pregnancy in a woman with known chronic hypertension Unclassified hypertension and/or proteinuria Hypertension and/or proteinuria found either I. At first examination after twentieth week of pregnancy (140 days) in a woman without known chronic hypertension or chronic renal disease or 2. During pregnancy, labor, or the puerperium where information is insufficient to permit classification is regarded as unclassified during pregnancy and is subdivided into I. Unclassified hypertension (without proteinuria) 2. Unclassified proteinuria (without hypertension) 3. Unclassified proteinuric hypertension Eclampsia The occurrence of generalized convulsions during pregnancy, during labor, or within 7 days of delivery and not caused by epilepsy or other convulsive disorders Notes on classification: Hypertension and/or proteinuria at the first visit before the twentieth week of pregnancy (in the absence of trophoblastic disease) is presumed to be caused by either I. Chronic hypertension (hypertension only) or 2. Chronic renal disease (proteinuria with or without hypertension) Unclassified hypertension and/or proteinuria may be reclassified after delivery I. If the hypertension and/or proteinuria disappears into a. Gestational hypertension (without proteinuria) or b. Gestational proteinuria (without hypertension) or c. Gestational proteinuric hypertension (preeclampsia) 2. If the hypertension and/or proteinuria persists after delivery or other tests confirm the diagnosis into a. Chronic hypertension (without proteinuria) or b. Chronic renal disease (proteinuria with or without hypertension) or 3. Chronic hypertension with superimposed preeclampsia Gestational proteinuric hypertension may be regarded as synonymous with "preeclampsia." "Gestational hypertension" is often regarded as synonymous with "pregnancy-induced hypertension," but the term "pregnancyinduced hypertension" is reserved in this classification for that form of hypertension that commonly but not exclusively occurs in primigravid women and is primarily caused by an abnormality of pregnancy, which if it is severe or progresses is associated with the development of proteinuria and other features of "preeclampsia."
nancy! The definition of hypertension is therefore based solely on the diastolic blood pressure as it has the advantage of being both simple and unequivocal. To minimize variations caused by exercise and posture it is recommended that the blood pressure should be measured with the patient lying on a bed or couch on
the right side at 30 degrees of lateral tilt and with the sphygmomanometer cuff at the same level as the heart. The blood pressure should normally be taken in the right arm, as most observers stand on the right side of the patient when taking the blood pressure and the right arm is more convenient. Taking the blood pres-
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Table II. Definitions Hypertension in pregnancy A. Diastolic blood pressure of ~ 110 mm Hg on any one occasion or B. A diastolic blood pressure of ~90 mm Hg on two or more consecutive occasions ~4 hours apart Proteinuria in pregnancy A. One 24-hour urine collection with a total protein excretion of ~300 mg per 24 hours or B. Two "clean-catch-midstream" or catheter specimens of urine collected ~4 hours apart with I. 1 gm albumin per liter or 2 + more on reagent strip or sulfosalicylic acid "cold" test or 2. 0.3 gm albumin per liter or 1 + on reagent strip if specific gravity < 1.030 and pH < 8
sure when standing on the customary right side of the patient with the patient lying on the left side at a 30degree lateral tilt is more difficult and the blood pressure measurements will be fallacious if the sphygmomanometer cuff is not at the same level as the heart. The diastolic blood pressure is taken as the "point of muffling" (phase IV) of the Korotkoff sounds because this measurement corresponds most closely to the true diastolic blood pressure in pregnancy. If the point of muffling is uncertain, the point of disappe.arance (phase V) is used and a special note made in the patient's records. Changes in blood pressure in normal pregnancy. The blood pressure normally falls in pregnancy and reaches its lowest level in the second trimester when the diastolic blood pressure is, on average, 15 mm Hg lower than before pregnancy." The fall occurs in both normotensive women and in women with chronic hypertension who may appear normotensive in early pregnancy. The blood pressure also normally rises in the third trimester and reaches prepregnancy levels by term." A rise in blood pressure has been used in previous definitions of hypertension in pregnancy, but this may cause considerable difficulties. A rise of up to 30 or 40 mm Hg may thus fall within the normal statistical range. Furthermore the use of a rise in blood pressure involves at least two observations, which increases the variability and may result in misdiagnosis if the blood pressure is abnormally low at any time in early pregnancy. The absolute level of blood pressure provides the best guide to fetal and maternal prognosis and the development of proteinuria. Including a rise of blood pressure does not increase precision of diagnosis. I Definition of hypertension in pregnancy. Any definition of hypertension that is based on a particular level of blood pressure is inevitably arbitrary, but the use of a diastolic blood pressure (phase IV) of ;,,90
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mm Hg on two or more occasions during pregnancy as the diagnostic criterion, as suggested by Nelson,' has the advantages of: (1) simplicity, precision, and convenience; (2) correspondence with defined statistical limits (a diastolic blood pressure of 90 mm Hg corresponds approximately to three SD above the mean in early and mid pregnancy to 2 SD above the mean between 34 and 38 weeks' gestation, and to 1.5 SD above the mean at term"); (3) a defined relationship to perinatal mortality (in gross overall terms, a diastolic blood pressure of 90 mm Hg corresponds to the points of inflexion of the curve relating diastolic blood pressure to perinatal mortality; above this point perinatal mortality is significantly increased"). Anxiety, excitement, and stress, may cause transient elevations of blood pressure in normal healthy women and single, isolated readings of blood pressure may lead to an erroneous diagnosis of "hypertension." The number of readings required to justify a diagnosis of "hypertension" is unknown but two consecutive readings of at least 4 hours apart accords with clinical experience and the practice of taking the blood pressure at intervals of 4 to 6 hours. Measurement of"4 hours or more" includes "6 hours or more," but the converse does not apply. If hypertension is severe, it may not be possible to wait 4 hours to make a diagnosis and to commence antihypertensive therapy. If treatment is given, the blood pressure may then fall and remain within the normal range for the rest of the pregnancy. To meet this contingency it is proposed that hypertension in pregnancy should be defined as either (I) one measurement of diastolic blood pressure ;,,110 mm Hg or (2) two consecutive measurements of a diastolic blood pressure of 90 mm Hg 4 or more hours apart. It has been suggested that different levels of diastolic blood pressure should be used for the diagnosis of hypertension in the different stages of pregnancy and in different communities. The use of different criteria at different stages of pregnancy, however, would cause confusion, particularly if the duration of pregnancy is unknown or wrong or if the criterion for diagnosis is changed during management. The use of different criteria in different populations and different centers would similarly lead to confusion and vitiate any comparison of results. It is better to have one agreed criterion for the diagnosis of hypertension and to recognize that "hypertension" may have a different significance in different populations, different stages in pregnancy, and different clinical circumstances.
Definition of proteinuria The definition of proteinuria in pregnancy depends on: (I) the nature and the normal range of the proteins excreted in the urine in pregnancy; (2) the methods
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used for their detection and measurement; (3) the period and timing of the urine collection, the urinary volume and concentration, and the activity and posture of the patient during the period of collection. Normal ranges of urinary protein excretion in pregnancy. A small amount of protein is normally present in the urine, and the average 24-hour urinary excretion of protein in healthy nonpregnant subjects is: total protein, 18 mg; albumin, 10 mg; and ~2-microglobulin, 1 to 2 mg." In pregnancy protein excretion may be considerably increased, and up to 300 mg of total protein per 24 hours is accepted as normal. The Committee of Terminology of the American College of Obstetricians and Gynecologists recommended that a concentration of ;;.300 mg of protein in a 24-hour urine collection or ;;.1 gm/L in a random urine sample should be regarded as abnormal but did not specify an upper limit in terms of excretion per 24 hours. The concentration of protein in the urine, however, is dependent on several factors, including the volume of urine excreted and the degree of concentration of any particular urine specimen. The total amount of protein excreted is affected by exercise and posture, and there may be up to a fivefold variation in urinary protein concentration in successive 4-hour periods." It is generally agreed that the total amount of protein excreted in a 24-hour urine collection provides the most reliable measure of the degree of proteinuria. However, there have been no adequate studies of 24-hour urinary protein excretion in healthy women in pregnancy and the normal range of protein excretion has not as yet been defined. In the absence of better information it is generally accepted that the finding of ;;.300 mg of total protein in a 24-hour urine collection, when measured by a reliable quantitative method, should be regarded as abnormal or as "significant" proteinuria. Detection and diagnosis of proteinuria. In practice proteinuria is detected most commonly by the use of reagent strips or "dipsticks" (such as Multistix, Ames Co., Elkhart, Ind.) or less commonly by the use of the sulfosalicylic acid "cold" test. Reagent strips may give false-negative results if the urine is dilute and falsepositive results if the urine is highly alkaline or contaminated with quaternary ammonia compounds, chlorhexidine, or vaginal discharge. The incidence of false-positive results in random urine specimens may be up to 25% in trace reactions and 6% with 1 + reactions in women with normal 24-hour urinary protein excretion." The diagnosis of "significant" proteinuria in pregnancy on the basis of tests of random urine specimens presents considerable problems, and although dipsticks provide a useful screening test for proteinuria, it is recommended that a 24-hour urinary protein measurement should be performed, wherever
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possible, as a confirmatory test in all patients in whom proteinuria is detected in a random urine specimen. The use of24-hour urine collections also presents problems because they are inconvenient, are often incomplete, and require storage at 4° C or the use of a preservative. Clinical circumstances may also require immediate action without a wait of ;;.24 hours to complete a collection and make a diagnosis. Where 24-hour urine collections are not available, alternative approaches to the diagnosis of "significant proteinuria" with random urine specimens can be used: (1) Measure specific gravity and pH to exclude very dilute or very concentrated and- very alkaline urine specimens. This may be done conveniently with multiple reagent strips such as Multistix SG (Ames). Very dilute urine specimens (specific gravity <1.010) may give false-negative results, and very concentrated (specific gravity ;;'1.030) and also very alkaline urine specimens may give false-positive results and may then be disregarded. (2) Set a high limit for diagnosis of "significant" proteinuria such as 2 + (1 gm albumin/L) or more, as proposed by the American Committee on Terminology. This definition will eliminate most false positive results but may lead to a significant number of women with "significant proteinuria" being diagnosed as "nonproteinuric" and is not ideal.
Classification and nomenclature The present classification follows that of the American Committee on Maternal Welfare as modified by the Committee on Terminology and by Gant and WorleylO but with some differences in nomenclature. Gestational hypertension, proteinuria, and proteinuric hypertension. The term "gestational hypertension," meaning pertaining to pregnancy, labor, or the puerperium, is applied to all hypertensive and/or proteinuric conditions that develop during pregnancy or labor in a previously normotensive, nonproteinuric woman. It is preferred to "pregnancy-induced hypertension," which may be taken to imply that pregnancy is the sole cause of the condition, whereas in some instances the hypertension is primarily caused by an underlying latent tendency to essential hypertension which becomes overt during pregnancy. It is also preferred to the term "pregnancy-associated hypertension," which tends to imply that the development of hypertension or proteinuria is purely coincidental, whereas in other cases the hypertension may be caused entirely by pregnancy. The term "gestational" in this classification is not intended to have any etiologic or pathologic implication but is intended simply to mean that hypertension and/or proteinuria developed during pregnancy and disappeared after delivery. Gestational hypertension may be caused by a number
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of different causes or underlying conditions including latent essential hypertension, "pregnancy-induced hypertension,"* or "supranormal" or "physiologic" hypertension. In individual patients it is not possible to distinguish reliably between these conditions by clinical or any other means, although groups of patients may have certain characteristics. Latent essential hypertension thus tends to occur in older, multigravid women with a family history of essential hypertension, whereas "pregnancy-induced" hypertension tends to occur in younger, primigravid women. "Supranormal hypertension" may occur later in pregnancy in women with "hyperplacentosis," as, for example, in multiple pregnancy. Gestational proteinuria may also be caused by a number of different conditions, including postural (orthostatic) proteinuria, pyuria, "pregnancy-induced proreinuria,"t exacerbation of undiagnosed chronic renal disease, acute renal disease, or renal tuberculosis. In many cases a definitive diagnosis is not possible and "gestational proteinuria" includes all proteinuric conditions of known or unknown origin that develop during pregnancy in the absence of hypertension and disappear either on treatment or after delivery. Gestational proteinuric hypertension may be regarded as synonymous with "preeclampsia" because the development of proteinuria and hypertension in pregnancy is closely correlated with the finding of specific "preeclamptic" changes in the renal glomeruli." Gestational proteinuric hypertension also includes acute nephritis and an exacerbation of chronic nephritis, but these conditions are so rare that the occurrence of gestational proteinuric hypertension may be presumed to be "preeclampsia" until proved otherwise. Gestational hypertension, proteinuria, and proteinuric hypertension are further subdivided according to whether the hypertension and/or proteinuria develop antenatally, for the first time in labor, or for the first time after delivery. This recommendation is important because the clinical, pathologic, and prognostic significance of hypertension and/or proteinuria occurring antenatally may be entirely different from that of hy-
*"Pregnancy-induced hypertension" in this context is defined as that form of hypertensivedisorder of pregnancycommonly but not exclusively found in primigravid women and primarily if not solely caused by an abnormality of the pregnancy that may initially present with hypertension alone but, if it issevereor progresses, isassociated withthe development of proteinuria and other features of "preeclampsia." t"Pregnancy-induced proteinuria" in this context is similarly defined as that form of proteinuria in pregnancy commonly but not exclusively, found in primigravid women and is primarily if not solely caused by an abnormality of pregnancy that may initially present with proteinuria but, if it is severe or progresses, is associated with the development of hypertension and other features of "preeclampsia."
April 1988 Am J Obstet Gynecol
pertension and/or proteinuria developing in labor or the puerperium. The subdivision of patients who develop hypertension antenatally from those who develop hypertension for the first time in labor is also important because it greatly affects the reported incidence of gestational hypertension and preeclampsia, which increases from approximately 10% in antenatal patients to approximately 30% when patients who develop hypertension for the first time in labor are included." A rise in blood pressure in labor may be a normal physiologic response to anxiety, effort, or stress and may not constitute any abnormality or disease state. A rise in blood pressure after delivery may similarly be a normal physiologic occurrence as the result of the acute hemodynamic changes that occur postpartum or of the administration of drugs such as ergonovine. Thus the finding of hypertension for the first time in labor or in the puerperium may have an entirely different clinical and prognostic significance from that of hypertension developing antenatally. The subdivision of gestational hypertension, proteinuria, and proteinuric hypertension by the time of first occurrence antenatally, in labor, or in the puerperium also overcomes the difficulties in previous classifications where terms such as "transient" or "transitory" hypertension were used to describe a temporary rise in blood pressure, particularly during labor. Chronic hypertension, chronic renal disease, and chronic hypertension with superimposed preeclampsia. Chronic hypertension is diagnosed as the finding of hypertension (1) at the first booking visit before the twentieth week of pregnancy in the absence of trophoblastic disease, (2) at any stage of pregnancy in women with known chronic hypertension, or (2) at >6 weeks after delivery. Chronic hypertension may be due to essential hypertension or to other, rarer causes such as pheochromocytoma. Some patients with known essential hypertension may have a fall in blood pressure to normotensive levels in pregnancy. Should the blood pressure rise later in pregnancy in such patients, a diagnosis of chronic rather than gestational hypertension should be made. Chronic renal disease may be diagnosed by a number of criteria including renal biopsy and other specific clinical or pathologic findings. In the absence of such findings the occurrence of "significant proteinuria" (with or without hypertension) (I) at the first booking visit before the twentieth week of pregnancy in the absence of trophoblastic disease, (2) at any stage in pregnancy in a woman with known chronic renal disease, or (3) at any stage in pregnancy and persisting >6 weeks after delivery is sufficient to justify a provisional diagnosis of chronic renal disease in pregnancy. Proteinuria in pregnancy may be intermittent and may be benign, but
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the occurrence of previously undiagnosed chronic renal disease in cases of intermittent proteinuria is sufficiently common to merit a provisional diagnosis of chronic renal disease in pregnancy pending further investigation post partum. The development of proteinuria in a patient with known chronic hypertension in pregnancy is a significant event, and on renal biopsy such patients have histologic changes specific to both chronic hypertension and "preeclampsia.'?" The preeclamptic changes ref verse after delivery while the hypertensive changes persist. The development of proteinuria in a patient with chronic hypertension indicates the development of preeclampsia as a new, additional disease and merits separate classification on both clinical and pathological grounds. Unclassified hypertension and/or proteinuria in pregnancy. A significant number of women present for the first time relatively late in pregnancy and are found to have hypertension and/or proteinuria at the first examination. If no information is available about the presence of hypertension or proteinuria either earlier in pregnancy or before pregnancy, it is impossible to say whether the condition preceded the pregnancy and is therefore "chronic" or developed during pregnancy and is "gestational." If the hypertension and proteinuria are found before the twentieth week, it is generally conceded that the condition should be regarded as "chronic" because the development of these signs in a previously normotensive, nonproteinuric patient in the absence of trophoblastic disease at this stage of pregnancy is so rare. However, if the patient is found to have hypertension and/or proteinuria at the first visit after the twentieth week or if the gestational age is uncertain, such patients are then allocated to a separate "unclassified" category. The category of "unclassified" is also used to include all cases where essential clinical information is lacking or where the diagnosis is uncertain. This category is useful and ensures that the "chronic" and "gestational" categories of the hypertensive disorders of pregnancy are not confused by the inclusion of equivocal cases. Although patients with hypertension and/or proteinuria may be "unclassified" during pregnancy they may be reclassified into appropriate diagnostic categories after delivery. Thus, if the hypertension and proteinuria disappear after delivery, the classification may be revised from "unclassified" to "gestational." On the other hand, if the hypertension and/or proteinuria persist and are still present 6 weeks after delivery, the diagnosis may be revised from "unclassified" to "chronic." The time limit up to which reclassification may be carried out is arbitrary. The traditional 6-week postnatal examination is a practical limit, and review of
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Table III. Suggested definition of "severe" hypertension A. A diastolic blood pressure 2:120 mm Hg on any one occasion or
B. A diastolic blood pressure 2:110 mm Hg on two or more consecutive occasions 2:4 hours apart
the diagnosis at this time should enable the majority of women with unclassified hypertension and/or proteinuria.to be reallocated to their correct "chronic" or "gestational" categories. In any epidemiologic studies of hypertension and proteinuria in pregnancy it will be essential to specify what proportion, if any, of "unclassified" patients were classified after delivery and at what stage in the puerperium. Eclampsia. Eclampsia is included as a separate category of hypertensive disorders of pregnancy, although it may be debated whether it represents a continuum or a complication of the hypertensive disorders of pregnancy. It is such a clear-cut entity with major clinical and prognostic implications that it merits inclusion as a separate condition. No attempt has been made to include other complications or degrees of severity in the present classification and definitions of the hypertensive disorders of pregnancy. It is recommended that complications should be classified according to a separate additional classification and that "severe hypertension" and "severe proteinuria" should be defined according to separate additional definitions. A suggested definition of "severe" hypertension is included (Table III) as it may serve to indicate a "high-risk" category of patients requiring immediate antihypertensive therapy. The proposed classification and definitions have been approved by the International Society for the Study of Hypertension in Pregnancy, and the International Committee of the society at its meeting in Nottingham, England in 1986 recommended their general adoption by all countries. They were also approved in principle at the meeting on classification at the International Federation of Obstetrics and Gynecology in West Berlin in 1985 and have been incorporated in a World Health Organization report on hypertension in pregnancy. A full motivation for these proposals including detailed methods for taking the blood pressure and testing the urine for protein have been published" and are available on request. All systems of classification, definitions, and terminology have their defects and deficiencies. Until such time as the causes of the hypertensive disorders of pregnancy are better understood, a classification that is based on simple clinical criteria may have considerable advantages, and it is hoped that
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these proposals will meet with general approval and acceptance and will be a step forward in mutual understanding. REFERENCES 1. Robertson RR. The natural history of oedema during pregnancy. J Obstet Gynaecol Br Commonw 1971;78:520. 2. Friedman EA, Neff RK. Pregnancy hypertension: a systematic evaluation of clinical diagnostic criteria. Littleton, Massachusetts: PSG Publishing, 1977:238. 3. MacGillivray I, Rose GA, Rowe D. Blood pressure survey in pregnancy. Clin Sci 1969;37:395. 4. MacGillivray I. Hypertension in pregnancy and its consequences. J Obstet Gynaecol Br Commonw 1961;557: 569. 5. Nelson TR. A clinical study of pre-eclampsia. J Obstet Gynaecol Br Emp 1955;62:48. 6. Friedman EA. Blood pressure, edema and proteinuria in pregnancy. Amsterdam: Elsevier, 1976:279. 7. Peterson PA, Evrin P, Berggard I. Differentiation of glo-
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8. 9. 10. II. 12. 13. 14.
merular tubular and normal proteinuria: determinations of urinary excretion of ~2 microglobulin, albumin and total protein. J Clin Invest 1969;48:1189. Chesley LC. The variability of proteinuria in the hypertensive complications of pregnancy. J Clin Invest 1939;18:617. Rennie IDB, Keen H, Cohwig J, Field M, Quartey E. Evaluation of clinical methods for detecting proteinuria. Lancet 1967;2:489. Gant N, Worley R. Hypertension in pregnancy. New York: Appleton-Century-Crofts, 1980: 101. Sheehan HL, Lynch JB. Pathology of toxaemia of pregnancy. Edinburgh: Churchill Livingston, 1973:2. Knutzen VK, Davey DA. Hypertension in pregnancy: perinatal mortality and causes of fetal death. S Afr Med J 1977;51:675. Pollak VE, Nettles JB. The kidney in toxaemia of pregnancy: a clinical and pathological study based on renal biopsies. Medicine 1960;39:469. Davey DA, MacGillivray I. The classification and definition of the hypertensive disorders of pregnancy. Clin Exp Hypertens [B] 1986; B5(1):97.
The relationship between calcium intake and pregnancy-induced hypertension: Up-to-date evidence Jose M. Belizan, MD,. Jose Villar, MD:' c and John Repke, MDc Rosario, Argentina, and Bethesda and Baltimore, Maryland In 1980 we pointed to a relationship between calcium intake and pregnancy-induced hypertension. The original epidemiologic observations showed an inverse association between calcium intake and incidence of eclampsia after adjusting by several confounding factors. A series of recent randomized clinical trials have demonstrated a reduction in blood pressure with calcium supplementation in animals, in healthy and mildly hypertensive subjects, and in pregnant women. It is hypothesized that parathyroid hormone plays a role since it is affected by calcium intake and can partially regulate the concentration of free cytosolic ionized calcium, thus triggering smooth muscle contraction. Randomized clinical trials showing a reduction in the incidence of pregnancy-induced hypertension with calcium supplementation have not as yet been published. However, preliminary observations appear to support this hypothesis. (AM J OBSTET GVNECOL 1988;158:898-902.)
Key words: Calcium intake, pregnancy-induced hypertension, parathyroid hormone In 1980 we published the first evidence pointing to a relationship between calcium intake and pregnancyinduced hypertension. I In this article we concluded that From the Centro Rosarino de Estudios Perinatales, Rosario: the Prevention Research Program, National Institute of Child Health and Human Development, National Institutes ofHealth, Bethesda,' and the Department of Gynecology and Obstetrics, The Johns Hopkins University School of Medicine, Baltimore.' Partially supported by grants from the National Dairy Board, the National Dairy Council and the International Development Research Center, Ottawa, Ontario, Canada. Reprint requests: Dr. Jose M. Belizan, Centro Rosarino de Estudios Perinatales, Bv. Orono 500,2000 Rosario, Argentina.
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further studies were needed to reject or confirm this hypothesis and that "such studies are warranted since a confirmation of the association between calcium deficit and EPH-gestosis could have significant public health implications in that the administration of calcium to pregnant women in early stages of pregnancy could prevent the development of this disease." Since the original report, several publications have given support to a negative relationship between high calcium intake and blood pressure! Presented here is a summary of the published data since 1980 on this subject, as well as a discussion of areas for future research.