Fetal growth restriction (FGR) is closely related to perinatal morbidity and mortality.1 Numerous risk factors for FGR have been established. Still, in many cases no underlying pathology can be identified. Previous studies have suggested that fetal leanness or asymmetry carries a high risk for perinatal complications,2–4 whereas FGR with normal body proportions would be more prone to long-term neurodevelopmental handicaps.5
Although it is well known that preeclampsia is associated with reduced fetal size, information on fetal proportion in preeclampsia is scarce. Early-onset preeclampsia (gestational age less than 37 weeks) is associated with placental vascular lesions or reduced uteroplacental blood supply6 leading to reduced birth weight,7,8 suggesting that preeclampsia and FGR in general might share pathophysiologic mechanisms. Shallow invasion by fetal trophoblasts in maternal spiral arteries in early pregnancy, which may cause occlusion of the vessels, has been observed both in preeclampsia and in FGR.9,10 Clinical studies have suggested that in early-onset preeclampsia, FGR often precedes the development of preeclampsia.7 However, recent findings of excess rates both of small (SGA) and large for gestational age (LGA) in preeclampsia11 and of normal birth weight in most cases of term preeclampsia11,12 challenge the hypothesis that placental dysfunction is essential in the development of preeclampsia.
The objective of the present population-based study was to evaluate the effects of early- and late-onset preeclampsia on fetal growth and body proportion.
MATERIALS AND METHODS
Since 1967, medical data on all births in Norway with gestational age at least 16 weeks have, by compulsory notification, been forwarded to the Medical Birth Registry of Norway.13 The population of pregnant women in Norway is relatively homogeneous. More than 99% of them receive standardized antenatal care (Backe B. Studies on antenatal care [doctoral thesis]. Trondheim, Norway: Tapir, 1994). At each antenatal visit, blood pressure (BP) is measured, and urine is examined for protein with a reagent strip. Medical data are collected in the pregnancy record brought by the women to the delivery unit, and selected items of data are transferred to the Registry notification form. Immediately after birth, birth weight is measured by the midwife to the nearest 10 g and crown–heel length to the nearest 1 cm. By the ninth day postpartum, the form is sent to the Registry. The form has been unchanged since the start of registration, except for the addition, in 1978, of Apgar scores.
The study was based on records of all births in Norway from 1967 through 1998 and comprised 1,869,388 births, more than one third of Norway's total population. This file has been linked to population census files containing socioeconomic data from the Central Bureau of Statistics and the National Education Register. We excluded women with a prior birth (n = 1,088,443), multiple births (n = 16,474), and those without data or invalid data on first day of the last menstrual period (n = 58,595) or newborn's crown–heel length (n = 19,156). The invalid data were detected by methods described previously.14,15 We also excluded women with chronic maternal disease (essential hypertension, connective tissue diseases, hyperthyroidism, hypothyroidism, chronic glomerulonephritis, renal failure, and diabetes mellitus) or gestational diabetes (n = 14,590), leaving 672,130 birth order one pregnancies for study. Variables used in the present study were pregnancy outcome, obstetric complications, and sociodemographic characteristics. Data on education were collected from census files and the education register. Gestational age was based on the first day of the last menstrual period.
Preeclampsia is usually notified to the Registry as a specific diagnosis. The notification form also contains information on separate symptoms of preeclampsia, such as hypertension, proteinuria, and edema. In Norway, the diagnosis is in accordance with the 1972 recommendations of the American College of Obstetricians and Gynecologists,16 which defined preeclampsia as increased BP after 20 weeks' gestation with proteinuria, edema, or both. According to clinical practice in Norway, pregnancies with edema but without proteinuria are not included in the definition.17 Hypertension is defined as persistent and consistent increased BP on at least two occasions or BP of 140/90 mm Hg or greater, or increase in diastolic BP of at least 15 mm Hg or systolic BP of at least 30 mm Hg from the woman's average levels before 20 weeks' gestation. Proteinuria is defined as excretion of 0.3 g or more per day, usually equivalent to at least 1+ on a urine reagent strip. In the present study, preeclampsia included all pregnancies with a notified diagnosis of preeclampsia or pregnancies recorded with hypertension and proteinuria in combination.
Severe preeclampsia is likely to result in a preterm birth. Therefore, we compared infants' size in preterm (less than 37 weeks' gestation) and term or postterm births (37 weeks or more) to mothers with and without preeclampsia.
Birth weight was adjusted for gestational age and gender, using birth weight ratios (ie, 100 × [the actual birth weight]/[the mean birth weight for that gestational age (completed weeks) and gender among the 672,130 births]). The two other main outcomes, crown–heel length and ponderal index (100 × g/cm3)18 were, in a similar way, adjusted for gestational age and gender. Births were categorized according to birth weight, crown–heel length, and ponderal index into four groups with cutoff points equivalent to the 2.5th, 10th, 90th, and 97.5th gestational age and gender-specific percentiles among the 672,130 births. Small for gestational age was divided into asymmetric and symmetric SGA, according to the definition of Walther and Ramaekers, who classified SGA as symmetric or asymmetric according to the ponderal index.3 Symmetric and asymmetric SGA infants below the 10th birth weight percentile were defined as those who had ponderal index at or above and below the 10th percentile, respectively. The cutoff point for asymmetric and symmetric SGA below the 2.5th birth weight percentile was at the 2.5th ponderal index percentile.
The association of preeclampsia with low birth weight-, short crown–heel length-, and low ponderal index percentiles were estimated by relative risks (RR) in terms of odds ratios (OR) obtained from logistic regression analyses (Statistical Package for the Social Sciences; SPSS Inc., Chicago, IL), in which we adjusted for education in years (fewer than 10, 10–12, more than 12, and unknown), maternal age in years (19 or less, 20–29, 30–34, and 35 or more), and year of birth (1967–76, 1977–86, and 1987–98). The effects of preeclampsia on mean birth weight, crown–heel length, and ponderal index were assessed by analysis of variance (SPSS), in which we adjusted for potential confounders.
In the study population of 672,130 pregnancies, 3585 (0.5%) cases of early preeclampsia and 21,889 (3.3%) cases of late (gestational age 37 weeks or more) preeclampsia occurred.
The proportion of women aged 35 years or more was 5.9% in women with early preeclampsia, compared with women with late preeclapsia (4.1%) and without preeclampsia (2.9%) (Table 1). Educational level was significantly associated with preeclamspia. However, the differences were small. There was a secular trend with more women being diagnosed with early and late preeclampsia in the late registry period.
Women with preeclampsia delivered on average significantly lighter, shorter, and leaner infants than those without preeclampsia; mean birth weight, crown–heel length, and ponderal index were 4.4% (Table 2), 0.8% (Table 3), and 2.6% (Table 4) lower than in births without preeclampsia, respectively. In preterm births (gestational age less than 37 weeks), mean differences in birth weight ratio ranged from −11% to −23% against near equal ratios in term and postterm births (Table 2). Likewise, mean differences in crown–heel length- and ponderal index ratios ranged from −1% to −5% and from −5% to −10% before term, against near equal ratios from 37 weeks' gestation (Tables 3 and 4).
Increased occurrences of weight-, crown–heel length-, and ponderal index percentiles below the 2.5th and 10th percentiles were found in preterm (Table 5) as well as term and postterm preeclampsia (Table 6). Both in preterm and late preeclampsia, excess risks were particularly observed for asymmetric rather than symmetric SGA. Newborns born to mothers with preterm preeclampsia were two to five times more likely than those who were delivered preterm without preeclampsia to be below the 2.5th or 10th birth weight-, crown–heel length-, and ponderal index percentiles (OR = 2.2–4.7) (Table 5). Newborns whose mothers had preterm preeclampsia were five and two times more likely to be asymmetric and symmetric SGA below the 2.5th birth weight percentile than newborns of mothers without preeclampsia (OR = 4.6 and 2.2, respectively) (Table 5). For asymmetric and symmetric SGA less than the 10th percentile, ORs were 5.5 and 3.2, respectively (Table 5). Infants born to mothers with preterm preeclampsia were less likely to be heavy, long, or to have high ponderal index for gestational age (ORs = 0.4–0.6) (Table 5).
In late preeclampsia (gestational age 37 weeks or more), newborns were two to three times more likely than newborns of mothers without preeclampsia to be below the 2.5th or 10th birth weight-, crown–heel length-, and ponderal index percentiles (OR = 1.6–3.4) (Table 6). Newborns whose mothers had preeclampsia were about five and two times more likely to be asymmetric and symmetric SGA below the 2.5th birth weight percentile than newborns of mothers without preeclampsia (OR = 4.8 and 2.3, respectively) (Table 6). For asymmetric and symmetric SGA less than the 10th percentile, ORs were 3.0 and 1.5, respectively (Table 6). In late preeclampsia, rates of birth weight and crown–heel length above the 90th and 97.5th percentiles and ponderal index above the 97.5th percentile were slightly but significantly higher than in term births without preeclampsia (ORs = 1.1–1.5) (Table 6).
In the present study, preterm preeclampsia was associated with lighter, shorter, and leaner newborns, whereas late preeclampsia had increased rates of both larger and smaller newborns.
A strength of this study is its large size. Furthermore, based on the total Norwegian birth population, the study was most likely not affected by selection bias. Some of the effect of preeclampsia on infants' size might be explained by shared risk factors for preeclampsia and small infants' size that were not adjusted for in the present analysis, such as thrombophilia, which have been associated with both conditions,19 but not consistently.20 However, most established risk factors, such as maternal short stature and overt renal disease, are weak or uncommon and would not influence the associations essentially. Owing to lack of data, we were not able to include in the study excessive weight gain and prepregnancy weight, which are both strong and common risk factors for preeclampsia and tend to increase fetal weight.21 However, it is likely that adjusting for maternal weight or weight gain would increase the effect of preterm preeclampsia on infants' size. Nor did our database include smoking status. It is well known that smoking is a strong and common risk factor for low birth weight. Smoking seems to be negatively associated with preeclampsia.22,23 Thus, adjusting for smoking would increase rather than decrease the effect of preeclampsia on infants' size. On the other hand, adjusting for obesity or smoking should reduce the association of late preeclampsia with large infant size in late pregnancy, but probably not to the extent that would significantly reverse the effect. Besides, although obesity becomes more prevalent in Norway, the Norwegian pregnancy population is still relatively lean.24
Although average birth weight of newborns to mothers with late preeclampsia approached those of mothers without preeclampsia (Table 2), the newborns were more likely to be SGA (Table 6). However, newborns whose mothers had preterm preeclampsia were both on average smaller (Table 2) and more likely than expected to be SGA (Table 6). Our results agree with earlier studies reporting that neonates to mothers with preeclampsia, particularly preterm, are smaller7,11,12,25–27 and support the prevailing hypothesis that placental hypoperfusion caused by shallow invasion of fetal trophoblasts in early pregnancy may cause preeclampsia or FGR, or both.9,10 Morphologic studies have reported that in pregnancies with asymmetric FGR, placental infarcts and other signs of reduced placental perfusion are common.28 Thus, our finding that newborns to mothers with early preeclampsia were significantly shorter and leaner, further suggests the “ischemic” hypothesis involving reduced perfusion of the fetoplacental unit.
Consistent with the present study, recent evidence indicates that in most cases of late preeclampsia, the newborn has normal weight,12 and more infants than expected are LGA.11 Moreover, in the present study, the subsets of newborns that were long or had high ponderal index were more common in preeclamptic than in non-preeclamptic term and postterm deliveries. Thus, our results do not support the widely accepted hypothesis that placental dysfunction is necessary in the development of preeclampsia. It is generally believed that preeclampsia is caused by products released by the ischemic placenta, causing endothelial activation, which results in hypertension and proteinuria.29 Decreased perfusion of the fetoplacental unit would decrease fetal size, even before the appearance of the defining criteria of preeclampsia (hypertension and proteinuria).7 Our finding of excess of large newborns in late preeclampsia rather suggests that placental dysfunction is absent or plays a minor role in a subset of preeclamptic pregnancies.
Our finding of excess of large newborns in late preeclampsia could be explained by the earlier demonstrated increased cardiac output in late-onset preeclamptic pregnancies.30 Consistently with that finding, Gant et al31 reported increased uteroplacental perfusion, as indicated by increased placental clearance of dehydroisoandrosterone sulfate, in term preeclampsia compared with pregnancies without preeclampsia, whereas in severe preeclampsia clearance was lower.
The present study supports the hypothesis that preeclampsia is an etiologically heterogeneous disorder32 that occurs in at least two separate subsets,11 one with normal or enhanced placental function and another involving placental dysfunction. In the subset with placental dysfunction and FGR, newborns often have asymmetric fetal body proportion, reduced fetal length, or are delivered preterm, which is consistent with the prevailing “hypoperfusion” model. Our results indicate that most cases of preeclampsia do not follow this model. It is unlikely that a single treatment or preventive measure will be effective. In future studies, it may be important to study the two subtypes separately to examine whether the subsets differ in severity or have different risk determinants.
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© 2003 The American College of Obstetricians and Gynecologists
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