An Epidemiologic Study of Contraception and Preeclampsia Hillary S Klonoff Cohen, PhD; David A Savitz, PhD; Robert C Cefalo, MD, PhD; Margaret F McCann, PhD The primary hypothesis of this study was th.
Epidemiologic Study of Contraception and Preeclampsia An Hillary S Klonoff-Cohen, PhD; David A Savitz, PhD; Robert C Cefalo, MD, PhD; Margaret F McCann, PhD primary hypothesis of this study was that contraceptive methods that prevent exposure to sperm and seminal fluid (condoms, diaphragms, spermicides, withdrawal) are associated with an increased risk of developing preThe eclampsia during the subsequent pregnancy A case-control study was conducted comparing the contraceptive and reproductive histories of 110 primiparous women with preeclampsia with 115 pregnant women without preeclampsia, aged 15 to 35 years, who gave birth at North Carolina Memorial Hospital, Chapel Hill, between 1984 and 1987 Controls were frequency matched to cases by age, race, and distance from the hospital Unconditional logistic regression analysis indicated a 2.37-fold (95% confidence interval, 1.01 to 5.58) increased risk of preeclampsia for users of contraceptives that prevent exposure to sperm A dose-response gradient was observed, with increasing risk of preeclampsia for those with fewer episodes of sperm exposure These results were supportive of the hypothesis that birth control methods that prevent sperm exposure may play a role in the etiology of preeclampsia (JAMA 1989;262:3143-3147) PREECLAMPSIA constitutes one of the most important unsolved problems in obstetrics.1 It is the third leading cause ofmaternal morbidity and a major cause of intrauterine growth retarda¬ tion and perinatal morbidity and mor¬ tality.2 For editorial comment see p 3184 The etiology of preeclampsia is large¬ ly unknown Genetic predisposition,35 prostacyclins,6 environmental factors such as a virus7 or solvents,8 and the immune system9"" have all been impliFrom the Department of Epidemiology, School of Public Health (Drs Klonoff-Cohen, Savitz, and McCann), and the Department of Obstetrics and Gynecology, Division of Maternal and Fetal Medicine, School of Medicine (Dr Cefalo), University of North Carolina at Chapel Hill Dr Klonoff-Cohen is now with the Department of Community and Family Medicine, School of Medicine, University of California\p=m-\SanDiego, La Jolla Reprint requests to 79680 Bermuda Dunes Dr, Bermuda Dunes, CA 92201 (Dr Klonoff-Cohen) cated, although none completely ex¬ plains the etiology of the disease Any plausible hypothesis has to explain why (1) preeclampsia is far more common in primigrávidas12; (2) with a first pregnan¬ cy of at least 37 weeks' duration, the risk of preeclampsia is reduced in subse¬ quent pregnancies with the same part¬ ner13; and (3) there appears to be an increased incidence of preeclampsia with paternal change in multiparous women,14"16 although this has recently been challenged by a case study.7 Several studies have considered a link between paternal factors and pre¬ eclampsia An elevated incidence of preeclampsia was found among artificial donor insemination pregnancies for pri¬ migrávidas (10%, expected value 5%) and multigravidas (7.8%, expected val¬ ue 0.9%), reflecting the effect of a changed paternity.17 In an oocyte dona¬ tion study,18 of the first 10 patients treated for infertility with oocyte dona- tion developed preeclampsia In addi¬ tion, Marti and Harrmann19 investi¬ gated exposure to paternal spermatic antigens to determine if continuous and regular exposure of the female genital tract to sperm reduced the incidence of preeclampsia by examining the use of oral contraceptives among 28 preeclamptic women They found that the control group had three times more epi¬ sodes of unprotected sexual intercourse than the case group, supporting a pro¬ tective effect of sperm contacts The study was limited by overly restrictive exclusion criteria and a failure to note the use of other types of birth control by 85% (24/28) of the cases In addition, the time period over which exposure was considered was not stated Nonethe¬ less, this was the first study, to our knowledge, to quantify the amount of sperm exposure and to consider a possi¬ ble connection between spermatozoal histocompatibility and preeclampsia No other studies to date have focused on the relationship between all types of birth control and preeclampsia To extend these findings, a case-con¬ trol study was designed to determine whether there was an increased risk of preeclampsia among women who used methods of birth control that prevent exposure of the endometrium to ejacu¬ late (eg, barrier methods, spermicides) compared with women who did not use those methods (eg, users of intrauterine devices, oral contraceptives, rhythm) With the nonbarrier methods, sperm comes in contact with the endometrium, where it is absorbed With the barrier methods, no sperm (or only dead sperm) come in contact with the endometrium, and the maternal immune system is pre¬ sumably not exposed to paternal anti¬ gens The total number of reported con- Downloaded From: http://jama.jamanetwork.com/ by a Florida International University Medical Library User on 05/31/2015 tacts with sperm was also evaluated to determine if fewer episodes of unpro¬ tected intercourse (resulting in fewer sperm contacts) increased the risk of preeclampsia METHODS 1.—Diagnostic Criteria* Mild Preeclampsia All of the following signs after 20 weeks of gestation: An increase in systolic pressure to 140 mm Hg or an increase in systolic pressure of >30 mm Hg above usual, taken times hours apart at bed rest An increase in diastolic pressure to 90 mm Hg or an Increase in diastolic pressure of 15 mm Hg more than usual, taken times hours apart at bed rest Presence of 2300 mg of protein In clean-catch urine in at least random urine specimens collected hours apart Edema of the face or hands of >1 + or a Subject Selection Cases and controls were selected from female residents of North Carolina aged 15 to 35 years who were hospital¬ ized at the University of North Carolina Memorial Hospital, Chapel Hill, for a live birth of 26 to 42 weeks' gestation between January 1, 1984, and January 30,1987 This time period was chosen to yield approximately 175 cases and 175 controls, which would provide sufficient statistical power (90%) to detect a risk ratio of 2.0 or greater for barrier contra¬ ception use.17 All eligible subjects were primiparous, including a small group of multigravid women who had a previous first-trimester spontaneous or induced abortion Multiparous women with preeclampsia were omitted since they are more likely to have some underlying disorder such as occult hypertension or renal disease that is responsible for the increased blood pressure Cases of preeclampsia were initially identified through review of the com¬ puterized discharge diagnoses, with re¬ view of medical records to determine eligibility Over a 3x/2-year ascertain¬ ment period, 420 potential cases were identified, among whom 64% were ex¬ cluded The reasons for exclusion were age of less than 15 or more than 35 years (20%); multiparity (20%); the presence of preexisting diseases, such as diabetes or hypertension (20%); and incorrect data in the chart (4%) This left 150 eligi¬ ble cases Eligible controls were women who had a live birth during the same 3V2year period There were 2100 eligible controls, of whom 420 (20%) were se¬ lected Among potential controls, the exclusion rate was almost identical to that among the cases: 30% because of the presence of other diseases, 20% be¬ cause of multiparity, and 10% because of age, resulting in 150 eligible subjects Controls were frequency matched to by age (in 5-year strata), (white or black), and geographic loca¬ tion (distance from the hospital) cases Table race Information on demographic vari¬ ables, medical history, antepartum problems, and labor and delivery was obtained through medical record re¬ view Written consent was obtained from the physician and then from the patient to participate in a 15-minute telephone interview The interview elicited information about sexual con- One gain of >5 lb In week Severe Preeclampsia of the following signs: Systolic pressure of 160 mm Hg or diastolic pressure of 110 mm Hg recorded times hours apart with patient at bed rest Proteinuria, g in 24 hours, or a to 4+ protein on dipstick Oligurla, urinary output of 13 Age at first sex, y ==17 >17 No of partners £2 >2 Age at pregnancy, £21 >21 y* No 89 18 29 78 Hypertension in subject's mother No history of maternal hypertension Hypertension In subject's father No history of paternal hypertension Smoking during pregnancy No smoking during pregnancy Alcohol during pregnancy No alcohol Infant during pregnancy weight, g £3200 >3200 Placental £590 >590 Gestational age, wk £39 >39 96 1.04-3.78 7.96 3.30-19.23 0.57 0,31-1.04 0.96 0.56-1.65 67 45 60 61 44 58 42 65 45 59 41 0.96 47 44 55 60 56 57 49 51 0.81 0.48-1.38 46 35 57 43 1.49 0.75-2.95 61 54 46 56 1.58 0.92-2.73 1.16 0.68-1.98 78 22 40 Demographics 70 37 64 43 51 66 34 65 35 60 40 48 52 Other Variables 51 63 49 44 44 39 68 61 60 40 56 52 48 52 54 49 46 61 34 73 54 46 43 57 32 68 36 76 32 33 74 32 75 31 69 30 70 56 50 42 21 91 52 51 68 19 81 37 34 66 33 75 67 38 74 0.82-2.41 1.24 0.71-2.17 1.59 0.92-2.76 2.02 1.09-3.76 0.87 0.49-1.53 1.16 Pregnancy Outcomes 64 61 39 60 42 70 37 63 2.60 1.51-4.48 45 55 1.76 1.02-3.06 2.81 1.63-4.83 59 41 47 42 69 38 64 36 44 49 68 61 *Mean age at pregnancy ( ± SD) was 21.69 ( : persons 27 73 ] 59 41 41 weight, g 29 63 37 prenatal visits 71 32 87 24 56 Total No of £10 >10 80 Total 95% Confidence Interval 67 33 Prenatal visit £13 wk >13 wk 83 17 107 Odds Ratio % Reproductive Variables 21 White Black Married at time of pregnancy Single at time of pregnancy No Variables 72 35 41 Working during pregnancy Not working during pregnancy % Biologic/lmmunologic Education, y £12 >12 Control Persons 58 4.83) years for case persons and 22.13 ( ± 5.15) years for control Response Rate Among 300 eligible subjects, 75% interviewed (73% of cases and 77% of controls) Loss was primarily caused by the inability to locate respondents (26% of cases and 22% of controls), with a small number of respondent refusals (0.7% of cases and 1.3% of controls) There were tremendous difficulties in locating and interviewing patients from this predominantly rural population be¬ cause of their transient life-style and lower socioeconomic status This result¬ ed in the lack of regular employment, an absence of telephones, no private physi¬ cians, and the hesitation by friends and relatives to divulge telephone numbers were because of some of the subjects' hospital debts Many of these women were sin¬ gle at the time of pregnancy or delivery but subsequently did marry and there¬ fore had different surnames at the time of the interview Nonrespondents were compared with respondents with respect to the only data available for nonrespondents: race, age, and prenatal care There was a higher nonresponse rate among black cases (34%) compared with white cases (23%), although white (27%) and black (30%) controls had a very similar nonre- Younger cases (=s21 years) higher nonresponse (39%) than cases (24%); however, nonre¬ sponse rate had a older sponse among controls was similar across age groups The nonresponse rate by number of prenatal care visits was similar for both cases and controls Even though there were some differ¬ ences in response, adjustment for race and age should eliminate any bias The characteristics of the case and control respondents are summarized in Table Cases and controls were very similar with respect to race, age, alcohol Downloaded From: http://jama.jamanetwork.com/ by a Florida International University Medical Library User on 05/31/2015 consumption, smoking history, educa¬ tion, age at menarche, age at first inter¬ course, and number of sexual partners Cases were more likely than controls to report a family history of preeclampsia, lower infant weight, lower placental weight, shorter gestational age, having worked during pregnancy, and fewer prenatal visits Sixty percent of cases were white and 40% were black (Table 2), derived from an obstetric population of 30% whites and 70% blacks According to the litera¬ ture, preeclampsia is typically a disease with a higher incidence in blacks,23 but this was not apparent in this study This may have been the result of more blacks than whites being excluded from the study primarily because of underlying hypertension and greater nonresponse among black cases The mean age for both cases and controls was 22 years Although subjects between 15 and 35 years of age were included, only 10% were less than 18 years old or over the age of 29 years Approximately half the cases were not married and half had fewer than 12 years of education Over one fourth of the cases reported a family history of preeclampsia Contraceptive Use and Preeclampsia Twenty percent of the 110 cases (21 women) and only 9% of the 115 controls (10 women) used barrier methods exclu¬ sively This resulted in a crude odds ratio of 2.48 (95% confidence interval, 1.13 to 5.49), comparing barrier with nonbarrier contraceptive users Eight preeclamptic women (but controls) had intercourse only once, no us¬ ing no form of birth control, and were placed in the nonbarrier category How¬ ever, they technically had not been pre¬ viously exposed to any sperm from their partners, so, theoretically, they belong in the barrier group This change would result in an even larger odds ratio of 3.76 for use of barrier contraceptives Among both cases and controls, the most frequent birth control practice used during intercourse with the father of the child prior to their first pregnancy was no birth control; the second most response was oral contracep¬ tives The greater use of barrier meth¬ ods among cases was largely accounted for by increased use of condoms (11 cases, controls) Four categories of possible confounders of the relationship between the bar¬ rier method of birth control and pre¬ eclampsia were considered: biological, reproductive, demographic, and other suspected variables (Table 2) The variables were considered one at a time in stratified analysis, and the common adjusted odds ratio for each variable compared with the crude odds ratio was of 2.48 There little indication of (adjusted odds ratios was confounding ranged from 2.40 to 2.60), except by gravidity (adjusted odds ratio, 2.71), marital status (adjusted odds ratio, 2.24), and paternity status (adjusted odds ratio, 2.97) However, the confi¬ dence intervals for these three odds ra¬ tios were very wide Furthermore, the calculation of an adjusted odds ratio is questionable when interaction is pres¬ ent and there are small numbers in some cells.22 Stratum-specific odds ratios were compared with the crude odds ratio to assess effect modification There was ratio for some indication that the odds use of barrier methods was especially elevated (odds ratio 3=3.4) in the follow¬ strata: single mothers, first preg¬ nancy, family history of preeclampsia, hypertension in the subject's mother or father, less than 12 years of education, and not working during pregnancy ing Logistic Regression Analysis In the unconditional logistic reg¬ ression model relating type of birth con¬ trol to preeclampsia, seven covariates thought to be the most important poten¬ tial confounders or effect modifiers were included: gravidity, marital sta¬ tus, smoking during pregnancy, alcohol consumption during pregnancy, family history of preeclampsia, working status during pregnancy, and a history of hy¬ pertension in the subject's mother Race, age, and geographic location were frequency matched Their inclu¬ sion in a conditional logistic regression model did not affect the odds ratio, so that only unconditional logistic regres¬ sion results are reported Only interpretable two-way interac¬ tions were considered for inclusion in the model The only significant interac¬ tion was contraceptive exposure by marital status, which had not been sug¬ gested in the literature Therefore, lo¬ gistic analysis was considered both in¬ cluding and omitting the interaction term The adjusted odds ratio for the final model, containing the above seven main effects and no interaction terms, was 2.37 (95% confidence interval, 1.01 to 5.58) The adjusted odds ratio for the final model containing the interaction term for exposure by marital status and the seven main effects was 0.39 (0.26 to 0.59) for married women and 26.08 (8.50 to 79.84) for single women Though im¬ precise, there is evidence of an in¬ creased risk of preeclampsia associated with barrier contraceptives only among single women Amount of Sperm Exposure and Changed Paternity A dose-response effect was observed when the total number of sperm con¬ tacts was analyzed, with categories es¬ tablished by dividing the study popula¬ tion (107 cases and 112 controls) into quartiles by total number of contacts Compared with women with 480 or more contacts, intervals of 181 to 479, seventy-three to 180, and fewer than 73 contacts produced odds ratios of 1.34, 1.80, and 2.41, respectively The logis¬ tic regression equation results suggest increasing risk of preeclampsia with de¬ creasing amounts of sperm and seminal fluid exposure by a factor of 1.34 per quartile The effect of changed paternity was evaluated in the small subpopulation of multigravidas (n = 47) When a partner other than the father was involved in a previous induced or spontaneous abor¬ tion, the crude odds ratio relating barri¬ er contraceptive use to the risk of pre¬ eclampsia was 2.34 (95% confidence interval, 0.68 to 8.03) A trend was also observed relating amount of exposure with the father of the child to preclampsia risk, with categories established by dividing this subpopulation into quar¬ tiles This trend was similar in magni¬ tude to that observed for all subjects Compared with women with 644 or more contacts, intervals of 288 to 643, one hundred fifty-one to 287, and fewer than 151 contacts produced odds ratios of 1.40,1.96, and 2.74, respectively COMMENT The results of this case-control study indicate that women who used barrier contraceptives were over twice as likely as women who used nonbarrier contra¬ ceptives to develop preeclampsia Fur¬ thermore, women who were exposed to smaller amounts of sperm were at greater risk of preeclampsia An interaction of contraception by marital status was noted, with an odds ratio for married women using barrier methods of 0.39, compared with an odds ratio for single women of 26.18 As indi¬ cated by the wide confidence intervals, this result could possibly reflect random error Alternatively, different factors might affect preeclampsia in married women compared with single women The irregularity of intercourse among unmarried women, differing influences in choice of birth control by marital sta¬ tus, varying levels of care in use of con¬ traceptives, or some other confounders not taken into account are potential ex¬ planatory factors that need to be inves¬ tigated in future studies A possible ex¬ planation for the differences in the odds Downloaded From: http://jama.jamanetwork.com/ by a Florida International University Medical Library User on 05/31/2015 ratio for married and single women may be the "slippage" that occurs when us¬ ing barrier methods Since married women typically have one steady part¬ ner with regular intercourse, the slip¬ page that occurs is most likely with the father of the child, thereby exposing the endometrium to the same paternal sperm antigens more frequently With unmarried women, however, there may be several partners involved, with sex on an irregular basis Thus, there would be less opportunity for inadvertent ex¬ posure to the father's sperm Preeclampsia may be influenced by factors such as a maternal inheritance of a predisposition to preeclampsia,4 gra¬ and a change of partner14 as vidity,1012 well as exposure to sperm and seminal fluid through intercourse Several mechanisms might explain an effect of the latter: trophoblast-lymphocyte cross-reactive antigens from the semi¬ nal plasma, when deposited in the vagi¬ na, could perhaps serve as an antigenic source of allogeneic recognition in wom¬ en24; an unidentified agent might be present in the sperm or seminal fluid; or certain forms of birth control through nonimmunologic mechanisms might prevent normal adaptive mechanisms in pregnancy While the percentage of women who had used barrier methods exclusively was higher among cases, there were many cases who had used nonbarrier methods This latter observation is not surprising given the multifactorial etiol¬ ogy of this condition Furthermore, among the cases who were nonbarrier users, there is a large group who have also used barrier methods for varying amounts of time Perhaps the amount of exposure without barrier method use was not sufficient to protect from preeclampsia As in any telephone survey, the na¬ ture of the questions, length of recall required, and the interview setting may Although this study is relatively large compared with previous studies on the etiology of preeclampsia, the ac¬ tual study size is small, and therefore the study should be replicated with a much larger sample This applies espe¬ cially to the apparent interaction with marital status Finally, regional pecu¬ all affect the accuracy of the informa¬ tion Emphasis was placed on the reli¬ ability and validity25 of the personal in¬ terviews, since all the critical exposure information was gathered in this way The agreement rate for the 10% sample that was reinterviewed was extremely high for contraceptive history (com¬ plete concordance for 90% of cases and 89% of controls) The agreement rate between the medical records and pa¬ tient's history for types of birth control used was also excellent (100%) The number of months of use for each type of birth control was verified in the medical records26,27 and found to be in exact agreement for 86% of cases and 84% of controls Any errors are unlikely to be different between cases and controls, because there is no publicly perceived association between preeclampsia and birth control methods, so the resulting bias would be toward the null Another potential limitation ad¬ dressed within this study was selection bias The University of North Carolina Memorial Hospital is a high-risk obstet¬ ric center for a large catchment area, which could result in the referral of cases from a wider geographic area than controls Therefore, controls were fre¬ quency matched to cases on geographic location to minimize this problem liarities in the choice of birth control methods of cases and controls because of education, religion, or culture may limit generalizability to other settings This study is consistent with the find¬ ings of Marti and Harrmann19 of a de¬ creased risk of preeclampsia with the use of oral contraceptives It might be speculated that women with hyperten¬ sion would not use oral contraceptives and therefore would be more likely to use barrier methods However, women with a history of hypertension were omitted from the study, and the use of oral contraceptives was similar for cases and controls The overall association between bar¬ rier methods and preeclampsia (odds ra¬ tio, 2.37) would have important public health consequences if the relationship proves to be causal This study suggests that barrier methods may contribute to as much as 60% of preeclamptic cases However, additional studies are needed before appropriate recommendations can be made regarding birth control methods based on their risk of pre¬ 188 Beer A Possible 19 Marti J, Harrmann H Immunogestosis: a new etiologic concept of essential EPH gestosis, with special consideration of the primigravid patient Am J Obstet Gynecol 1977;128:489-493 20 Management of Preeclampsia Washington, DC: American College of Obstetricians and Gynecologists; 1986:19 Technical bulletin 21 QueenanJ, Hobbins J Protocols for High-Risk Pregnancies Oradell, NJ: Medical Economics Books; 1983 22 Kleinbaum D, Kupper L, Morgenstern H Epidemiologic Research: Principles and Quantitative Methods Belmont, Calif: Lifetime Learning Publishers; 1982 23 Chesley L Hypertensive Disorders in Pregnancy East Norwalk, Conn: Appleton & Lange; eclampsia We are indebted to Randy Cohen, MD, for his expert advice, David Kleinbaum, PhD, and Joanne Mills, MSPH, for their statistical assistance, and Deborah Schmidt for her technical prowess References Pritchard JA, MacDonald PC, Gant NF, eds Williams Obstetrics 17th ed East Norwalk, Conn: Appleton & Lange; 1985 Garrey M Ostehiem Illustrated 2nd ed New York, NY: Churchill Livingstone; 1982 Sutherland A, Cooper D, Howie P, Liston W, MacGillvray I The incidence of severe preeclampsia among mothers and mothers-in-law of preeclamptics and controls Br J Obstet Gynaecol 1981;88:785-791 Chesley L, Cooper D Genetics ofhypertnsio in pregnancy: possible single gene control of preeclampsia in the descendants of eclamptic women Br J Obstet Gynaecol 1986;93:898-908 Cooper D Genetic control of susceptibility to eclampsia and miscarriage Br J Obstet Gynaecol 1988;95:644-653 O'Brien W, Knuppel R, Saba H, Angel J, Benoit B, Bruce A Serum prostacyclin binding and half\x=req-\ life in normal and hypertensive pregnant women Obstet Gynecol 1989;73:43-46 Kilpatrick D, Jazwinska E, Liston W, Smart G Severe preeclampsia in multiparous women: indication of an environmental triggering agent? Scott Med J 1987;32:8-10 Eskenazi B, Bracken M, Holford T, Grady J Exposure to organic solvents and hypertensive disorders of pregnancy Am J Ind Med 1988;14:177\x=req-\ immunologic bases of preeclampsia/eclampsia Semin Perinatol 1978;2:39\x=req-\ 56 10 Beer A, Need J Immunological aspects of preeclampsia/eclampsia Birth Defects 1985; 21:131-154 11 Scott J, Beer A Immunologic aspects of preeclampsia Am J Obstet Gynecol 1976;125:418-425 12 MacGillvray I Some observations on the incidence of preeclampsia J Obstet Gynaecol Br Em- pire 1958;65:536-539 13 Campbell D, MacGillvray I, Carr-Hill P Preeclampsia in second pregnancy Br J Obstet Gynaecol 1985;92:131-140 14 Need J Preeclampsia in pregnancy by different fathers Br MedJ 1975;1:548-549 15 Ikedife D Eclampsia in multipara Br Med J 1980;5:985-986 16 Feeney J, Scott J Preeclampsia and changed paternity Br J Obstet Gynecol Reprod Biol 1980;11:35-38 17 Need J, Bell B, Meffin E Preeclampsia in pregnancies from donor inseminations J Reprod Immunol 1983;5:329-338 18 Serhal P, Craft I Immune basis for preeclampsia: evidence from oocyte recipients Lancet 1987;1:744 1978 24 Kajino T, Torrey J, McIntyre A, Faulk W Trophoblast antigens in human seminal plasma Am J Reprod Immunol 1988;17:91-95 25 Udry R Frequency of intercourse by days of the week J Sex Res 1970;6:229-234 26 Tilley B A comparison of pregnancy history recall and medical records Am J Epidemiol 1985;121:269-281 27 Rosenberg M Agreement between womens' history of oral contraceptive use and physicians' records Am J Epidemiol 1983;12:84-87 Downloaded From: http://jama.jamanetwork.com/ by a Florida International University Medical Library User on 05/31/2015 ... pregnan¬ cies and hydatidiform moles; and age less than 15 or greater than 35 years The phenomenon of intrapartum and postpartum (transient) hypertension of labor was also excluded in this study. .. (73% of cases and 77% of controls) Loss was primarily caused by the inability to locate respondents (26% of cases and 22% of controls), with a small number of respondent refusals (0.7% of cases and. .. patients were adopted from the American College of Obstetri¬ cians and Gynecologists20 and modified for this study (Table l).121 The full spec¬ trum of severity of preeclampsia was included, with