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Reprint requests: José Villar, MD, UNDP/UNFPA/WHO/World Bank Special Programme of Research Development and Research Training in Human Reproduction, Department of Reproductive Health and Research, World Health Organization, 1211 Geneva 27, Switzerland.
United Nations Development Programme/United Nations Population Fund/World Health Organization/World Bank Special Program of Research, Development and Research Training in Human Reproduction, Department of Reproductive Health and Research, World Health Organization, Geneva, Switzerland
Preeclampsia, gestational hypertension, and unexplained intrauterine growth restriction may have similar determinants and consequences. In this study, we compared determinants and perinatal outcomes associated with these obstetric conditions.
Study design
We analyzed 39,615 pregnancies (data from the WHO Antenatal Care Trial), of which 2.2% were complicated by preeclampsia, 7.0% by gestational hypertension, and 8.1% by unexplained intrauterine growth restriction (ie, not associated with maternal smoking, maternal undernutrition, preeclampsia, gestational hypertension, or congenital malformations). We compared the risk factors associated with these groups. Fetal death, preterm delivery, and severe neonatal morbidity and mortality were the primary outcomes. Logistic regression analyses were adjusted for study site, socioeconomic status, and (if appropriate) birth weight and gestational age.
Results
Diabetes, renal or cardiac disease, previous preeclampsia, urinary tract infection, high maternal age, twin pregnancy, and obesity increased the risk of both hypertensive conditions. Previous large-for-age birth, reproductive tract surgery, antepartum hemorrhage and reproductive tract infection increased the risk for gestational hypertension only. Independent of maternal age, primiparity was a risk factor only for preeclampsia. Both preeclampsia and gestational hypertension were associated with increased risk for fetal death and severe neonatal morbidity and mortality. Mothers with preeclampsia compared with those with unexplained intrauterine growth restriction were more likely to have a history of diabetes, renal or cardiac disease, chronic hypertension, previous preeclampsia, body mass index more than 30 kg/cm2, urinary tract infection and extremes of maternal age. Conversely, unexplained intrauterine growth restriction was associated with higher risk of low birth weight in previous pregnancies, but not with previous preeclampsia. Both conditions increased the risk for perinatal outcomes independently but preeclampsia was associated with considerable higher risk.
Conclusion
Preeclampsia and gestational hypertension shared many risk factors, although there are differences that need further evaluation. Both conditions significantly increased morbidity and mortality. Conversely, preeclampsia and unexplained intrauterine growth restriction, often assumed to be related to placental insufficiency, seem to be independent biologic entities.
Hypertension complicates approximately 9% of all pregnancies with preeclampsia-eclampsia (up to 4%) being a major cause of maternal and perinatal morbidity and mortality.
Currently, preeclampsia (de novo hypertension after mid pregnancy plus new-onset proteinuria) and gestational hypertension (de novo hypertension after mid pregnancy but no proteinuria) are considered either separate diseases affecting similar organs
or different severities of the same underlying disorder. According to the latter hypothesis, gestational hypertension is merely an early or mild stage of preeclampsia, perhaps preceding renal involvement and thus proteinuria.
Intrauterine growth restriction (IUGR), as reflected by small for gestational age (SGA), of diverse causes, affects a fair number of newborn infants worldwide, mainly in developing countries.
Some forms of IUGR have been etiologically linked to preeclampsia, based on similar placental disease described as abnormal implantation and characterized by failure of trophoblasts to differentiate, to invade, and to remodel the spiral arteries.
These similarities underlie the hypothesis that preeclampsia and IUGR secondary to placental insufficiency share cause but have different clinical manifestations.
Obviously, a clearer understanding of each of the 3 disorders described previously is a goal of studies that examine, whether they share a common cause. Such studies were recently recommended
and should lead to improved methods of prevention, detection, and treatment. The presence of the large database from our “WHO multicentre randomized trial evaluating a new model of antenatal care,”
provided an opportunity to compare preeclampsia, gestational hypertension, and IUGR in terms of risk or protective factors and immediate perinatal outcomes.
Material and methods
This is a secondary analysis of data collected in the World Health Organization (WHO) Antenatal Care Trial.
This trial using a cluster randomization design (the clusters being the antenatal care clinics) was conducted in Rosario, Argentina, Havana, Cuba, Jeddah, Saudi Arabia, and Khon Kaen, Thailand. It enrolled 24,678 women in 53 antenatal clinics and took place between August 1996 and December 1998. In addition, data from 5 hospitals (17,073 pregnant women) affiliated to 1 of the participating centers (the Centro Rosarino de Estudios Perinatales CREP, Rosario, Argentina), that applied all the trial's data collection procedures to their entire pregnant population during the same study period, were also available for analysis. This complete data set has been recently used for another observational study.
All study clinics had a standard antenatal care system following protocols and predefined activities, including procedures for glucose tolerance test, as well as screening and treatment for urinary and reproductive tract infections. All data were extracted prospectively from medical records available at all the participating clinics and hospitals.
The original trial, its population and primary outcomes are described in detail in the literature.
Of relevance to the current analysis, the incidences of preeclampsia, SGA, neonatal mortality and neonatal intensive care unit stay more than 7 days were evaluated by using the χ2 test for heterogeneity and did not differ among participating countries.
The 2 arms of the original trial had similar rates of most of perinatal outcomes without reaching statistical significant levels, including preeclampsia/eclampsia and IUGR.
The best obstetric estimate of gestational age was determined as outlined in the WHO Trial Manual
Preeclampsia was defined as de novo hypertension (blood pressure ≥140 mm Hg systolic or ≥90 mm Hg diastolic after mid pregnancy plus proteinuria ≥2+ on qualitative examination [dipstick] or 300 mg or more in a 24-hour urine sample) and was restricted to cases of preeclampsia-eclampsia occurring anytime during pregnancy and up to 24 hours postpartum.
Gestational hypertension was defined as de novo hypertension as above after mid pregnancy and no proteinuria.
In the original trial, the new model conducted routine urinary screening with dipstick for proteinuria. Although, as we have discussed in previous publications, there was no significant different rate of detection of preeclampsia, we have adjusted for treatment group in all the analyses by adding to all regression models a variable indicating the treatment group of the original trial.
IUGR was diagnosed, when birth weight was below the 10th percentile of that anticipated for gestational age.
We selected this fetal growth chart recommended by WHO for international comparisons, and it is the same we used in previous analyses of this data set.
Socioeconomical status for each woman was evaluated by using an index derived from statistical analysis, including maternal education, marital status, and house characteristics.
Other essentials of the original trial included data forms translated and adapted to local terminology and practice, trained female interviewers who abstracted information, and if needed, queried mothers during the postpartum period and a data quality-monitoring unit at each research center.
The participating staff, while aware that a trial was being conducted, was not informed of the specific hypotheses being tested. Finally, unknown to its clinic staff, each center was audited twice by external supervisors, acquiring a random sample of 759 women, that when analyzed by kappa statistics validated the agreement between observers during data acquisition.
Kappa statistics were 0.93 or higher for birth weight, preeclampsia and maternal morbidity; 0.90 for gestational hypertension and 0.97 for IUGR. Kappa statistics for baseline characteristics were 0.79 or higher. The intraclass correlation coefficient for gestational age at birth was 0.93 and 0.99 for birth weight.
Data from 41,751 pregnant women were initially available for analysis; 929 women, who delivered before gestational week 22, or whose newborn infant weighed less than 500 g were excluded, as were 741 women lost to follow-up, leaving data from 40,081 births. We further excluded 466 newborn infants with clinical evidence of congenital malformations or structural defects (Figure). We calculated the rate of multiple pregnancies by study group; however, for the analysis of risk factors and outcomes, we selected the first-born infant and considered the pregnancy as singleton. The final analysis population was 39,615 women and their pregnancies.
FigureStudy population flow chart. During the analysis comparisons were made between: (1) Preeclampsia vs gestational hypertension compared with reference group and (2) preeclampsia vs unexplained IUGR compared with reference group . All study groups are mutually exclusives; each woman was included in only one of these groups.
For the current analysis, the study population was classified according to presence of preeclampsia/eclampsia, gestational hypertension, and IUGR; pregnancies with combinations of these entities were also identified. IUGR in the presence of either preeclampsia and/or gestational hypertension was considered secondary to the hypertensive condition, and these cases were analyzed within those groups. Women without any of these conditions constituted the reference group.
IUGR newborns were further divided in terms of perceived cause or risk factors into 4 subgroups: (1) IUGR associated with smoking, (2) IUGR associated with undernutrition (defined as a maternal body mass index [BMI] <19.8 kg/m2 and/or severe anaemia in pregnancy <9.0 g/L of hemoglobin), (3) IUGR secondary to preeclampsia or gestational hypertension, and (4) all the remaining IUGR cases without congenital malformations were considered unexplained IUGR. All study groups are mutually exclusives and each woman was included only in 1 of them. The unexplained IUGR group was further evaluated by selecting newborn infants with a birth weight below the 5th percentile for gestational age derived from the same fetal growth chart.
We defined determinants for the conditions studied, a series of sociodemographic characteristics, elements in the pregnancy history, medical, and obstetric complications of current pregnancy and compared them among preeclamptic, gestational hypertension, and unexplained IUGR groups. IUGR secondary to preeclampsia is not considered in the latter group, but included in the preeclampsia group.
Perinatal outcomes were fetal death, preterm delivery, newborn length of stay at the neonatal intensive care unit (NICU) or other special care unit for 7 days or more (used as a proxy indicator for severe neonatal morbidity) and neonatal death until hospital discharge. For the rate of days of stay in the NICU, the denominator was all newborn infants who survived the first week of life. Finally, we also compared perinatal outcomes among IUGR infants born to mothers with preeclampsia or gestational hypertension with unexplained IUGR.
The proportion of cases with preeclampsia, gestational hypertension, and IUGR was estimated as a fraction of the total study population. Risk factors were compared by computing the proportion of subjects in each study group. A separate multinomial logit model
was developed for each risk factor, considering study group as dependent variable and adjusting for possible confounders. All regression models included socioeconomic status (SES) and study site. From these models, adjusted odds ratios (OR) with their corresponding 95% CI were obtained for the risk factors in the preeclampsia and gestational hypertension groups compared with the reference group. A similar approach was carried out for comparing preeclampsia and unexplained IUGR with the reference group.
were used to analyze the relationships between preeclampsia, gestational hypertension and IUGR groups with perinatal outcomes. ORs derived from these models were adjusted by study site, treatment group in the original trial, and SES. Birth weight and gestational age were included in the analysis comparing outcomes for the preeclampsia and gestational hypertension groups. The linearity assumption for the continuous variables was evaluated, and nonlinear terms were used to improve the goodness of fit (Hosmer-Lemeshow statistics).
All protocols were approved by the WHO Committee for Research into Human Subjects and the Institutional Review Boards of the participating institutions. Analyses were made with SAS software version 8.2 (SAS, Cary, NC).
Results
The Figure depicts the study population. The incidence of preeclampsia was 2.2% (0.5% associated with IUGR) and that of gestational hypertension 7.0%, (0.9% associated with IUGR). The total incidence of IUGR was 13.3%. In addition to the 1.4% secondary to preeclampsia or gestational hypertension, 1.1% of the IUGR cases were associated with smoking, 2.7% with undernutrition, and 8.1% categorized as unexplained IUGR. The incidence of IUGR among preeclamptic women was 22.2%, and among women with gestational hypertension was 13%.
Do preeclampsia and gestational hypertension share similar risk factors?
Table I depicts rates and ORs (95% CI) comparing all women with preeclampsia or gestational hypertension with the reference group. Both gestational hypertension and preeclampsia were associated with a host of risk factors when compared with the reference group. Diabetes, renal or cardiac disease, preeclampsia in the previous pregnancy, urinary tract infection, high maternal age, twin pregnancy, or obesity increased the risk of both hypertensive conditions. SES was similarly distributed in these conditions (Table I).
Table IRisk factors for preeclampsia and gestational hypertension compared with the reference group
Previous large-for-gestational-age (LGA) birth, history of reproductive tract surgery, antepartum hemorrhage, and reproductive tract infection increased the risk for gestational hypetension only. After adjusting for young maternal age (<16 years), primiparity remained as independent risk factor for preeclampsia, but only marginally for gestational hypertension. Interestingly, history of chronic respiratory conditions was independently associated with preeclampsia but not with gestational hypertension (Table I). Unfortunately, we did not have information related to any medication taken for treatment of respiratory ailments.
Do pregnancies complicated by preeclampsia and gestational hypertension have similar perinatal outcomes?
Women with gestational hypertension had a mean birth weight and gestational age similar to those of the reference group. Women with preeclampsia had a lower mean gestational age (37.5 weeks) and mean birth weight (2845 g), than those in the reference and gestational hypertension groups (Table II).
Table IIGestational age and birth weight according to study subgroups
Gestational age and birth weight significantly different from the values for the reference group (P < .01).
358
Reference group
30,927
38.9
2.2
30,985
3,264
507
For definition of study subgroups see Figure. Differences in sample size with those in the Figure are due to missing values for gestational age or birth weight.
∗ Gestational age and birth weight significantly different from the values for the reference group (P < .01).
Fetal death was significantly higher in the preeclampsia group 2.2%, compared with either the gestational hypertension (1.4%), or reference (0.9%) groups. ORs adjusted for site and SES were 2.5 (95% CI 1.6-4.1) in the preeclampsia group and OR 1.6 (95% CI 1.1-2.3) in the gestational hypertension group, when compared with the reference group (Table III).
Table IIIPerinatal outcomes for preeclampsia and gestational hypertension compared with the reference group
The rate of preterm delivery in preeclamptic women (27.4%) was significantly higher than in women in gestational hypertension (11.0%) or in the reference (8.8%) groups (preeclampsia, adjusted OR = 3.8; 95% CI 3.3-4.5; gestational hypertension, adjusted OR = 1.2; 95% CI 1.1-1.4). Importantly, the rate of very early preterm delivery was 4.8% for preeclampsia, higher than that of the gestational hypertension (1.1%) and the reference (1.6%) groups (Table III). Among preeclamptic women, 74% of the preterm deliveries were medically indicated, compared with 39% in women with gestational hypertensions and 6.8% in the reference group (data not shown in table). The crude ORs for fetal death, preterm delivery, and very early preterm delivery were similar to the adjusted ORs for all groups (Table III).
Table III also presents crude and adjusted ORs for neonatal morbidity and mortality. In the crude analysis, preeclampsia increased the odds 6.0-fold for NICU stay 7 days or longer and 4.6-fold for neonatal death versus the reference group. Gestational hypertension also significantly increased the odds for these 2 outcomes, but in a smaller magnitude. Adjusting for birth weight (the most important variable), SES, treatment group of the original trial and geographical area, the increased odds for preeclampsia was smaller, OR = 1.5 (95% CI 1.2-2.0) for NICU stay 7 days or longer and disappears for neonatal death (OR = 0.9; 95% CI 0.5-1.8) (Table III). Similar adjustments, however, did not completely eliminate the significant increase in risk for NICU stay 7 days or longer (OR = 1.2; 95% CI 1.0-1.5) and the neonatal mortality risk even increased (OR 1.8; 95% CI 1.0-3.3), when associated with gestational hypertension (Table III).
Do preeclampsia and unexplained IUGR share similar risk factors?
Mothers with preeclampsia were more likely to have a history of diabetes, renal or cardiac disease, chronic hypertension, previous preeclampsia, BMI >30 kg/cm2, urinary tract infection and extremes of maternal age than those with IUGR. Conversely, “unexplained IUGR” was associated with higher rates of low birth weight in previous pregnancies. Primiparity and multiple pregnancies were risk factors shared by both conditions. SES was similar in the 3 groups (Table IV).
Table IVRisk factors for preeclampsia and unexplained IUGR compared with the reference group
We further explored the relationship between preeclampsia and “severe unexplained IUGR” (defined as birth weight <5th percentile for gestational age) in relation to the same risk factors as in Table IV. There were 1381 newborn infants in this subgroup, with lower mean birth weight (2402 g, SD 346), but similar mean gestational age (39.6 weeks, SD 1.9) than the overall group. Risk factors were similarly distributed as in Table IV with only wider confidence intervals. These results are not included here but are available on request and in the online version.
Do pregnancies complicated by preeclampsia or unexplained IUGR have similar perinatal outcomes?
As expected by group's definitions, the mean birth weight among IUGR newborn infants was lower (2556 g) than that of the preeclamptic group (2845 g). However, gestational age was lower in the preeclamptic group, 37.5 weeks than the IUGR group 39.4 weeks (Table II). Both unexplained IUGR (OR = 1.8; 95% CI 1.3-2.4) and preeclampsia (OR = 2.5; 95% CI 1.6-4.0) groups were associated with a higher crude and adjusted risk of fetal death than the reference group (Table V).
Table VPerinatal outcomes for preeclampsia and unexplained IUGR compared with the reference group
IUGR group had a lower rate of preterm delivery (5.8%) than the preeclampsia group (27.4%), and that of the reference group (8.8%) (OR = 3.8; 95% CI 3.2-4.4 for preeclampsia and OR = 0.7; 95% CI 0.6-0.8 for IUGR). The rate of very early preterm delivery (<32 weeks) was 4.8% among women with preeclampsia, much higher than those other 2 groups. Of preterm deliveries in the preeclampsia group, 74% were medically indicated; conversely, 59% of preterm in the IUGR group and 71% of those in the reference group followed the spontaneous onset of preterm labor (data not shown in the table).
Newborn infants from preeclamptic pregnancies were at a considerably higher risk of NICU stay 7 days or more, than those from pregnancies with IUGR after adjusting by study site and SES (Table V). These differences are present despite the lower mean birth weight of the IUGR group. Neonatal mortality was increased in both the preeclampsia and IUGR groups, although the preeclampsia group has considerable higher risk in both crude and adjusted analyses (Table V). As expected, outcomes were poorer for the “severe unexplained IUGR” group (birth weight <5th percentile) for fetal death, NICU stay 7 days or longer and neonatal mortality (data not shown, available on request and in the online version).
Finally, we compared the perinatal outcomes among infants with IUGR secondary to preeclampsia (N = 194), IUGR secondary to gestational hypertension (N = 355), and unexplained IUGR (N = 3224). Infants with IUGR secondary to preeclampsia had lower mean birth weight (2164 g) than IUGR secondary to gestational hypertension (2427 g) and the unexplained IUGR (2555 g). Mean gestational age was also lower for preeclamptic IUGR group (37.5 weeks), than the other 2 groups (38.6 weeks) and (39.4 weeks) for the gestational hypertension IUGR and unexplained IUGR, respectively. Reflecting these values, the incidence of preterm delivery among infants with IUGR secondary to preeclampsia was 28.9%, versus 13.5% among IUGR secondary to gestational hypertension and 5.8% among the unexplained IUGR (data not shown in the table).
We compared for these 3 IUGR subgroups the risk of NICU stay 7 days or longer and neonatal death (Table VI). Because of the differences in birth weight and gestational age described previously, we further adjusted by these 2 variables and presented crude and adjusted ORs in Table VI. IUGRs secondary to preeclampsia had the highest risk for both adverse outcomes after adjusting by study site and SES. These differences were eliminated, however, after adjusting by birth weight and gestational age, suggesting that the excess risks are explained by these mediating variables (Table VI).
Table VIPerinatal outcomes for IUGR infants secondary to preeclampsia, gestational hypertension, or unexplained IUGR
This study examined whether preeclampsia, gestational hypertension, and unexplained IUGR (the latter often assumed to be due to placental insufficiency), could be linked by comparing their risk factors and perinatal consequences in a large recently collected data base from 4 distinct ethnic populations. We found similarities between preeclampsia and gestational hypertension, but our results suggest that unexplained IUGR (eg, those not associated with smoking, undernutrition, secondary to hypertensive conditions, or congenital malformations) is a different entity from preeclampsia. Furthermore, we have confirmed that preeclampsia is a major risk for severe perinatal morbidity and mortality, but that gestational hypertension without proteinuria also independently increases perinatal risk.
Our data are based on a large, prospective study of all women who initiated antenatal care during a fixed period at clinics serving 4 specific geographic areas. Data were recorded as part of the WHO Antenatal Care Trial, data collection, standardized and monitored specifically for preeclampsia and eclampsia, which were part of the predetermined primary outcomes of the original trial. Ultrasound measures were used to corroborate uncertain gestational age. Clinical management of the primary outcomes followed local standard protocols.
Baseline factors of the original trial were well balanced by intervention groups. There was a marginal difference between the 2 antenatal care models in the incidence of preeclampsia that was not statistically significant. Nevertheless, adjustments were made by treatment arm of the original trial for the outcome analyses.
History of renal disease, diabetes, cardiac disease, and preeclampsia are risk factors for both preeclampsia and gestational hypertension suggesting that the 2 conditions are related to renal pathophysiologic changes and/or vascular anomalies. This underlying renal or vascular disease, as well as being overweight, can predispose for both conditions during future gestations.
However, there are some differences: preeclampsia, but not gestational hypertension, was independently associated with primiparity, as there were chronic respiratory diseases, in agreement with the reported
Furthermore, there is a suggestion that unlike preeclampsia, gestational hypertension may be associated with reproductive tract infection, hemorrhage during pregnancy, and history of reproductive tract surgery. We did not have detailed information of the timing and treatment provided and severity of these risk factors, which might be markers of some underlying gynecologic condition. For example, there is an association between uterine malformations and unilateral renal agenesis with gestational hypertension and preeclampsia.
Preeclampsia, as it is well known, increases the risk for severe perinatal outcomes, mostly by its effect on reducing birth weight. However, in agreement with other recent multicenter studies of nonproteinuric hypertensive pregnant women,
gestational hypertension on its own also increased the risk of fetal death, severe neonatal morbidity, and mortality. These results should remind clinicians about the need for a close surveillance of women with gestational hypertension and that even if early delivery is now associated with good outcomes, the increase cost of this strategy cannot be avoided. Unfortunately, detailed long-term consequences of either entity could not be evaluated by us; for example, markers of inflammatory response have been found to be elevated later in life in women who had preeclampsia develop.
Such markers could help to differentiate the 2 hypertensive conditions.
We have categorized IUGR after excluding congenital malformations and structural defects, as those related to undernutrition, to smoking, to be secondary to preeclampsia or gestational hypertension and finally, those unexplained IUGR considered as related to placental insufficiency. Placental insufficiency is recognized as the most common cause of fetal growth restriction among clinically healthy, nonsmoking women with adequate nutritional status.
However, we recognize that this classification has limitations. For example, misclassification of newborn infants could have occurred, when we excluded smoker mothers, as this pattern was based only on self-reporting habits or because the definition of nutritional status was based on BMI and severe anaemia only. Furthermore, the “unexplained IUGR group,” a broad category might have been differentiated further, if more detailed clinical and/or laboratory information (ie, biologic markers of placental insufficiency) had been sought in the original trial. Had such data been available, we could have excluded more women without evidence of placental compromise from the “unexplained IUGR” group, and excluding these newborn infants would have reduced the contribution of “constitutionally small” infants to the IUGR group. However, while no doubt there are such newborn infants within the “unexplained IUGR” cohort, we believe their proportion to be small. The reason for this view is that, the “unexplained IUGR group” (<10th percentile) has considerable higher morbidity and mortality than the reference group, that should not be the case if our IUGR group were diluted with many constitutionally small infants.
Other data support the validity of the “unexplained IUGR” group designation. Two recent publications have challenged the constitutionally small notion in IUGR less than 10th percentile. In 1 from Canada , the increase in the proportion of IUGR less than 10th percentile was associated with higher perinatal mortality, when comparing primiparous with multiparous
A parsimonious explanation for intersecting perinatal mortality curves: understanding the effect of plurality and of parity. The Fetal and Infant Health Study Group of the Canadian Perinatal Surveillance System.
Customized birth weight for gestational age standards: perinatal mortality patterns are consistent with separate standards for males and females but not for blacks and whites.
Finally, confining our own analysis to newborn infants less than 5th percentile (“severe unexplained IUGR”), a group, no doubt with less “constitutionally small” newborn infants, produced a distribution of risk factors almost identical to that in the overall “unexplained IUGR” group.
Finally, placental insufficiency could be a pathway, for other conditions affecting the vascular structure of the placenta or reducing blood flow to the fetus, including infections with cytomegalovirus or toxoplasma, which are not always clinically diagnosed during pregnancy.
We noted that diabetes, renal cardiac disease, and chronic hypertension are highly associated with preeclampsia, but are not independent risk factors for unexplained IUGR (Table IV). This may appear to contradict the literature, but merely reflects the exclusion of IUGR secondary to preeclampsia from the “unexplained” category and suggests that the previously noted medical disorders primarily affect fetal growth by increasing the risk for preeclampsia, and if IUGRs secondary to preeclampsia are removed, the association is no longer present. We did not have accurate information as to when the preeclampsia first presented, a factor that may be different according to the risk factors like diabetes (mostly associated with early-onset preeclampsia). As we have grouped all preeclampsia cases into 1 entity, it may be possible that some subgroups of preeclampsia are associated with unexplained IUGR, while others reflect a different pathophysiology.
Uterine artery Doppler flow and uteroplacental vascular pathology in normal pregnancies and pregnancies complicated by preeclampsia and small for gestational age fetuses.
Increased placental expression of tissue factor is associated with abnormal uterine and umbilical Doppler waveforms in severe preeclampsia with fetal growth restriction.
Interestingly, recent studies have explored a range of markers that could differentiate these 2 conditions. Levels of urinary placental growth (PIGF) factors were shown to be lower about 5 weeks before overt preeclampsia, but such reduction was not observed in women destined to have growth-restricted newborn infants.
A systematic review of all these evidence is much needed for a complete interpretation of this literature.
In summary, preeclampsia and gestational hypertension seem to be related conditions, both increasing the risk for morbidity and mortality; conversely, preeclampsia and unexplained IUGR appear to be independent entities. Further efforts to characterize them by using biochemical or genetic markers could contribute to their better understanding and, ultimately, their prevention.
Acknowledgment
We thank all women that participated in the study.
Appendix
The World Health Organization Antenatal Care Trial Research Group consists of the following additional members: Olav Meirik, Epidemiologist; Allan Donner, Consultant Epidemiologist-Statistician; Alain Pinol, Systems Analyst; Milena Vucurevic and Catherine Hazelden, Statistical Assistants; Ana Langer, Focal person, satisfaction studies; Gunilla Lindmark, Obstetrician/Gynaecologist; Miranda Mugford, Focal person, economical evaluation; Vivian Wong, Obstetrician/Gynaecologist; Julia Fox-Rushby, Health Economist; Gustavo Nigenda, Public Health Specialist; Mariana Romero, Public Health Epidemiologist; Georgina Rojas, Psychologist; and Chusri Kuchaisit, Public Health Nurse. Data Coordinators: Eduardo Bergel, Argentina; Elva Diaz, Cuba; Mohammed Gandeh, Saudi Arabia; and Yaowaret Singuakool, Thailand. Field Coordinators: Alicia del Pino, Argentina; Juan Vazquez, Cuba; Abdul-hameed Helal, Saudi Arabia; and Kamron Chaisiri, Thailand.
References
Villar J.
Say L.
Gülmezoglu M.
Merialdi M.
Lindheimer M.
Betran A.
et al.
Eclampsia and pre-eclampsia: a worldwide health problem for 2000 years.
in: Critchley H. Maclean A. Poston L. Walter J. RCOG Press,
London2003: 189-207
A parsimonious explanation for intersecting perinatal mortality curves: understanding the effect of plurality and of parity. The Fetal and Infant Health Study Group of the Canadian Perinatal Surveillance System.
Customized birth weight for gestational age standards: perinatal mortality patterns are consistent with separate standards for males and females but not for blacks and whites.
Uterine artery Doppler flow and uteroplacental vascular pathology in normal pregnancies and pregnancies complicated by preeclampsia and small for gestational age fetuses.
Increased placental expression of tissue factor is associated with abnormal uterine and umbilical Doppler waveforms in severe preeclampsia with fetal growth restriction.
Supported by the United Nations Development Programme/United Nations Population Fund/World Health Organization/World Bank Special Program of Research, Development and Research Training in Human Reproduction, Department of Reproductive Health and Research, World Health Organization, Geneva, Switzerland. Additional support was provided by the Municipal Government, City of Rosario, Argentina; Ministry of Health, Cuba; National Institute of Public Health, Mexico; The Population Council-Regional Office for Latin America and the Caribbean; Ministry of Health, Saudi Arabia; Swedish Agency for Research Cooperation with Developing Countries; Swedish International Development Agency; Ministry of Public Health and Faculty of Medicine, Khon Kaen University, Thailand; Department for International Development of the United Kingdom; Mother Care-John Snow Inc.; National Institute for Child Health and Human Development, National Institutes of Health, United States; and The World Bank.
The views expressed in this document are solely the responsibility of the authors and do not necessarily represent the views of the World Health Organization or its Member States.
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