Published online before print February 7, 2008, doi: 10.1161/HYPERTENSIONAHA.107.096248
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(Hypertension. 2008;51:1231.)
© 2008 American Heart Association, Inc.
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History of Fetal Growth Restriction Is More Strongly Associated With Severe Rather Than Milder Pregnancy-Induced Hypertension
From the Medical Birth Registry of Norway (S.R., L.M.I.), Locus of Registry Based Epidemiology, Institute of Community Medicine and Primary Health Care, University of Bergen and Norwegian Institute of Public Health, Bergen, Norway; Institute of Clinical Medicine (S.R.), University of Bergen, Bergen, Norway; and the Department of Obstetrics and Gynecology (S.R.), Haukeland University Hospital, Bergen, Norway.
Correspondence to Svein Rasmussen, Kvinneklinikken, N-5021 Bergen, Norway. E-mail Svein.Rasmussen{at}mfr.uib.no
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Abstract |
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We assessed whether fetal growth restriction without pregnancy-induced hypertension (PIH) is associated with the different clinical subgroups of PIH in the subsequent pregnancy. We also assessed the maternal and paternal contributions to this effect. Pairs of first and second, second and third, third and fourth, and fourth and fifth births were identified among all of the births in Norway: 137 375 pairs with same mother and father, 18 376 pairs with same mother and different fathers, and 18 916 pairs with same father and different mothers. Second births in each pair were restricted to those that occurred in 1998–2005. Odds ratios to predict early onset, severe, and mild preeclampsia and transient hypertension in the second birth from birth weight <1500 g in the first compared with 3500 to 3999 g were 13.8, 7.1, 3.5, and 2.2, respectively. Odds ratios to predict early onset, severe, and mild preeclampsia and transient hypertension from birth weight below the 2.5th percentile compared with percentiles 10.0 to 89.9 were 4.2, 2.5, 2.1, and 1.7, respectively. Men who fathered a child with low birth weight in 1 woman were not more likely to later father a PIH pregnancy in another woman. The results indicate that placental dysfunction and PIH share a genetic factor that can be expressed as fetal growth restriction in 1 pregnancy and PIH in a subsequent pregnancy. Future genetic study is needed to confirm whether the association is caused by delayed genetic expression of endothelial dysfunction and whether the clinical subgroups of PIH have different genetic backgrounds.
Key Words: hypertension • pregnancy • preeclampsia • birth weight • small for gestational age • fetal growth restriction
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Introduction |
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There is evidence to suggest that at least some cases of pregnancy-induced hypertension (PIH; preeclampsia and transient hypertension) differ from fetal growth restriction only in the maternal response to a shared placental pathology.1,2 It has been proposed that decidual (placental bed) occlusive vasculopathy, involving shallow invasion of fetal trophoblasts in the decidual spiral arteries,3,4 tends to recur from one pregnancy to another in the same woman.5 Furthermore, clinical studies have reported that fetal growth restriction often antedates the diagnostic findings of preeclampsia.6 Consistently, we have reported that women with small for gestational age (SGA) births in the first pregnancy have an increased risk of preeclampsia in the next.7 Although many cases of PIH in parous women are recurrent, our study also showed that a significant number of preeclamptic pregnancies also occur for the first time in parous women.7
Recently, we reported that the risk of SGA in a pregnancy with PIH increased with the severity of PIH,8 which indicates a more important role of placental dysfunction in severe preeclampsia than in the milder subgroups of PIH. Thus, one might expect that the earlier reported association of SGA in a previous pregnancy with PIH in the subsequent pregnancy7 is particularly present in severe PIH and early onset preeclampsia, indicating severe disease.9 Such a differential association with earlier SGA would provide additional evidence for the relative importance of placental dysfunction in the development of different subgroups of PIH. Such knowledge would also be of value in clinical risk assessment in a subsequent pregnancy. We are not aware of studies on the association of earlier fetal growth restriction with the different subgroups of PIH in the current pregnancy. Neither has the paternal effect on such an association been assessed. It has earlier been reported that a man who had fathered a preeclamptic pregnancy in 1 woman had an increased risk of fathering a preeclamptic pregnancy in another woman,10 which suggests paternal genetic factors in preeclampsia. One might, thus, expect that a man who has fathered a pregnancy with fetal growth restriction in 1 woman is more likely to father a PIH pregnancy in another woman. On the other hand, we recently reported a lack of association between father’s size at birth and PIH in his partner, although mothers’ own birth weight was associated with later risk of PIH.11
The purpose of the present study was to evaluate the associations of SGA without PIH in a previous pregnancy with the different subgroups of PIH in the subsequent pregnancy and to assess the maternal and paternal contributions to this effect.
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Methods |
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Since 1967, all of the births in Norway are notified to the Medical Birth Registry of Norway based on compulsory notification.12 More than 99% of pregnant women receive standardized antenatal care.13 The registry is composed of medical data on all of the live births and abortions at
16 weeks’ gestation, including abortions induced on medical indications. Data are transferred by the midwives to the notification form from the pregnancy record, which the women bring to the delivery unit. Within the ninth day postpartum, the notification form is completed and sent to the Medical Birth Registry. In December 1998, a revised version of the notification form was implemented to include new items like data on maternal smoking habits and subgroups of PIH, which are notified by the checking of boxes.12
Record Linkage
From 1967 through June 2005, 2 236 250 births were registered. Father’s identification was unknown for 168 217 births (7.5%). We used the parents’ national identification number to identify 972 914 pairs of first and second, second and third, third and fourth, and fourth and fifth births, composed of 911 135 pairs with the same mothers and fathers and 61 779 with same mothers and different fathers (Figure). Similarly, 73 062 pairs of births with the same fathers and different mothers were identified. We restricted the second birth in each pair of births to those that occurred from December 1998, when the revised notification form was introduced: 150 354 pairs with same mother and father, 20 232 pairs with same mother and different fathers, and 23 115 pairs with same father and different mothers. In pairs with the same father and different mothers, the first birth included only mothers’ birth order 1, whereas the second had birth order 1+. We excluded sibships with multiple births, pairs of births with PIH in the first birth, and women with their first births before 1967, leaving for analysis 137 375 pairs with same mother and father, 18 376 pairs with the same mother and different fathers, and 18 916 pairs with the same father and different mothers (Figure and Table 1).
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Definition and Subgroups of PIH
Clinical criteria of PIH in Norway have been in accordance with the recommendations by the American College of Obstetricians and Gynecologists in 1972,14 which are also referred to in the Medical Birth Registry’s instructions for completion of the notification form. Transient hypertension implies PIH without proteinuria and with blood pressure (BP) 140/90 mm Hg (1 or both values exceeded) or rise in systolic BP 30 mm Hg or diastolic BP 15 mm Hg after 20 weeks of gestation. Mild preeclampsia implies systolic BP 140 to 159 mm Hg, diastolic BP 90 to 109 mm Hg, rise in systolic BP 30 mm Hg or diastolic BP 15 mm Hg, and proteinuria 1+. Proteinuria is defined as excretion of 0.3 g per day, usually equivalent to 1+ on a urine reagent strip. Severe preeclampsia implies BP 160/110 mm Hg and/or proteinuria 2+. We defined early onset preeclampsia as presentation of hypertension and proteinuria before 34 weeks of gestation.
Statistical Analysis
To measure the association between birth weight in the first pregnancy and PIH in the second, odds ratios (ORs) obtained by logistic regression were used, in which we adjusted for maternal age in years (
19, 20 to 29, 30 to 34, and 35), smoking (Table 2), and birth order (Table 3). To increase sample size in multivariate analyses involving several maternal characteristics, we included pairs of second and third, third and fourth, and fourth and fifth pregnancies in addition to pairs of first and second pregnancies (Table 4
). Thus, the risk of PIH was assessed 4 times in a single woman. The data were organized in a 2-level hierarchy with clusters of level-1 data (the current pregnancy of birth orders 2, 3, 4, and 5) nested within each level 2 unit (the woman). To avoid biased risk estimates, the nested structure of the data necessitated multilevel logistic regression analysis. The effect of low birth weight on PIH may be caused by fetal growth restriction, preterm delivery, or both, because fetal growth restriction, as well as preterm delivery, may in some cases share a placental dysfunction-related cause.15 Therefore, we included birth weight percentiles in the multivariate model. In the multilevel models, ORs for the association of PIH with birth weight percentiles in the immediate previous birth were computed. The ORs were adjusted for change of partner, chronic kidney disease, smoking, maternal age (19, 20 to 29, 30 to 34, and 35 years), diabetes types 1 and 2, gestational diabetes, chronic hypertension, and interbirth interval (<1 year, increments of 1 year, and 10+ years). To assess whether an effect of fetal growth restriction on subsequent PIH increased with time from the previous birth, we added an interaction term between SGA (birth weight percentile <10) and interbirth interval in a logistic regression model.
To calculate birth weight percentiles, birth weight was regressed against gestational age in fractional polynomial regression models.16 Separate multilevel regression analyses were performed for each of the 4 combinations of gender and birth order (1 and 2+). Gestational age was estimated by subtracting the date of the first day in the last menstrual period from the date of birth. Outliers in gestational age were removed using a linear regression approach in which gestational age was regressed against birth weight in the strata of whole weeks of gestation. To achieve normal distribution, birth weight was power transformed. From SD scores we calculated the birth weight percentiles (2.5, 5.0, 10.0, 25.0, 75.0, 90.0, 95.0, and 97.5), which are widely used cutoff points in obstetrics. The statistical analysis was carried out with SPSS (SPSS Inc) and the MlWin program (MlWin, Centre for Multilevel Modeling, University of Bristol). We confirm that research ethics committees in Norway regularly exempt research on anonymized registry data from ethical review.
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Results |
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The occurrence of all subtypes of PIH in the second pregnancy increased with decreasing birth weight in the first (Table 2). This trend was particularly evident in severe and early onset preeclampsia and less in the milder subtypes. Thus, severe and early onset preeclampsia were 7 and 14 times more likely to occur in women who delivered a newborn with weight <2000 g than 3500 to 3999 g (ORs: 7.0 to 7.1 and 13.8 to 14.2, respectively). Transient hypertension and mild preeclampsia were
2 and 4 times more likely to occur (ORs: 2.0 to 2.4 and 3.6, respectively). The trend of increased risk of PIH with decreasing previous birth weight persisted after the change of paternity from the first to the second pregnancy (Table 3; P<0.001). However, men who fathered a child with low birth weight in 1 woman were not more likely to later father a PIH pregnancy in another woman (P=0.5; Table 3).
The occurrence of all subtypes of PIH in the current pregnancy increased with decreasing birth weight percentiles in the immediately previous pregnancy. After adjusting for several maternal characteristics (Table 4), the association between PIH and earlier low birth weight percentile persisted, and the effects of adjusting were small. The trend was more evident in severe- and early onset preeclampsia than in transient hypertension and mild preeclampsia. For birth weight below the 2.5th percentile in the immediate previous delivery, adjusted ORs for severe- and early onset preeclampsia were 2.5 and 4.2, respectively, whereas ORs for transient hypertension and mild preeclampsia were 1.7 and 2.1, respectively.
To assess whether the effect of fetal growth restriction on subsequent PIH increased with time from the immediately previous birth, we added an interaction term between SGA (birth weight percentile <10) and interbirth interval in a logistic regression, adjusting for maternal age (data not shown). The interaction was significant, implying that the association between fetal growth restriction and subsequent PIH increased with the interbirth interval.
Limiting the multivariate analyses to pairs of births with the first birth at term (37 weeks of gestation) did not significantly change the effects; the adjusted effects of preterm and term SGA births on PIH in general in the subsequent pregnancy were similar (data not shown). Thus, the adjusted OR of PIH in general subsequent to birth weight below the 2.5th percentile was 1.8 (95% CI: 1.3 to 2.5) and 1.7 (95% CI: 1.4 to 2.1) for preterm and term birth, respectively.
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Discussion |
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Women with an SGA birth had a markedly increased risk of PIH in the subsequent pregnancy. Particularly, their risk of severe and early onset preeclampsia was increased. However, men who fathered an SGA birth in 1 woman were not more likely to father a PIH pregnancy in another woman.
Strengths and Weaknesses: Possible Sources of Confounding
Major strengths of the present study were its large size, the population-based design, and the prospective collection of data, thereby reducing recall and selection bias. Shared risk factors for fetal growth restriction and PIH, such as hereditary thrombophilia and maternal short stature, which have been associated with both conditions,17–19 but not consistently,20 might explain some of the effect of SGA on later PIH. However, these risk factors are uncommon or weakly associated with either SGA or PIH and would, therefore, not cause the association of SGA with later PIH. Neither would the association be caused by low socioeconomic level, because it has been reported to be only weakly associated or unassociated with PIH.21 The lack of data precluded inclusion in the study of excessive weight gain and prepregnancy weight, which are both strong and common risk factors for PIH but tend to increase fetal weight. Thus, adjusting for weight gain and prepregnancy weight would increase rather than decrease the effect of SGA on PIH. In addition, although obesity has become more prevalent in Norway, the pregnancy population is still relatively lean.22 Our database holds data on maternal smoking, which seems to be negatively associated with PIH,23 although a risk factor for fetal growth restriction. As expected, adjustment for smoking increased rather than decreased the association of SGA with later PIH (data not shown).
Comparison With Other Studies
Our results agree with our earlier finding that low birth weight and SGA were associated with preeclampsia in subsequent pregnancies.7 However, in that study, lack of data did not allow for subdivision of PIH according to severity. Our results were also consistent with the earlier reported considerable recurrence rates of preeclampsia,7,9,10 fetal growth restriction,24 and SGA.25
Do Fetal Growth Restriction and PIH Share a Genetic Background?
Subsequent to an SGA birth, all of the subtypes of PIH occurred more often. This is consistent with a hypothesis that fetal growth restriction and PIH share a pathophysiologic mechanism that may cause fetal growth restriction in one pregnancy and PIH in a subsequent one. Consistent with this, fetal growth restriction and PIH are thought to initiate with improper remodeling of the uterine spiral arteries, caused by inadequate trophoblast invasion in early pregnancy, leading to reduced placental and fetal perfusion and subsequent dysfunction of the maternal vascular endothelium.1 This suggests that at least some cases of PIH differ from fetal growth restriction only in the maternal response to a shared pathology.1,2
However, neither all of the pregnancies with fetal growth restriction nor all of the pregnancies with a history of fetal growth restriction develop PIH. Roberts and Gammill1 proposed that the maternal response to reduced placental perfusion, leading to PIH in the same pregnancy, requires an interaction between reduced placental perfusion and maternal factors, such as genetic susceptibility for PIH. This is consistent with the association in the present study of SGA without PIH with later PIH, which may be caused by recurrent placental dysfunction and subsequent delayed expression of genetic or environmental susceptibility for endothelial dysfunction. Numerous genes, such as the set of genes that expresses thrombophilia, have been reported for susceptibility to both fetal growth restriction and PIH.19,26 Other genes that may be more specific for endothelial dysfunction, such as the endothelin-1 gene,25 would be candidate genes for expression of the maternal response to placental dysfunction. One may speculate that expression of genetic susceptibility for endothelial dysfunction and, subsequently, PIH, may be trigged by well-known risk factors for both preeclampsia and cardiovascular disease, such as diabetes mellitus, chronic hypertension, hyperhomocysteinemia, and high maternal age.
The present study confirms previous studies that interpregnancy interval and maternal age are independently associated with PIH.7,27,28 Moreover, we found a significant interaction between interpregnancy interval and newborn’s size in their associations with PIH. This indicates that the effect of earlier fetal growth restriction without PIH on PIH in the next pregnancy increased with interbirth spacing or, more specifically, that expression of genetic susceptibility for PIH tends to increase with time from delivery of a growth-restricted fetus.
The trend of increasing risk of PIH with decreasing fetal size was more evident in severe- and early onset preeclampsia than in transient hypertension and mild preeclampsia. For birth weight less than the 2.5th percentile in the immediate previous birth, severe- and early onset preeclampsia were 3 to 4 times more likely to occur (ORs: 2.5 and 4.2, respectively), whereas transient hypertension and mild preeclampsia were about twice as likely (ORs: 1.7 and 2.1, respectively). This is consistent with recent reports that the risk of SGA in a pregnancy with PIH increased with the severity of PIH8 and that early diagnosis of preeclampsia, which indicates severe disease, tripled the recurrence risk.9 This also agrees with our earlier results that preterm preeclampsia was associated with lighter, shorter, and leaner newborns, whereas late preeclampsia had increased rates of both larger and smaller newborns.29 Thus, our results provide additional evidence for the differential importance of placental dysfunction in the development of different subgroups of PIH and that PIH is an etiologically heterogeneous disorder with various degrees of placental and endothelial dysfunction.29
Paternal Influence
Although the maternal effect of small birth size with later PIH was considerable (Tables 2 and 3), a corresponding paternal effect was lacking. The lacking paternal effect was unexpected, because it has been shown that men who had fathered a preeclamptic pregnancy in 1 woman had an increased risk of fathering a preeclamptic pregnancy in another woman.10 However, although statistically significant, this increased paternal recurrence risk of preeclampsia was small, and one might expect an even lower paternal effect of birth size on later preeclampsia. In a pregnancy to a woman with earlier growth restriction, maternal susceptibility genes for PIH may operate in addition to susceptibility genes for PIH from either fetus’s parent, which operate through the fetus or the placenta. However, a father’s susceptibility gene for PIH would only be passed through the fetus or the placenta and will not be expressed as PIH. The lacking paternal effect is also consistent with the recently reported lacking association between father’s size at birth and PIH in his partner, although mothers’ own birth weight was associated with later risk of PIH.11 This is also consistent with the lower paternal versus maternal intergenerational recurrence rates of preeclampsia,30 low birth weight,31 and the increased subsequent cardiovascular mortality in mothers with preeclampsia and not in their partners.32
Perspectives
The results indicate that placental dysfunction and PIH share a pathophysiologic mechanism or genetic factor that can be expressed as fetal growth restriction in one pregnancy and PIH in a subsequent pregnancy in the same woman. The association of low birth weight and SGA with later PIH was particularly evident with severe- and early onset preeclampsia compared with milder PIH. Thus, our results provide additional evidence that PIH is an etiologically heterogeneous disorder with various degrees of placental and endothelial dysfunction. Furthermore, the results of our study indicate that expression of genetic susceptibility for PIH tends to increase with time from delivery of a growth-restricted fetus. Future genetic study is needed to confirm whether the markedly increased risk of PIH in a pregnancy subsequent to a pregnancy with fetal growth restriction is caused by delayed genetic expression of endothelial dysfunction. Future study is also needed to confirm whether different genetic backgrounds of the clinical subgroups of PIH cause the more pronounced effect of SGA on later early onset and severe preeclampsia than milder PIH.
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Acknowledgments |
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Disclosures
None.
Received June 12, 2007; first decision July 12, 2007; accepted November 26, 2007.
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[Abstract/Free Full Text]
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