maternal obesity and excess of fetal growth in pre-eclampsia

Maternal obesity and excess of fetal growth inpre-eclampsiaS Rasmussen,a,b LM Irgens,c J Espinozad

a Department of Clinical Science, University of Bergen, Bergen, Norway b Department of Obstetrics and Gynaecology, Haukeland University

Hospital, Bergen, Norway c Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway d Department of

Obstetrics and Gynecology, Baylor College of Medicine and Texas Children’s Hospital Pavilion for Women, Houston, TX, USA

Correspondence: S Rasmussen, Department of Obstetrics and Gynaecology, Haukeland University Hospital, N-5021 Bergen, Norway.

Email [email protected]

Accepted 12 November 2013. Published Online 3 March 2014.

Objective To assess whether the reported excess of large for

gestational age (LGA) neonates in pre-eclamptic women delivering

at term is attributable to maternal obesity.

Design, setting and population Population-based observational

study including 77 294 singleton pregnancies registered in the

Medical Birth Registry of Norway between 2007 and 2010.

Methods Comparison of birthweight percentiles and z-scores

between women with and without pre-eclampsia.

Main outcome measures Odds ratio (OR) of LGA and z-scores of

birthweight in relation to pre-eclampsia.

Results Pre-eclamptic women delivering at term had increased risk

of having LGA neonates. Unadjusted ORs with 95% confidence

interval (95% CI) of LGA above the 90th and 95th birthweight

centiles were 1.4, 95% CI 1.2–1.6 and 1.6, 95% CI 1.3–1.9,respectively. The excess of LGA persisted after including gestational

diabetes and diabetes types 1 and 2 in a multivariate analysis

(corresponding ORs 1.3, 95% CI 1.1–1.5 and 1.4, 95% CI 1.2–1.7),but disappeared after adjusting for maternal prepregnant body

mass index (ORs 1.1, 95% CI 0.9–1.2 and 1.1, 95% CI 0.9–1.3).

Conclusions This study suggests accelerated fetal growth in a subset

of pre-eclamptic women delivering at term. The excess of LGA

neonates is attributable to maternal obesity among pre-eclamptic

women delivering at term. The maternal obesity epidemic may lead

to an increased prevalence of both pre-eclampsia and LGA neonates

among women delivering at term.

Keywords Birthweight, body mass index, large for gestational age,

pre-eclampsia.

Please cite this paper as: Rasmussen S, Irgens LM, Espinoza J. Maternal obesity and excess of fetal growth in pre-eclampsia. BJOG 2014; DOI 10.1111/

1471-0528.12677.

Introduction

Impaired placentation seems to play an important role in the

pathogenesis of pre-eclampsia.1 Accumulating evidence

indicates that products released by the ischaemic placenta

including anti-angiogenic factors, may lead to endothelial

dysfunction resulting in the clinical manifestation of

pre-eclampsia.2–4 In addition, it has been proposed that due

to the limited perfusion of the placenta the fetuses are often

growth restricted.5–8 Moreover, fetal growth restriction may

predate the diagnostic findings of pre-eclampsia in the same

pregnancy, as demonstrated by longitudinal studies indicating

that fetal growth restriction with limited placental perfusion is

associated with a three-fold increased risk of pre-eclampsia.9

Large population based studies10–12 have also reported

excess of large-for-gestational-age (LGA) fetuses in

pre-eclampsia and have challenged the hypothesis that pla-

cental dysfunction is the only subjacent mechanism of dis-

ease in pre-eclampsia. These observations have even raised

the question whether pre-eclampsia has more than one

aetiological entity.13,14 Recently, is has been proposed that

a relative uteroplacental ischaemia due to a mismatch

between limited uteroplacental blood flow and increased

fetal demand for nutrients,15,16 may be involved in the

pathogenesis of late-onset pre-eclampsia.17,18 It is possible

that the increasing prevalence of maternal obesity may lead

to excessive fetal size and increased prevalence of

pre-eclampsia in pregnant women at term.

The aim of this population-based study was to assess

whether the reported excess of LGA in late onset

pre-eclampsia is attributable to obesity.

Methods

During 2007–10 a total of 248 056 births were notified to

the Medical Birth Registry of Norway. During this study

1ª 2014 Royal College of Obstetricians and Gynaecologists

DOI: 10.1111/1471-0528.12677

www.bjog.org

period there were 77 294 singleton births with gestational

age 22–44 weeks and data on maternal body mass index

(BMI), which were included (they represent 33% of

all singleton births with gestational age 22–44 weeks,

n = 235 572). Established in 1967, the Medical Birth Regis-

try of Norway is based on compulsory notification of all

liveborn neonates and stillbirths after 16 weeks of gestation,

in 1999 extended to 12 weeks of gestation. Medical data

are collected in a pregnancy record, which is kept by each

woman and brought to the delivery unit at the time of

delivery. Selected items of data are transferred by the mid-

wives to the Medical Birth Registry notification form by

simply checking boxes.19 Transition to on-line electronic

recording, representing an extract of the clinical record,

began in 2006 and is now implemented in most delivery

units in Norway.

The dependent variable was infant size in terms of gen-

der-specific, birth order-specific (1 and 2+) and gestational

age-specific birthweight empirical centiles (<5th, <10th,>90th, and >95th centiles) based on all 679 009 singleton

births with gestational age 22–44 weeks notified to the

Medical Birth Registry in 1999 to 2010. Additionally, gen-

der-, birth order- and gestational age-specific z-scores of

birthweight were calculated by polynomial multilevel regres-

sion because some women were included in the database

more than once from different pregnancies. Gestational age

was based on ultrasound scanning between 17 and 19 weeks

of gestation. In pregnancies lacking such data (3%) gesta-

tional age was based on the last menstrual period.

Independent variables comprised maternal age (<20, 20–24, 25–29, 30–34, 35–39 and >39 years), marital status

(married/cohabiting, other), smoking at the beginning of

pregnancy (not, occasionally, daily, smoking pattern not

specified), chronic maternal disease (asthma, chronic

hypertension, chronic renal disease, rheumatoid arthritis,

maternal heart disease, thyroid disease and diabetes mell-

itus types 1 and 2), pregnancy complications (pre-

eclampsia, placental abruption, gestational diabetes), and

maternal prepregnant BMI, categorised according to the

definitions of the World Health Organization into

<18.5 kg/m2 (underweight), 18.5–24.9 (normal), 25.0–29.9(overweight) and ≥30.0 or more (obese).20 From 2007

onwards data on maternal BMI were registered in 33% of

all births notified to Birth Registry in Norway. To assess

any bias in relative risk estimates of exposure–outcome

associations we performed separate analyses in the sub-

groups with and without BMI.

In Norway, the diagnosis of pre-eclampsia is in accor-

dance with the recommendations of the American College

of Obstetricians and Gynecologists,21 which defined

pre-eclampsia as the presence of systolic blood pressure of

≥140 mmHg or a diastolic pressure of ≥90 mmHg on at

least two occasions 6 hours apart after 20 weeks of gesta-

tion with proteinuria defined as excretion of ≥0.3 g/day,

equivalent to at least 1+ on a urine reagent strip.

Severe pre-eclampsia is likely to result in a preterm birth.

Therefore, we compared infants’ size in the following groups:

≥37 weeks of gestation, late preterm (34–366/7 weeks) and

early preterm (<34 weeks) births in mothers with and

without pre-eclampsia. Associations between the infant size

and pre-eclampsia were assessed by logistic multilevel regres-

sion analysis while adjusting for possible confounders

(maternal age, marital status, chronic maternal disease,

pregnancy complications, smoking habits and maternal

BMI). As the birthweight centiles were birth-order-specific,

we did not adjust for birth order. Possible co-linearity

between type 2 diabetes or gestational diabetes and maternal

BMI was assessed using a variance inflation factor in linear

regressions with z-scores of birthweight as the outcome

variable and BMI and type 2 diabetes or gestational diabetes

as independent variables. Differences between groups in

maternal characters and z-scores of birthweight were

assessed by exact two-sided Pearson chi-square test and

analysis of variance, respectively.

The statistical analysis was carried out with SPSS version

18.0.3 (Statistical Package for the Social Sciences; SPSS Inc,

Chicago, IL, USA) and the MLWIN programme version

2.27 (MLwiN, Centre for Multilevel Modelling, University

of Bristol, Bristol, UK).

Results

In the study population of 77 294 pregnancies, there were

2057 (2.7%) cases of term pre-eclampsia (gestational age

≥37 weeks), 350 (0.5%) cases of late preterm pre-eclampsia

(34–36 weeks) and 216 (0.3%) cases of early preterm

pre-eclampsia (<34 weeks).

Women with pre-eclampsia tended to be older, heavier,

nulliparous and have a higher frequency of gestational

diabetes and chronic disease, including diabetes mellitus

type 1 or 2, than those without pre-eclampsia. Also,

there were fewer smokers among women with pre-

eclampsia (Table 1). These differences were more marked

in early preterm pre-eclampsia (Table 1). There was no

significant difference in marital status.

Women with preterm pre-eclampsia (<37 weeks of ges-

tation) were less likely to have heavy newborns (birth-

weight above the 90th or 95th centile), particularly those

with early preterm pre-eclampsia (<34 weeks) (Table 2).

In contrast, among women with term pre-eclampsia rates

of birthweight above the 90th and 95th weight centiles

were significantly higher than in term births without

pre-eclampsia (Table 2). Unadjusted odds ratios (ORs) of

LGA above the 90th and 95th birthweight centiles were

1.4, 95% confidence interval (95% CI) 1.2–1.6 and 1.6,

95% CI 1.3–1.9. However, after adjusting for maternal

2 ª 2014 Royal College of Obstetricians and Gynaecologists

Rasmussen et al.

BMI, the excess of birthweight above the 90th and 95th

centiles in women with term pre-eclampsia disappeared

(OR 1.1, 95% CI 0.9–1.2 and 1.1, 95% CI 0.9–1.3), whilethe excess risk persisted after adjusting for pregestational

and gestational diabetes without including BMI in the

model (ORs for LGA above the 90th and 95th birthweight

centiles 1.3, 95% CI 1.1–1.5 and 1.4, 95% CI 1.2–1.7).To control for the effect of gestational age, z-scores were

calculated for women with and without pre-eclampsia in

singleton births with gestational age 22–44 weeks. To

increase the sample size in this analysis, 679 009 singleton

births in 1999 to 2010 were included. A comparison

between these two groups demonstrated a significant

(P < 0.001) displacement to the left of the birthweight dis-

tribution in pre-eclampsia (Figure 1). The displacement was

more significant in preterm pre-eclampsia (Figure 1B,C). In

contrast, the birthweight distribution in term pre-eclampsia

was still to the left of non-pre-eclamptic women, but it was

broader because of an excess occurrence of both small for

gestational age (SGA) and LGA neonates (Figure 1A).

Figure 2 shows the birthweight distribution in BMI

groups with term births. In women with pre-eclampsia

with normal BMI (18.5–24.9 kg/m2) no excess occurrence

of large newborns was observed.

We assessed any evidence of selection bias in the sub-

group with BMI data by performing separate analyses cor-

responding to Table 2 in the women with and without

BMI data. Adjusted ORs of the 5th, 10th, 90th and 95th

Table 1. Distribution of maternal characteristics in early and late pre-eclampsia and non-pre-eclamptic pregnancies

Pre-eclampsia No pre-eclampsia

<34 weeks

(n = 216)

34–36 weeks

(n = 350)

37 + weeks

(n = 2057)

(n = 74 671)

n (%) n (%) n (%) n (%)

Maternal age (years)

<20 7 (3) 12 (3) 65 (3) 1845 (2)

20–24 30 (14) 64 (18) 382 (19) 11 610 (16)

25–29 61 (28) 105 (30) 681 (33) 23 912 (32)

30–34 69 (32) 103 (29) 591 (29) 23 763 (32)

35–39 43 (20) 53 (15) 281 (14) 11 536 (15)

>39 6 (3) 13 (4) 57 (3) 2003 (3)

Birth order

1 114 (53) 202 (58) 1252 (61) 32 366 (43)

2 64 (30) 98 (28) 515 (25) 26 163 (35)

3+ 38 (18) 50 (14) 290 (14) 16 142 (22)

Marital status

Married/cohabiting 194 (90) 314 (90) 1855 (90) 68 381 (92)

Other 22 (10) 36 (10) 202 (10) 6290 (8)

Smoking

Daily 31 (14) 56 (16) 334 (16) 11 559 (15)

Occasionally 2 (1) 8 (2) 44 (2) 1820 (2)

Pattern not specified 20 (9) 30 (9) 216 (11) 7621 (10)

Chronic maternal disease 42 (19) 48 (14) 266 (13) 7139 (10)

Asthma 18 (8) 19 (5) 129 (6) 3817 (5)

Chronic hypertension 17 (8) 15 (4) 66 (3) 391 (1)

Chronic renal disease 2 (1) 4 (1) 16 (1) 548 (1)

Rheumatoid arthritis 1 (1) 1 (0.3) 12 (1) 329 (0.4)

Maternal heart disease 2 (1) 5 (1) 13 (1) 683 (1)

Thyroid disease 6 (3) 6 (2) 51 (3) 1748 (2)

Body mass index before pregnancy (kg/m2)

<18.5, underweight 2 (1) 9 (3) 44 (2) 3112 (4)

18.5–24.9, normal 85 (39) 171 (49) 905 (44) 46 334 (62)

25–29.9, overweight 68 (32) 96 (27) 544 (26) 16 640 (22)

30+, obese 61 (28) 74 (21) 564 (27) 8585 (12)

Diabetes mellitus type 1 8 (4) 16 (5) 30 (2) 276 (0.4)

Diabetes mellitus type 2 3 (1) 4 (1) 19 (1) 176 (0.2)

Gestational diabetes 4 (2) 12 (3) 55 (3) 1015 (1)


Obesity and excess fetal growth in pre-eclampsia

percentiles were similar in the subgroups with and without

BMI (data not presented).

Discussion

Main findingsThis population-based study demonstrates an excess of

LGA neonates born at term after a pre-eclamptic preg-

nancy. The excess of LGA neonates was independent of

gestational diabetes and diabetes mellitus types 1 and 2,

but was attributable to an excess of maternal obesity

among pre-eclamptic women delivering at term.

Strengths and limitationsStrengths of the study include its large size and its popula-

tion-based design, which eliminate selection and recall

bias. Birthweight and several variables that could poten-

tially affect birthweight have previously been validated with

satisfactory results including gestational age, birth order,

pre-eclampsia and diabetes.22–24 A limitation was that data

on maternal BMI were available only in a subset of

women. However, the statistical analysis demonstrated that

this group of women was representative of the total popu-

lation. Our database lacked data on ethnicity. However,

women of different ethnicity represent only a small pro-

portion of the population. Moreover, previous reports

have indicated that women of foreign ethnicity living in

Norway tend to more often have macrosomic newborns in

diabetic as well as non-diabetic pregnancies and less often

in pre-eclampsia.25 Hence, adjusting for ethnicity would

not dilute the association between pre-eclampsia and large

newborn size.

Table 2. Odds ratios with 95% CI of birthweight centiles according to pre-eclampsia and week of gestation at delivery

Category of gestational

age and pre-eclampsia (PE)

n Total (%) Unadjusted

OR (95% CI)

Adjusted*

OR (95% CI)

Adjusted**

OR (95% CI)

<5th birthweight centile

<34 weeks, no PE 24 675 (3.6) Reference Reference Reference

34–36 weeks, no PE 105 2478 (4.2) Reference Reference Reference

37+ weeks, no PE 3449 71,518 (4.8) Reference Reference Reference

<34 weeks, PE 11 216 (5.1) 1.5 (0.8–2.5) 1.8 (0.8–3.7) 1.3 (0.4–3.7)

34–36 weeks, PE 46 350 (13.1) 3.4 (3.2–3.6) 3.9 (2.7–5.7) 3.5 (3.5–3.6)

37+ weeks, PE 222 2057 (10.8) 2.4 (1.5–3.8) 2.7 (2.4–3.2) 2.4 (1.5–3.9)

<10th birthweight centile




<34 weeks, PE 40 216 (18.5) 2.6 (2.4–2.8) 2.8 (1.8–4.3) 2.7 (2.6–2.9)

34–36 weeks, PE 96 350 (27.4) 4.2 (3.8–4.6) 4.5 (3.4–5.9) 4.5 (4.0–4.9)

37+ weeks, PE 349 2057 (17.0) 1.9 (1.7–2.1) 1.9 (1.7–2.1) 1.9 (1.7–2.1)

>90th birthweight centile




<34 weeks, PE 5 216 (2.3) 0.2 (0.1–0.4) 0.2 (0.1–0.4) 0.1 (0.1–0.2)

34–36 weeks, PE 26 350 (7.4) 0.8 (0.6–1.0) 0.6 (0.4–1.0) 0.5 (0.4–0.7)

37+ weeks, PE 233 2057 (11.3) 1.4 (1.2–1.6) 1.3 (1.1–1.5) 1.1 (0.9–1.2)

>95th birthweight centile




<34 weeks, PE 2 216 (0.9) 0.2 (0.1–0.6) 0.2 (0.04–0.7) 0.2 (0.1–0.3)

34–36 weeks, PE 16 350 (4.6) 0.9 (0.7–1.3) 0.7 (0.4–1.3) 0.6 (0.4–1.3)

37+ weeks, PE 134 2057 (6.5) 1.6 (1.3–1.9) 1.4 (1.2–1.7) 1.1 (0.9–1.3)

*Adjusted for maternal age (<19, 20–24, 25–29, 30–34, 35–39, 40+, years), asthma, chronic hypertension, chronic renal disease, rheumatoid

arthritis, maternal heart disease, thyroid disease, smoking (no, occasionally, daily, pattern not specified), and diabetes (no, type 1, type 2,

gestational).

**Adjusted for maternal age (<19, 20–24, 25–29, 30–34, 35–39, 40+, years), asthma, chronic hypertension, chronic renal disease, rheumatoid

arthritis, maternal heart disease, thyroid disease, smoking (no, occasionally, daily, pattern not specified), diabetes (no, type 1, type 2, gestational),

and maternal body index (continuous).


Rasmussen et al.

Our observation of an excess of LGA neonates in

pre-eclamptic term deliveries in the unadjusted analysis is

consistent with previous population-based studies.10,12,26

However, in a smaller study the authors did not find an

excess of LGA associated with pre-eclampsia even before

adjusting for BMI.27 These conflicting reports may be the

result of a selection bias in the latter study performed at a

single tertiary-care centre.

InterpretationConsistent with prior reports.10,12,26 the present study

demonstrated that term pre-eclampsia is associated with an

excess of both SGA and LGA neonates. In addition, our

population-based study provides evidence that the excess of

LGA neonates in term pre-eclampsia can be attributed to

maternal obesity. The excess of SGA in preterm pre-eclamp-

sia supports the prevailing hypothesis that chronic uteroplac-

ental ischaemia, due to placental vascular insults, shallow

trophoblast invasion of the spiral arteries or abnormal fetal–placental circulation, plays an important role in preterm

pre-eclampsia, fetal growth restriction or both.18,28–31

It has been suggested that the excess of large fetuses in

term pre-eclampsia indicates that placental dysfunction

plays a minor role in this subset of pre-eclamptic pregnan-

cies.10,12,26 Morphological and experimental studies are in

agreement with these results. Egbor et al.30 reported that

early onset pre-eclampsia is associated with abnormal pla-

cental morphology, whereas placentas from late-onset

pre-eclampsia are morphologically similar to placentas

from gestationally age-matched non-pre-eclamptic pregnan-

cies. Hence, it is possible that in a subset of women

with late onset pre-eclampsia the disease process may be

associated more with maternal factors including obesity

than with placental factors. Earlier reports have indicated

an increased uteroplacental perfusion, as determined by

placental clearance of dehydroisoandrosterone sulphate32

and increased maternal cardiac output in late-onset

pre-eclamptic pregnancies.33 These observations suggest an

increased uteroplacental perfusion in late-onset pre-eclamp-

sia, presumably as a compensatory mechanism due to a

mismatch between uteroplacental blood flow and increased

demand for nutrients. However, additional studies are

required to confirm this hypothesis.

In the present study, we found that in term pre-eclampsia

the excess of LGA did not persist after adjusting for mater-

nal BMI as a continuous variable. This observation suggests

that maternal obesity accounts for the association between

A

B

C

Figure 1. Distribution of z-scores of birthweight in pre-eclamptic and

non-pre-eclamptic pregnancies according to gestational age at birth. A

total of 679 009 singleton births in 1999–2010 with gestational age

22–44 weeks.

Figure 2. Distribution of z-scores of birthweight in term (37 weeks of

gestation or more) pre-eclamptic and non-pre-eclamptic pregnancies.

Additionally, a subgroup of pre-eclamptic women with body mass index

18.5–24.9 kg/m2 (normal) is shown. Singleton births in 2007–10.



term pre-eclampsia and LGA. Our results are consistent

with the report of Xiong et al.10 that adjusting for high and

low maternal weight reduced the effect of term pre-eclamp-

sia on LGA. These results are also consistent with a solid

body of evidence indicating that maternal obesity is a risk

factor for both pre-eclampsia31,34–36 and LGA.16,37–40 In

obese women, even in the absence of pregestational diabetes

or gestational diabetes, it is possible that fetal overgrowth

may lead to a mismatch between increasing fetal needs for

nutrients and the ability of the placenta to keep up with

these needs. This in turn may lead to fetal signalling to

increase the maternal blood pressure in an attempt to com-

pensate for a relative uteroplacental ischaemia.17,18 The

mechanisms of disease in lean and obese women with

pre-eclampsia remain unclear. However, a two-stage

hypothesis has been proposed whereby the first stage is

characterised by abnormal fetal trophoblast invasion of the

maternal spiral arteries, and the second stage is character-

ised by widespread inflammation and dysfunction of the

maternal endothelium associated with the clinical presenta-

tion of pre-eclampsia.31 Obese women may be at higher risk

for pre-eclampsia as a result of the oxidative stress associ-

ated with increased circulating concentration of lipid perox-

ides.31,34 Several studies have reported that maternal obesity

is associated with fetal macrosomia, even in the absence of

maternal diabetes.16,37–40 The combination of increased

nutrients to the fetus and fetal hyperinsulinaemia in obese

women may explain the increased frequency of LGA in

obese women without diabetes.15,16 Moreover, although

glucose is a major source of energy in the fetus, other

maternal nutrients may influence fetal growth. Evidence in

support of this view is the observation that when maternal

glucose concentrations are properly controlled in women

with gestational diabetes, maternal triglyceride and free fatty

acids are independent predictors for the delivery of a LGA

neonate.41 This is in keeping with our results that maternal

obesity may account for the excess of macrosomic neonates

in pre-eclamptic women delivering at term.

Conclusions

The results of this study suggest an excess of both acceler-

ated and impaired fetal growth in pre-eclamptic pregnan-

cies. The excess of LGA neonates can be attributed to an

excess of maternal obesity among pre-eclamptic women

delivering at term. We anticipate that the increasing preva-

lence of obesity may lead to higher rates of both

pre-eclampsia and the delivery of LGA neonates in preg-

nant women at term, further straining the resources allo-

cated for antenatal care. Future longitudinal studies should

further explore the associations of maternal obesity with

fetal macrosomia and late onset pre-eclampsia. Such studies

would require analyses of obese and lean women with

respect to fetal growth, preferably including data on placen-

tal perfusion and morphology.

Disclosure of interestsNone declared.

Contribution to authorshipSR prepared the analytical database, conducted the analyses

and wrote the report. SR, LMI and JE discussed core ideas

and study design and edited the report. All authors are

guarantors of the paper.

DisclaimerThis study has used data from the Medical Birth Registry

of Norway. The interpretation and reporting of these data

is the sole responsibility of the authors, and no endorse-

ment by the Medical Birth Registry of Norway is intended

nor should be inferred.

Details of ethics approvalBased on anonymised registry data, the Regional Ethics

Committee exempted this study from ethical review.

FundingNo external funding.&

References

1 Roberts JM, Hubel CA. The two stage model of preeclampsia:

variations on the theme. Placenta 2009;30(Suppl A):S32–7.

2 Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, et al.

Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may

contribute to endothelial dysfunction, hypertension, and proteinuria

in preeclampsia. J Clin Invest 2003;111:649–58.

3 Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, et al.

Circulating angiogenic factors and the risk of preeclampsia. N Engl J

Med 2004;350:672–83.

4 Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP, et al.

Soluble endoglin and other circulating antiangiogenic factors in

preeclampsia. N Engl J Med 2006;355:992–1005.

5 Chauhan SP, Scardo JA, Magann EF, Devoe LD, Hendrix NW, Martin

JN Jr. Detection of growth-restricted fetuses in preeclampsia: a

case-control study. Obstet Gynecol 1999;93:687–91.

6 Haddad B, Kayem G, Deis S, Sibai BM. Are perinatal and maternal

outcomes different during expectant management of severe

preeclampsia in the presence of intrauterine growth restriction? Am

J Obstet Gynecol 2007;196:e1–5.

7 Roberts DJ, Post MD. The placenta in pre-eclampsia and intrauterine

growth restriction. J Clin Pathol 2008;61:1254–60.

8 Belghiti J, Kayem G, Tsatsaris V, Goffinet F, Sibai BM, Haddad B.

Benefits and risks of expectant management of severe preeclampsia

at less than 26 weeks gestation: the impact of gestational age and

severe fetal growth restriction. Am J Obstet Gynecol 2011;205:

e1–6.

9 Mirza FG, Strohsnitter WC, Rivera J, Gyamfi-Bannerman C.

Intrauterine growth restriction with abnormal umbilical artery

Dopplers: a harbinger for preeclampsia? J Matern Fetal Neonatal

Med 2012;25:2658–61.


Rasmussen et al.

10 Xiong X, Demianczuk NN, Buekens P, Saunders LD. Association of

preeclampsia with high birth weight for age. Am J Obstet Gynecol

2000;183:148–55.

11 Xiong X, Demianczuk NN, Saunders LD, Wang FL, Fraser WD.

Impact of preeclampsia and gestational hypertension on birth

weight by gestational age. Am J Epidemiol 2002;155:203–9.

12 Rasmussen S, Irgens LM. Fetal growth and body proportion in

preeclampsia. Obstet Gynecol 2003;101:575–83.

13 Irgens LM. Commentary: on the clinical prediction of pre-eclampsia

and its enigmatic aetiology. Int J Epidemiol 2007;36:420–1.

14 Roberts JM, Catov JM. Preeclampsia more than 1 disease: or is it?

Hypertension 2008;51:989–90.

15 Hoegsberg B, Gruppuso PA, Coustan DR. Hyperinsulinemia in

macrosomic infants of nondiabetic mothers. Diabetes Care 1993;16:

32–6.

16 Yu CK, Teoh TG, Robinson S. Obesity in pregnancy. BJOG

2006;113:1117–25.

17 Espinoza J, Uckele JE, Starr RA, Seubert DE, Espinoza AF, Berry SM.

Angiogenic imbalances: the obstetric perspective. Am J Obstet

Gynecol 2010;203:e1–8.

18 Espinoza J. Uteroplacental ischemia in early- and late-onset

pre-eclampsia: a role for the fetus? Ultrasound Obstet Gynecol

2012;40:373–82.

19 Irgens LM. The Medical Birth Registry of Norway. Epidemiological

research and surveillance throughout 30 years. Acta Obstet Gynecol

Scand 2000;79:435–9.

20 World Health Organization. Global Database on Body Mass Index.

Geneva: World Health Organization, 2013. [http://apps.who.int/bmi/

]. Accessed 9 November 2013.

21 Gifford RW, August PA, Cunningham G, Green LA, Lindheimer MD,

McNellis D, et al. Report of the National High Blood Pressure

Education Program Working Group on High Blood Pressure in

Pregnancy. Am J Obstet Gynecol 2000;183:S1–22.

22 Gissler M, Louhiala P, Hemminki E. Nordic Medical Birth Registers in

epidemiological research. Eur J Epidemiol 1997;13:169–75.

23 Engeland A, Bjørge T, Daltveit AK, Vollset SE, Furu K. Validation of

disease registration in pregnant women in the Medical Birth Registry

of Norway. Acta Obstet Gynecol Scand 2009;88:1083–9.

24 Thomsen LC, Klungsøyr K, Roten LT, Tappert C, Araya E, Bærheim G,

et al. Validity of the diagnosis of pre-eclampsia in the Medical Birth

Registry of Norway. Acta Obstet Gynecol Scand 2013;92:943–50.

25 Vangen S, Stoltenberg C, Holan S, Moe N, Magnus P, Harris JR,

et al. Outcome of pregnancy among immigrant women with

diabetes. Diabetes Care 2003;26:327–32.

26 Chen XK, Wen SW, Smith GN, Yang Q, Walker MC. New-onset

hypertension in late pregnancy and fetal growth: different

associations between singletons and twins. Hypertens Pregnancy

2007;26:259–72.

27 Powe CE, Ecker J, Rana S, Wang A, Ankers E, Ye J, et al.

Preeclampsia and the risk of large-for-gestational-age infants. Am

J Obstet Gynecol 2011;204:e1–6.

28 Brazy JE, Grimm JK, Little VA. Neonatal manifestations of severe

maternal hypertension occurring before the thirty-sixth week of

pregnancy. J Pediatr 1982;100:265–71.

29 Moore MP, Redman CW. Case–control study of severe

pre-eclampsia of early onset. Br Med J (Clin Res Ed) 1983;287:

580–3.

30 Egbor M, Ansari T, Morris N, Green CJ, Sibbons PD. Morphometric

placental villous and vascular abnormalities in early- and late-onset

pre-eclampsia with and without fetal growth restriction. BJOG

2006;113:580–9.

31 Gilbert JS, Ryan MJ, LaMarca BB, Sedeek M, Murphy SR, Granger

JP. Pathophysiology of hypertension during preeclampsia: linking

placental ischemia with endothelial dysfunction. Am J Physiol Heart

Circ Physiol 2008;294:H541–50.

32 Gant NF, Hutchinson HT, Siiteri PK, MacDonald PC. Study of the

metabolic clearance rate of dehydroisoandrosterone sulfate in

pregnancy. Am J Obstet Gynecol 1971;111:555–63.

33 Easterling TR, Benedetti TJ, Schmucker BC, Millard SP. Maternal

hemodynamics in normal and preeclamptic pregnancies: a

longitudinal study. Obstet Gynecol 1990;76:1061–9.

34 Zavalza-Gomez AB. Obesity and oxidative stress: a direct link to

preeclampsia? Arch Gynecol Obstet 2011;283:415–22.

35 Bodnar LM, Ness RB, Harger GF, Roberts JM. Inflammation and

triglycerides partially mediate the effect of prepregnancy body mass

index on the risk of preeclampsia. Am J Epidemiol 2005;162:1198–

206.

36 Sohlberg S, Stephansson O, Cnattingius S, Wikstrom AK. Maternal

body mass index, height, and risks of preeclampsia. Am J Hypertens

2012;25:120–5.

37 Djelantik AA, Kunst AE, van der Wal MF, Smit HA, Vrijkotte TG.

Contribution of overweight and obesity to the occurrence of

adverse pregnancy outcomes in a multi-ethnic cohort: population

attributive fractions for Amsterdam. BJOG 2012;119:283–90.

38 Freeman DJ. Effects of maternal obesity on fetal growth and body

composition: implications for programming and future health. Semin

Fetal Neonatal Med 2010;15:113–18.

39 Sebire NJ, Jolly M, Harris JP, Wadsworth J, Joffe M, Beard RW, et al.

Maternal obesity and pregnancy outcome: a study of 287,213

pregnancies in London. Int J Obes Relat Metab Disord 2001;25:

1175–82.

40 Schaefer-Graf UM, Heuer R, Kilavuz O, Pandura A, Henrich W,

Vetter K. Maternal obesity not maternal glucose values correlates

best with high rates of fetal macrosomia in pregnancies

complicated by gestational diabetes. J Perinat Med 2002;30:313–

21.

41 Schaefer-Graf UM, Graf K, Kulbacka I, Kjos SL, Dudenhausen J,

Vetter K, et al. Maternal lipids as strong determinants of fetal

environment and growth in pregnancies with gestational diabetes

mellitus. Diabetes Care 2008;31:1858–63.



http://apps.who.int/bmi/

Need to evaluate empirical evidence before formulating theory

S Lisonkova, KS JosephDepartment of Obstetrics and Gynaecology, University of British Columbia, Vancouver, BC, Canada

Mini commentary on ‘Maternal obesity and excess of fetal growth in pre-eclampsia’

Professor Rasmussen and colleagues

attempted to answer the causal ques-

tion: Does pre-eclampsia increase

the risk of large-for-gestational-age

(LGA) infants? This issue is important

because previous findings of an excess

of macrosomic and LGA infants

among women with pre-eclampsia

have intrigued researchers and influ-

enced pre-eclampsia theory.

Numerous studies have shown that

women with pre-eclampsia are at

high risk for small-for-gestational-age

infants. This is consonant with the

widely accepted theory that pre-eclam

psia is caused by an aberrant develop-

ment of the placental vasculature.

However, this fundamental aspect of

the pathophysiology of pre-eclampsia

needed to be expanded to accommo-

date the unexpected finding of a

simultaneous excess of LGA infants

among women with pre-eclampsia

(Maulik J Matern Fetal Neonatal Med

2003;13:145–6). The combination of

fetal growth restriction and excess fetal

growth appeared to support a previ-

ous theory that pre-eclampsia involves

heterogeneous processes; one originat-

ing in abnormal placentation, and the

other involving maternal factors and

enthothelial injury but no placental

dysfunction (Ness et al. Am J Obstet

Gynecol 1996;175:1365–70). Whereas

this theory regarding the placental and

maternal origins of pre-eclampsia is

supported by several empirical

findings, the apparent excess of LGA

infants among women with pre-eclam-

psia cannot serve to bolster this propo-

sition. As Rasmussen et al. show, the

association between pre-eclampsia and

LGA is spurious and entirely explained

by the confounding effect of maternal

prepregnancy body size.

This cautionary tale should give us

pause; empirical evidence needs to be

assessed carefully before it can

become the underpinning for theory.

Fundamental epidemiological princi-

ples should always receive proper

attention; adjustment for confound-

ers and care in avoiding residual con-

founding are key issues.

Another case in point is the empiri-

cal finding that preterm infants of

women with pre-eclampsia have lower

perinatal mortality than preterm

infants born to women without

pre-eclampsia. This paradoxical obser-

vation is in fact part of a more general

phenomenon: perinatal mortality rates

are relatively lower among low birth-

weight and preterm babies of several

vulnerable groups including women

who smoke. From a prognostic (non-

causal) standpoint, the lower risk of

perinatal death among preterm babies

of women with pre-eclampsia and

women who smoke is accurate. How-

ever, from a causal perspective, the

association between pre-eclampsia/

smoking and perinatal death is proba-

bly spurious; neither pre-eclampsia

nor smoking confers benefit on the

fetus or infant. The phenomenon is

best explained with the fetuses-at-risk

formulation, which shows that perina-

tal mortality rates are higher among

women with pre-eclampsia and those

who smoke at all gestational ages

(Lisonkova et al. Am J Obstet Gynecol

2013;209:544.e1–544.e12). Under the

fetuses-at-risk model, perinatal deaths

at any gestation are viewed as incident

cases that occur among the population

of fetuses at risk of perinatal death at

that gestation. This viewpoint con-

trasts with the traditional gestational

age-specific perinatal mortality rate

calculation in which rates are based

on perinatal deaths occurring among

births at a particular gestational age.

Pre-eclampsia has been called a dis-

ease of theories (Higgins et al. Curr

Opin Obstet Gynecol 1998;10:129–33).Carefully evaluated empirical evi-

dence should guide the refinement of

these theories, a process that will

eventually uncover the aetiology of

this puzzling and complex disease.

Disclosure of interestsNeither author has anything to dis-

close.


Rasmussen et al.

maternal obesity and excess of fetal growth in pre-eclampsia

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