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Recurrence of hypertensive disorder in second pregnancy

      Objective

      The purpose of this study was to investigate the recurrence of hypertensive disorders in pregnancy with regard to the type of disorder, the onset of hypertension, and the modulating effect of overweight and weight gain between pregnancies.

      Study design

      Maternity records from 896 parous women with hypertensive disorders in pregnancy in the first pregnancy were reviewed to reclassify disease status and calculate odds ratios for recurrence.

      Results

      Recurrence of hypertensive disorders in pregnancy occurred in 58% to 94% of second pregnancies, depending on first pregnancy disorder. Overweight (odds ratio, 1.82) and weight gain (odds ratio, 2.20) were related to recurrence among women with gestational hypertension. Early hypertension (≤34 weeks of gestation) increased the recurrence risk for women with gestational hypertension (odds ratio, 1.85) and preeclampsia (odds ratio, 3.42).

      Conclusion

      Recurrence of hypertensive disorders in pregnancy is common, but not specified by type of disorder in first pregnancy. Overweight and weight gain between pregnancies are associated with recurrent hypertensive disorders in pregnancy in women with gestational hypertension. Early onset of hypertension is a risk factor, independent of body weight.

      Key words

      Hypertensive disorder in pregnancy (HDP) entails a risk of recurrence in a subsequent pregnancy.
      • Campbell D.M.
      • MacGillivray I.
      • Carr-Hill R.
      Pre-eclampsia in second pregnancy.
      • Hargood J.L.
      • Brown M.A.
      Pregnancy-induced hypertension: recurrence rate in second pregnancies.
      • Zhang J.
      • Troendle J.F.
      • Levine R.J.
      Risks of hypertensive disorders in the second pregnancy.
      • Trogstad L.
      • Skrondal A.
      • Stoltenberg C.
      • Magnus P.
      • Nesheim B.I.
      • Eskild A.
      Recurrence risk of preeclampsia in twin and singleton pregnancies.
      There is also evidence that the different clinical forms of HDP (gestational hypertension, preeclampsia, eclampsia, and even chronic hypertension in first and in later pregnancies) may be related.
      • Arngrimsson R.
      • Bjornsson S.
      • Geirsson R.T.
      • Bjornsson H.
      • Walker J.J.
      • Snaedal G.
      Genetic and familial predisposition to eclampsia and pre-eclampsia in a defined population.
      • Arngrimsson R.
      • Sigurardottir S.
      • Frigge M.L.
      • Bjarnadottir R.I.
      • Jonsson T.
      • Stefansson H.
      • et al.
      A genome-wide scan reveals a maternal susceptibility locus for pre-eclampsia on chromosome 2p13.
      • Barden A.E.
      • Beilin L.J.
      • Ritchie J.
      • Walters B.N.
      • Graham D.
      • Michael C.A.
      Is proteinuric pre-eclampsia a different disease in primigravida and multigravida?.
      • Chesley L.C.
      History and epidemiology of preeclampsia-eclampsia.
      • Livingston J.C.
      • Sibai B.M.
      Chronic hypertension in pregnancy.
      • Ros H.S.
      • Cnattingius S.
      • Lipworth L.
      Comparison of risk factors for preeclampsia and gestational hypertension in a population-based cohort study.
      Therefore, in HDP studies, it may be preferable to include all clinical forms of the disorder and not only the first, but also later pregnancies.
      Several risk factors have been associated with HDP, and the contribution of each of these factors may differ according to the type of the disorder and the population that is studied. Among these are family history
      • Arngrimsson R.
      • Bjornsson S.
      • Geirsson R.T.
      • Bjornsson H.
      • Walker J.J.
      • Snaedal G.
      Genetic and familial predisposition to eclampsia and pre-eclampsia in a defined population.
      • Chesley L.C.
      • Annitto J.E.
      • Cosgrove R.A.
      The familial factor in toxemia of pregnancy.
      • Mogren I.
      • Hogberg U.
      • Winkvist A.
      • Stenlund H.
      Familial occurrence of preeclampsia.
      • Cincotta R.B.
      • Brennecke S.P.
      Family history of pre-eclampsia as a predictor for pre-eclampsia in primigravidas.
      and previous HDP.
      • Campbell D.M.
      • MacGillivray I.
      • Carr-Hill R.
      Pre-eclampsia in second pregnancy.
      • Hargood J.L.
      • Brown M.A.
      Pregnancy-induced hypertension: recurrence rate in second pregnancies.
      • Zhang J.
      • Troendle J.F.
      • Levine R.J.
      Risks of hypertensive disorders in the second pregnancy.
      • Livingston J.C.
      • Sibai B.M.
      Chronic hypertension in pregnancy.
      Overweight is a known risk factor for gestational hypertension, preeclampsia, eclampsia, and chronic hypertension in both first and later pregnancies.
      • Ros H.S.
      • Cnattingius S.
      • Lipworth L.
      Comparison of risk factors for preeclampsia and gestational hypertension in a population-based cohort study.
      • Sibai B.M.
      • Gordon T.
      • Thom E.
      • Caritis S.N.
      • Klebanoff M.
      • McNellis D.
      • et al.
      Risk factors for preeclampsia in healthy nulliparous women: a prospective multicenter study: the National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.
      • Thadhani R.
      • Stampfer M.J.
      • Hunter D.J.
      • Manson J.E.
      • Solomon C.G.
      • Curhan G.C.
      High body mass index and hypercholesterolemia: risk of hypertensive disorders of pregnancy.
      • Must A.
      • Spadano J.
      • Coakley E.H.
      • Field A.E.
      • Colditz G.
      • Dietz W.H.
      The disease burden associated with overweight and obesity.
      • Barden A.E.
      • Beilin L.J.
      • Ritchie J.
      • Walters B.N.
      • Michael C.
      Does a predisposition to the metabolic syndrome sensitize women to develop pre-eclampsia?.
      • LaCoursiere D.Y.
      • Bloebaum L.
      • Duncan J.D.
      • Varner M.W.
      Population-based trends and correlates of maternal overweight and obesity, Utah 1991-2001.
      Early onset of hypertension also has been linked to a higher recurrence rate of hypertensive disorders.
      • Zhang J.
      • Troendle J.F.
      • Levine R.J.
      Risks of hypertensive disorders in the second pregnancy.
      In this study, we investigated the recurrence of HDP with regard to the type of disorder in the second pregnancy. We also hypothesized that the risk for recurrence would be influenced by the gestational length at the onset of hypertension and by overweight and weight gain between pregnancies.

      Material and methods

      Among the 42,460 deliveries at Landspítali University Hospital in Reykjavík during the years 1984 to 1999, 4245 women with HDP were identified by a search of the hospital database (ICD 9 and ICD 10 codes for gestational hypertension, preeclampsia, eclampsia, chronic hypertension, and superimposed preeclampsia on chronic hypertension). A subset of this group was selected for further consideration in a comprehensive genetic and epidemiologic study series.
      Using the Icelandic Genealogy Database, which stores all available genealogy data for the last 11 centuries in Iceland,
      • Gulcher J.
      • Stefansson K.
      Population genomics: laying the groundwork for genetic disease modeling and targeting.
      we were able to cluster the women to families going back 3 generations. When this definition of families was used, >95% of the 4245 women on the HDP list were found to have at least 1 relative on the list. From these, 1866 women in the largest family clusters were selected as a basis for this study series.
      The population in Iceland is uniformly white Caucasian of Nordic descent. The antenatal care system in Iceland is well organized, and the maternity care attendance rate is high (99.5%), usually commencing in the first trimester. Maternity records include information that is gathered at the first visit in late first trimester and information on the pregnancy and birth until discharge from hospital. All maternity records for the women in the study were scrutinized by 1 of the authors (S.H.). Because of different definitions for the types of HDP that were used in these records for this time period, it was necessary to reclassify and confirm or reject the hypertensive disorder in each pregnancy. Among the variables that were used for this reclassification were blood pressure at first visit, gestational age at diagnosis of hypertension and/or proteinuria (if present), and information on prepregnancy body mass index (BMI). We used a simplified classification that is based on the National High Blood Pressure Education Program definitions (Table I).
      Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy.
      Table ISimplified classification of hypertensive disorders in pregnancy that is based on the National High Blood Pressure Education Program definitions
      Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy.
      DisorderDefinition
      HypertensionBlood pressure ≥140 mm Hg systolic and/or ≥90 mm Hg diastolic measured 2 times with at least a 6-hour interval
      ProteinuriaUrinary excretion of ≥0.3 g protein/24-hr specimen or ≥2+ on qualitative examination (“dipstick”)
      Chronic hypertensionKnown hypertension before pregnancy or hypertension diagnosed for the first time before week 20 of gestation
      Gestational hypertensionHypertension diagnosed after week 20 of gestation
      PreeclampsiaGestational hypertension and proteinuria
      EclampsiaSeizures in women with hypertension
      Superimposed preeclampsiaOccurrence of proteinuria in women with chronic hypertension
      After this revision, we selected those women from the group of 1866 who had ≥2 singleton births and confirmed HDP in the first pregnancy, which produced a total of 896 women. Women with hypertension that was known to be due to renal or vascular diseases were excluded. The disorder type in the second pregnancy, if present, was evaluated, and the recurrence rates were presented as percentages. For the 662 women, who had gestational hypertension or preeclampsia (including 3 women with eclampsia) in their first pregnancy, we analyzed the effects of overweight, weight gain between pregnancies, and gestational age at diagnosis on the recurrence risks of HDP in their second pregnancy. Maternal height and prepregnancy weight data for both first and second pregnancy were available for all women and were used to calculate the BMI, which was categorized by the method described by the National Heart, Lung and Blood Institute.
      Obesity: preventing and managing the global epidemic: report of a WHO consultation of obesity.
      Overweight was defined as BMI ≥25 kg/m2. Significant weight gain between pregnancies was defined arbitrarily as an increase in BMI by >2 units (kg/m2), which would amount to approximately 6 kg in women of average height. Information from routine second trimester ultrasound screening at 19 to 20 weeks of gestation was used to assign gestational age. In the few cases without ultrasound evaluation, gestational age at diagnosis and delivery was calculated from the last menstrual period.
      SPSS software (version 11; SPSS Inc, Chicago, IL) was used for statistical calculations. Adjusted odds ratios and associated 95% confidence intervals (CIs) were calculated with logistic regression models. Results were corrected for maternal age.
      The study was approved by The National Bioethics Committee and the Data Protection Authority of Iceland.

      Results

      Table II gives a summary of the type of HDP in the first pregnancy, the recurrence rate, and type of disorder in the second pregnancy. The overall recurrence of HDP was 73%. Women who had preeclampsia in the first pregnancy had the lowest rate of recurrence of HDP in the second pregnancy (58.3%). The highest concordance between diagnosis in first and second pregnancy was seen in women with gestational hypertension and chronic hypertension.
      Table IIType of recurrent HDP in second pregnancy by type of HDP in first pregnancy
      Second pregnancy (n)
      No women had eclampsia in second pregnancy.
      First pregnancyNormalGestational hypertensionPreeclampsiaChronic hypertensionSuperimposed preeclampsiaAll recurrences
      Gestational hypertension (n = 511)153 (29.9%)239 (46.8%)25 (4.9%)82 (16%)12 (2.3%)358 (70.1%)
      Preeclampsia/eclampsia (n = 151)63 (41.7%)52 (34.4%)17 (11.3%)16 (10.6%)3 (2%)88 (58.3%)
      Chronic hypertension (n = 200)24 (12%)69 (34.5%)6 (3%)91 (45.5%)10 (5%)176 (88%)
      Superimposed preeclampsia (n = 34)2 (5.9%)10 (29.4%)4 (11.8%)14 (41.2%)4 (11.8%)32 (94%)
      Total (n = 896)242 (27%)370 (41.3%)52 (5.8%)203 (22.7%)29 (3.2%)654 (73%)
      No women had eclampsia in second pregnancy.
      In Table III, the risk estimates for recurrent HDP in the second pregnancy are shown for women who had gestational hypertension in their first pregnancy. In this group, both overweight before the first pregnancy and weight gain between the pregnancies were associated with an increased risk of recurrent HDP. Early onset of gestational hypertension (≤34 gestational weeks) was also associated with an increased risk of recurrent HDP, predominantly with chronic hypertension; this association remained unchanged after correction for overweight (data not shown).
      Table IIIRisk estimation (odds ratio; 95% CI) for recurrence of HDP in women with gestational hypertension in first pregnancy (n = 511)
      Type of HDP in second pregnancy
      Risk factorGestational hypertensionPreeclampsiaChronic hypertension
      Includes superimposed preeclampsia.
      All recurrent HDP
      Overweight (n = 130)1.35 (0.91-2.01)1.45 (0.61-3.45)1.17 (0.71-1.94)1.82 (1.13-2.92)
      Weight gain (n = 171)1.27 (0.88-1.84)0.84 (0.35-2.02)1.83 (1.15-2.89)2.20 (1.41-3.42)
      Hypertension diagnosed ≤34 wk (n = 244)0.99 (0.70-1.41)0.58 (0.25-1.35)2.80 (1.74-4.51)1.85 (1.25-2.74)
      Includes superimposed preeclampsia.
      The risk estimates for recurrent HDP in second pregnancy for women who had preeclampsia in their first pregnancy are summarized in Table IV. Possible effects of overweight or weight gain between pregnancies on the recurrence risk could not be established. The onset of hypertension ≤34 gestational weeks was associated with an increased risk of recurrent HDP; again, the highest risk correlated with chronic hypertension by the second pregnancy.
      Table IVRisk estimation (odds ratio; 95% CI) for recurrence of HDP in women with preeclampsia in first pregnancy (n = 151)
      Type of HDP in second pregnancy
      Risk factorGestational hypertensionPreeclampsiaChronic hypertension
      Includes superimposed preeclampsia.
      All recurrent HDP
      Overweight (n = 29)0.96 (0.43-2.17)1.34 (0.40-4.46)0.76 (0.21-2.82)0.86 (0.38-1.93)
      Weight gain (n = 43)1.20 (0.59-2.45)1.87 (0.66-5.31)1.53 (0.56-4.22)1.50 (0.72-3.12)
      Hypertension diagnosed ≤34 wk (n = 78)1.66 (0.86-3.20)1.33 (0.47-3.77)6.01 (1.67-22.1)3.42 (1.71-6.84)
      Includes superimposed preeclampsia.

      Comment

      In our study population of women with HDP, the risk of recurrent disorder was 58% to 94%, depending on the type in first pregnancy. As shown in Table II, the whole spectrum of HDP occurred in the second pregnancy, regardless of the initial type, which reflects the complex relationship between the different types. Overweight and weight gain between pregnancies increased this risk, which was seen most clearly in women with gestational hypertension. Early onset of hypertension increased the risk of recurrent HDP in women with gestational hypertension or preeclampsia in the first pregnancy.
      The incidence of recurrent HDP in second pregnancy has been evaluated in several studies.
      • Campbell D.M.
      • MacGillivray I.
      • Carr-Hill R.
      Pre-eclampsia in second pregnancy.
      • Hargood J.L.
      • Brown M.A.
      Pregnancy-induced hypertension: recurrence rate in second pregnancies.
      • Zhang J.
      • Troendle J.F.
      • Levine R.J.
      Risks of hypertensive disorders in the second pregnancy.
      • Trogstad L.
      • Skrondal A.
      • Stoltenberg C.
      • Magnus P.
      • Nesheim B.I.
      • Eskild A.
      Recurrence risk of preeclampsia in twin and singleton pregnancies.
      Some of these studies are small, and the HDP definitions vary, which makes comparisons difficult. The overall recurrence of HDP in our study was high, but the pattern of recurrence for the different types was similar to what has been described before. In the large and comprehensive study by Campbell et al,
      • Campbell D.M.
      • MacGillivray I.
      • Carr-Hill R.
      Pre-eclampsia in second pregnancy.
      the recurrence of mild preeclampsia (equivalent to gestational hypertension) in second pregnancy was 29% and of proteinuric preeclampsia (equivalent to preeclampsia) 7.5%. We found a higher recurrence rate of gestational hypertension (46.8%) and preeclampsia (11.3%). The latter finding approaches the 14.1% recurrence rate of preeclampsia that was found in a recent Norwegian study.
      • Trogstad L.
      • Skrondal A.
      • Stoltenberg C.
      • Magnus P.
      • Nesheim B.I.
      • Eskild A.
      Recurrence risk of preeclampsia in twin and singleton pregnancies.
      One third of the women with preeclampsia in our study had gestational hypertension in the second pregnancy, which is close to what other investigators have observed.
      • Campbell D.M.
      • MacGillivray I.
      • Carr-Hill R.
      Pre-eclampsia in second pregnancy.
      • Hargood J.L.
      • Brown M.A.
      Pregnancy-induced hypertension: recurrence rate in second pregnancies.
      • Zhang J.
      • Troendle J.F.
      • Levine R.J.
      Risks of hypertensive disorders in the second pregnancy.
      In an Australian study, only 3% of 140 women with gestational hypertension or preeclampsia in the first pregnancy were noted to have chronic hypertension by the second pregnancy; in our study, this figure was 17%.
      • Hargood J.L.
      • Brown M.A.
      Pregnancy-induced hypertension: recurrence rate in second pregnancies.
      The difference may simply be the result of the small sample size in the Australian study. Alternatively, this difference may reflect a failure to identify chronic hypertension in the first pregnancy in our study, which we believe is unlikely, considering that early pregnancy blood pressure was available for all women in the study. Furthermore, this difference could be the result of a higher susceptibility for chronic hypertension in our study population, which is possible because of higher BMI or more weight gain between pregnancies, which are variables that were not considered in the other study.
      Less than one half of the women in our study with chronic hypertension in the first pregnancy were noted still to have chronic hypertension by their second pregnancy. One third of the women had gestational hypertension, but very few of the women experienced more severe forms of HDP (Table II). It was interesting to note that 12% of the women who were classified as having chronic hypertension in their first pregnancy were found to be normotensive throughout the second pregnancy. The term chronic hypertension was used in this study as defined by National High Blood Pressure Education Program (Table I). It is not implied in this definition that there is a recurrence in subsequent pregnancies, even though hypertension might arise at some point in later life. The group with chronic hypertension might also include women with “white coat hypertension” in early pregnancy.
      • Brown M.A.
      • Mangos G.
      • Davis G.
      • Homer C.
      The natural history of white coat hypertension during pregnancy.
      Family history of preeclampsia has been shown to be associated with a 4-fold increased risk of preeclampsia in primigravid women.
      • Cincotta R.B.
      • Brennecke S.P.
      Family history of pre-eclampsia as a predictor for pre-eclampsia in primigravidas.
      The presence of a familial factor in other forms of HDP and in both primigravid and multigravid women has been suggested in eclampsia and preeclampsia,
      • Arngrimsson R.
      • Bjornsson S.
      • Geirsson R.T.
      • Bjornsson H.
      • Walker J.J.
      • Snaedal G.
      Genetic and familial predisposition to eclampsia and pre-eclampsia in a defined population.
      • Chesley L.C.
      • Annitto J.E.
      • Cosgrove R.A.
      The familial factor in toxemia of pregnancy.
      gestational hypertension,
      • Arngrimsson R.
      • Sigurardottir S.
      • Frigge M.L.
      • Bjarnadottir R.I.
      • Jonsson T.
      • Stefansson H.
      • et al.
      A genome-wide scan reveals a maternal susceptibility locus for pre-eclampsia on chromosome 2p13.
      and chronic hypertension.
      • Livingston J.C.
      • Sibai B.M.
      Chronic hypertension in pregnancy.
      It is not evident from these studies, however, whether family history is a risk factor for recurrent disorder. From our analysis of the study cohort, it seems that, on close inspection, most HDP cases have a family history of the disorder, because >95% of the women who were identified initially with HDP had at least 1 relative on the HDP list. It is difficult therefore to distinguish between individuals with and without family history and to evaluate any familial effect. The women who were studied here all had a number of relatives with some form of HDP, which may explain the high recurrence rate found in this study. However, in the absence of a clear alternative (ie, patients with no relatives with HDP) that question cannot be addressed. To account for the fact that some women within the cohort were related, we did a separate analysis on a subset of women (n = 441) who were not related to each other (data not shown). This did not show a difference in the overall rate or type of recurrence.
      Overweight is an increasing health problem worldwide and is associated with many medical disorders, among them chronic hypertension.
      • Must A.
      • Spadano J.
      • Coakley E.H.
      • Field A.E.
      • Colditz G.
      • Dietz W.H.
      The disease burden associated with overweight and obesity.
      The relation between overweight and all the different HDP forms in first or later pregnancies is evident from several studies.
      • Ros H.S.
      • Cnattingius S.
      • Lipworth L.
      Comparison of risk factors for preeclampsia and gestational hypertension in a population-based cohort study.
      • Sibai B.M.
      • Gordon T.
      • Thom E.
      • Caritis S.N.
      • Klebanoff M.
      • McNellis D.
      • et al.
      Risk factors for preeclampsia in healthy nulliparous women: a prospective multicenter study: the National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.
      • Thadhani R.
      • Stampfer M.J.
      • Hunter D.J.
      • Manson J.E.
      • Solomon C.G.
      • Curhan G.C.
      High body mass index and hypercholesterolemia: risk of hypertensive disorders of pregnancy.
      • Barden A.E.
      • Beilin L.J.
      • Ritchie J.
      • Walters B.N.
      • Michael C.
      Does a predisposition to the metabolic syndrome sensitize women to develop pre-eclampsia?.
      • LaCoursiere D.Y.
      • Bloebaum L.
      • Duncan J.D.
      • Varner M.W.
      Population-based trends and correlates of maternal overweight and obesity, Utah 1991-2001.
      In our study, overweight and weight gain were associated with an increased recurrence risk of HDP in women with gestational hypertension; these risk factors also were more common (Table III, Table IV) compared with women with preeclampsia. The highest incidence of overweight (44%) was seen in women with chronic hypertension in the first pregnancy. Overweight seems to be related more strongly to gestational hypertension and chronic hypertension than to preeclampsia and may at least partly explain the higher recurrence rate that is observed for gestational hypertension when compared with preeclampsia.
      We evaluated the effect of an early diagnosis of hypertension on the recurrence risk. Onset of hypertension at ≤34 weeks of gestation in the first pregnancy doubled the risk for recurrent HDP in women with gestational hypertension. When a woman also experienced proteinuria (and thus preeclampsia), the risk was more than 3-fold. Early diagnosis of hypertension is therefore a marker of the severity, also in women who will not proceed to preeclampsia. This suggests, at least in part, a common mechanism underlying these conditions.
      In summary, women who had HDP in their first pregnancy had a high risk of repeated HDP in the second pregnancy, but not necessarily the same type. This risk was higher if the onset of hypertension in the first pregnancy was ≤34 weeks of gestation and was associated independently with overweight and weight gain between pregnancies. Women who meet these criteria should be informed about this after a first affected pregnancy, and if the woman is overweight, she should be offered advice on life style adjustment. In the second pregnancy, increased surveillance would be appropriate.

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