Increased BMI has a linear association with late-onset preeclampsia: A population-based study.

BACKGROUND: To investigate the ongoing controversy on the effect of BMI (body mass index) on EOP (early onset preeclampsia) vs LOP (late onset), especially focusing on diabetes and maternal booking/pre-pregnancy BMI as possible independent variables.
METHODS: 18 year-observational cohort study (2001-2018). The study population consisted of all consecutive births delivered at the Centre Hospitalier Universitaire Hospitalier Sud Reunion's maternity (ap. 4,300 birth per year, only level 3 maternity in the south of Reunion Island, sole allowed to follow and deliver all preeclampsia cases of the area). History of pregnancies, deliveries and neonatal outcomes have been collected in standardized fashion into an epidemiological perinatal data base.
RESULTS: Chronic hypertension and, history of preeclampsia in multigravidas, were the strongest risk factors for EOP. Primiparity, age over 35 years and BMI ≥ 35 kg/m² were rather associated with LOP. In a multivariate analysis with EOP or LOP as outcome variables compared with controls (normotensive), maternal age and pre-pregnancy BMI were independent risk factors for both EOP and LOP (p < 0.001). However, analyzing by increment of 5 (years of age, kg/m² for BMI) rising maternal ages and incidence of preeclampsia were strictly parallel for EOP and LOP, while increment of BMI was only associated with LOP. Controlling for maternal ages and booking/pre-pregnancy BMI, diabetes was not an independent risk factor neither for EOP or LOP.
CONCLUSIONS: Metabolic factors, other than diabetes, associated with pre-pregnancy maternal corpulence are specifically associated with LOP. This may be a direction for future researches on the maternal preeclamptic syndrome. This may explain the discrepancy we are facing nowadays where high-income countries report 90% of their preeclampsia being LOP, while it is only 60-70% in medium-low income countries.

Introduction

The recognition of different preeclampsia phenotypes, in particular differentiation between early onset preeclampsia (EOP) and late onset preeclampsia (LOP) has been of pivotal importance in our quest of comprehending the pathophysiology of this still enigmatic syndrome [1,2]. Classical risk factors for preeclampsia may be summarized as: nulliparity, primipaternity, advanced maternal age, previous preeclampsia, high body mass index (BMI), gestational diabetes, multiple gestations, assisted reproduction and pre-existing medical conditions such as chronic hypertension, antiphospholipid antibody syndrome and renal disease [3-5].

Over the past 2 decades, large epidemiologic studies have clearly established that obesity is a major risk for both gestational hypertension and preeclampsia. The risk of preeclampsia typically doubles with each 5–7 kg/m2 increase in pre-pregnancy [6,7]. The mechanisms have only be partially explored; increased cytokine-mediated inflammation and oxidative stress, increased shear stress, dyslipidemia, and increased sympathetic activity1 have all been proposed as possible pathways. An overview of the major processes involved in the pathogenesis of preeclampsia can be referred in reviews [8,9]. It is however less clear whether or not an increasing BMI is associated with all types of PE, in particular EOP and LOP. The data of the 5600 healthy nulliparous pregnant women in the multicentre SCOPE study, just using a binary BMI cut-off of 30, appeared to indicate that obesity was associated with both EOP and LOP, but this paper used a simple binary cut-off of BMI 30 to split the cohort in obese versus non-obese [10].

The problem of maternal corpulence (BMI) is interesting for preeclampsia: it is of note that in the paramount epidemiological efforts made by our masters during the 20th century [11] in big texbooks (Kosmak 1931, Dieckman 1952, Davis 1952, Leon Chesley 1978 & 1999, McGillivray 1983), overweight and obesity were not cited as a problem. Probably in those years obesity was not yet the enormous public health problem on this planet that we are facing nowadays; the real epidemic of obesity has started around the year 1975 [12]. The interest in the effect of obesity as risk factor for preeclampsia seems to have raised in the beginning of 1990’s [13], and it became a kind of tsunami since the beginning of the 21st century [6,14-15].

The purpose of the current study involving a large retrospective cohort study (18 year survey, 1736 singleton PE cases) was to resolve the ongoing controversy on the effect of BMI on EOP vs LOP, especially focusing on diabetes and maternal BMI as possible independent variables, and to compare our data with the aforementioned SCOPE study.

Material and methods

From January 1st, 2001, to 31 December 2018, the hospital records of all women delivered at the maternity of the University South Reunion Island (ap. 4 300 births per year) were abstracted in standardized fashion. The study sample was drawn from the hospital perinatal database which prospectively records data of all mother-infant pairs since 2001. Information is collected at the time of delivery and at the infant hospital discharge and regularly audited by appropriately trained staff. This epidemiological perinatal data base contains information on obstetrical risk factors, pregnancy complications, description of deliveries and neonatal outcomes. As participants in the French national health care system, all pregnant women in Reunion Island have their prenatal visits, biological and ultasonographic examinations, and anthropological characteristics recorded in their maternity booklet.

Preeclampsia, gestational hypertension and eclampsia were diagnosed according to the definition issued by the International Society for the Study of Hypertension in Pregnancy (ISSHP) relatively to the guidelines in force at the year of pregnancy.

Design and study population

The maternity department of Saint Pierre hospital is a tertiary care centre that performs about 4 300 deliveries per year, thus representing about 80% of deliveries of the Southern area of Reunion Island, but is the only level 3 maternity (the other maternity is a private clinic, level 1 which is not allowed to follow/deliver preeclamptic pregnancies). Level 1 maternities are allowed to manage pregnancies after 35 weeks of gestation, without severe risk factors (preeclampsia, multiple pregnancies, in utero fetal deaths, medical termination of pregnancies, complicated gestational diabetes). Level 2 maternities are allowed to manage deliveries of 33 weeks onward; there are never been level 2 maternities in South-Reunion. Level 3 maternities take care of all pregnancies delivering after 21 weeks gestation and all complicated pregnancies (see level 1 exclusions). Reunion Island is a French overseas region in the Southern Indian Ocean. The entire pregnant population has virtually access to maternity care. This is provided free of charge by the French healthcare system, which combines freedom of medical practice with nationwide social security. Pregnancies are well followed (an average of 9 prenatal visits and 4 ultrasonographies. The mean gestational age at first (“datation”) ultrasonography being 11 weeks.

Definition of exposure and outcomes

The maternal outcomes of interest for this study were obstetric illness (pregnancy-induced hypertension, pre-eclampsia, eclampsia), and way of delivery (normal vaginal delivery, instrumental vaginal delivery—forceps or vacuum—, caesarean section, postpartum haemorrhage,).

Preterm and very preterm birth was defined as delivery before 37 and 33 weeks of gestation, low birth weight (LBW) and very low birth weight (VLBW) as birth weight below 2500 and 1500 g respectively. Infants were considered SGA when the sex and age-adjusted birth weight was below the tenth percentile according to normal tables for our population. Pre-existing renal disorders included glomerulonephritis, reflux- nephropathy and diabetic nephropathy were excluded.

Pre-pregnancy BMI (ppBMI),was calculated on the recalled pre-pregnancy weight by patients themselves in the majority of cases, controlled by the booking weight at first visit (average 6–8 weeks), always written down in the maternity booklet.

Statistical analysis

Data is presented as numbers and proportions (%) for categorical variables and as mean and standard deviation (SD) for continuous ones. Comparisons between groups were performed by using χ2-test; odds ratio (OR) with 95% confidence interval (CI) was also calculated. Paired t-test was used for parametric and the Mann-Whitney U test for non-parametric continuous variables. P-values <0.05 were considered statistically significant. Epidemiological data have been recorded and analysed with the software EPI-INFO 7.1.5 (2008, CDC Atlanta, OMS), EPIDATA 3.0 and EPIDATA Analysis V2.2.2.183. Denmark.

Further, to validate the independent association of maternal pre-pregnancy BMI, or maternal ages and other confounding factors on EOP or LOP we realized a multiple regression logistic model. Variables associated with in bivariate analysis, with a p-value below 0.1 or known to be associated with the outcome in the literature were included in the model. A stepwise backward strategy was then applied to obtain the final model. The goodness of fit was assessed using the Hosmer-Lemeshow test. A p-value below 0.05 was considered significant. All analyses were performed using MedCalc software (version 12.3.0; MedCalc Software's, Ostend, Belgium).

Ethics approval

This study was conducted in accordance with French legislation. As per new French law applicable to trials involving human subjects (Jardé Act), a specific approval of an ethics committee (comité de protection des personnes- CPP) is not required for this non-interventional study based on retrospective, anonymized data of authorized collections and written patient consent is not needed. This study was registered on UMIN Clinical Trials Registry (identification number is UMIN000037012)

Results

During the 18-year period, there were 96,861 births in the South of the Reunion Island with an incidence of preeclampsia of 1842 (1.9%), of which 106 multiple pregnancies (5.8%). The study population therefore consisted of 1736 singleton preeclamptic pregnancies (OR for multiple pregnancies as compared with singletons 3.1 [95%CI 2.4–3.9], p< 0.0001).

Table 1 synthesizes all comparisons between EOP and LOP preeclamptic patients (Odds ratios being EOP vs LOP). We put on the left column all results which were not significant. All items statistically significant have been assembled in the right column. EOP women were older than LOP 29.5 vs 28.6 years, p = 0.009, primigravidas (OR 0.78 [0.63–0.96] were prone to LOP. History of abortion or miscarriage were similar in both groups, but history of previous perinatal death or previous preeclampsia was a risk factor for EOP (OR 1.78 [1.2–2.7], p = 0.05 and 1.73 [1.17–2.54], p = 0.001 respectively). EOP women had a tendency to have lower pre-pregnancy BMI (26.4 vs 27.1 kg/m², p = 0.06), but no significant differences for being overweight (BMI ≥ 25 kg/m²) or obese (BMI ≥ 30 kg/m²) for the crude results. For these crude results also, Gestational Diabetes Mellitus (GDM) was protective for EOP, OR 0.68 [0.50–0.92], p = 0.01 (but no difference for pre-pregnancy diabetes, p = 0.51). Chronic hypertension (superimposed PE) was a strong factor for EOP, OR 1.47 [1.07–2.0], p = 0.02.

Table 1

Crude differences between EOP and LOP.

Non significant resultsLeft numbers EOP N = 574Right numbers LOP N = 1162	P value	Significant resultsEOP vs LOPODDS ratios[95% CI]	P value
Gestity (mean, SD)) 2.91 vs 2.73	0.10	Mother Age (years, SD)29.5 vs 28.6	0.009
Parity (mean, SD 1.29 vs 1.17	0.16	Primigravidity 0.78 [0.63–0.96]	0.02
Primiparity 45.3% vs 49.7% OR 0.84	0.09	Chronic hypertension1.47 [1.07–2]	0.02
Adolescents (<18y) 3.1% vs 3.5% OR 0.89	0.67	Gestational diabetes 0.68 [0.50–0.92]	0.01
35 years + 26.1vs 23.8% OR = 1.13	0.29	Atcd perinatal. Deaths1.78 [1.2–2.7]	0.01
Grand multiparae (5+) 11.0% vs 9.4% OR = 1.19	0.29	Atcd preeclampsia1.73 [1.17–2.5]	0.01
Single 35.2% vs 38.2% OR = 0.88	0.22	ppBMI* 26.4 vs 27.1 Kg/m²	0.06
High school & university56.2% vs 55.1%	0.70
BMI ≥ 25 kg/m²53.8% vs 53.6%	0.93
BMI ≥ 30 kg/m² 26.7% vs 30.2%OR = 0.84	0.15	HELLP syndrome 12% vs 3.5% 3.7 [2.5–5.6]	0.01
Pre-existing diabetes3.9% vs 4.6%	0.51	Placental abruption5.6% vs 0.9% 6.8 [3.4–14]	< 0.001
Smoking9.6% vs 8.6%	0.50
Hypercholesterolemia 0.2% vs 0.2%	NS
Atcd miscarriage30.5% vs 31.0%	0.84	Low birthweight <2500g OR = 664	< 0.001
Atcd abortion26.9% vs 23.0%	0.14	Very low birthweight < 1500g 68% vs 1.4%OR = 155	< 0.001
Atcd thyroid disease#2.4% vs 1.5% OR = 1.52	0.21	SGA * 33.1% vs 25.0%1.47 [1.17–1.85]	< 0.001
Atcd renal disease 1.6% vs 0.9% OR = 1.67	0.25	Perinatal mortality rate 14.3% vs 1.3% 12.7 [7.3–22]	< 0.001
Medically induced preg3.6% vs 2.6%	0.25	Medical termination 3.8% vs 1.2%OR = 46.3	< 0.001
Eclampsia 2.6% vs 2.8%	0.86	In utero fetal deaths 6.8% vs 1.2% 6.0 [3.2–11]	< 0.001
Female sex 54.2% vs 51.9%	0.54
Fetal malformations2.3% vs 2.1%	NS

# goitre, hypo-hyperthyroidy, thyroidectomy, thyroid node, thyroiditis.

* ppBMI pre-pregnancy BMI.

As expected, women who developed EOP had poorer clinical outcomes, with major complications like HELLP syndrome, OR 3.7 [2.5–5.6], p = 0.0001, and placental abruption, OR 6.8 [3.4–14.6] p< 0.001. Neonatal outcome was severely affected by a preterm onset of the disease with intra-uterine fetal deaths 6 times higher than the LOP group (as well as termination of pregnancy for preeclampsia). Perinatal mortality was of 14.3% in EOP vs 1.3% in LOP, OR 12.7 [7.3–22.3], p< 0.0001. Women with LOP had a higher risk of post-partum hemorrhage, OR for EOP 0.30 [0.13–0.7], p = 0.003 (not shown in the Table). No difference was found for eclampsia in the two groups.

Table 2 reports the logistic regression model controlled for maternal age, pre-pregnancy BMI (ppBMI), smoking, gestational diabetes, chronic hypertension and primiparity as compared with controls (women without preeclampsia). Chronic hypertension was the strongest independent risk factor for both EOP and LOP, with an OR of 8.2 [6.1–11.0], p< 0.001and 4.95 [3.9–6.3], p <0.001, respectively. Maternal age and pre-pregnancy BMI were independent risk factors for both EOP and LOP. Smoking was protective for LOP (OR 0.74 [0.59–0.91], p = 0.006) but not for EOP. In the multivariate analysis, when controlling for maternal ages and BMI, gestational diabetes was not a risk factor for preeclampsia OR 1.08, p = 0.26, protective for EOP OR 0.73 [0.56–0.98], p = 0.03.

Table 2

Logistic multivariate regression analysis.

All PE (all preeclampsia N = 1,736), EOP (N = 574) and LOP (N = 1,162) vs controls, no preeclampsia (N = 71,078).

	All PEaOR	P val	EOPaOR	P val	LOPaOR	P val
Maternal age(increment by 5 years)	1.04 [1.03–1.05]	< 0.001	1.05 [1.03–1.06]	< 0.001	1.03 [1.02–1.04]	< 0.001
BMI (kg/m²)(increment by 5kg/m²)	1.05 [1.04–1.05]	< 0.001	1.03 [1.02–1.05]	< 0.001	1.05 [1.04–1.06]	< 0.001
Gestational Diabetes	1.08	0.26	0.73 [0.56–0.98]	0.03	1.15	0.09
Chronic hypertension	5.62 [4.7–6.8]	< 0.001	8.2 [6.1–11.0]	< 0.001	4.95 [3.9–6.3]	< 0.001
Tobacco	0.76 [0.64–0.90]	0.002	0.87	0.38	0.74 [0.74–0.91]	0.006
Primiparity	2.43 [2.2–2.7]	< 0.001	2.17 [1.8–2.7]	< 0.001	2.44 [2.1–2.8]	< 0.001

Women where we could define the pre-pregnancy BMI: N = 965/1162 (83.0%) LOP; N = 456/574 (79.4%) EOP; N = 64,102/71,078 (90.1%) controls.

Since the logistic regression model demonstrate a strong correlation with ppBMI, we sought to look at the respective incidences of EOP and LOP in Reunion Island (Fig 1) and compared with the international data from the SCOPE study (Fig 2), starting from lean women (<20Kg/m2) to morbid obesity (>40 kg/m²). A linear association was confirmed in both groups (EOP and LOP) with a stronger correlation with LOP. Whatever the maternal BMI, the incidence of EOP was relatively constant and almost flat, while there is a linear rise of the incidence of LOP with higher ppBMI. In addition, we wanted to verify this ppBMI effect over time (Fig 3). As a matter of fact, in Reunion island, there is a major public-health problem of a secular rise of obesity. Maternal obesity (ppBMI ≥ 30 kg/m²) was approximately of 11–12% in the years 2001–2003 with a positive temporal trend that reached 23% in 2018. Interestingly, the incidence of EOP was quite stable during the study period (ranging between 0.7 and 1.1‰) while LOP seems to follow closely the obesity trend doubling in the study period (from 12‰ in 2001 to 24‰ in 2018).

Fig 1

Prevalence (%) of EOP and LOP per categories of BMI, South Reunion 2001–2018.

1,736 preeclampsia. 1,587 preeclampsia with BMI, 491 EOP (30.9%) and 1,096 LOP.

Fig 2

SCOPE study.

Prevalence (%) of EOP and LOP per categories of BMI,. 278 preeclampsia 28 EOP (10,0%), 250 LOP (34 weeks +).

Fig 3

Evolution per year 2001–2018 in South-Réunion of the incidence of obesity (in per cents), and the incidence of preeclampsia, early onset preeclampsia and late onset preeclampsia (per 1000).

Another maternal characteristic that was revealed by the logistic regression model was a correlation between maternal age and the development of preeclampsia (p<0.001) so we plotted the incidence of preeclampsia according to this variable (Fig 4). There is a regular rise of EOP and LOP with maternal ages, describing two parallel lines of EOP and LOP. Also Table 3 shows the bivariate interaction between maternal ages and BMI both together. Adjusted Odds ratios for maternal ages and BMI are similar in EOP women (1.035 [1.02–1.05], 1.039 [1.03–1.05] respectively. This is not the case for LOP: aOR for maternal ages is 1.015 [1.006–1.024] while it raises at 1.056 [1.05–1.06] for maternal pre-pregnancy BMI. In all preeclamptic women, there is a higher increment for BMI, aOR 1.05 (i.e. an increment of 5% for each increment of 5kg/m²) than for maternal ages aOR 1.03 (an increment of 3% for each increment of 5 years of age). But this effect is concentrated only in LOP. Figs 1 and 2 and 4 show geometrically that indeed, in one case (pre-pregnancy BMI) the two curves diverge by an angle of ap. 30°, while it is a parallel rise when we consider maternal ages.

Fig 4

Incidence of preeclampsia, EOP (N = 574), LOP (N = 1,162) by mother ages.

Table 3

Logistic bivariate regression analysis between maternal ages and pre-pregnancy BMI.

All PE (all preeclampsia N = 1,736), EOP (N = 574) and LOP (N = 1,162) vs controls, no preeclampsia (N = 71,078).

	All PEaOR	P val	EOPaOR	P val	LOPaOR	P val
Maternal age(increment by 5 years)	1.021[1.04–1.029]	< 0.001	1.035[1.021–1.048]	< 0.001	1.015[1.006–1.024]	< 0.001
BMI (kg/m²)(increment by 5kg/m²)	1.050[1.043–1.057]	< 0.001	1.039[1.026–1.053]	< 0.001	1.056[1.047–1.064]	< 0.001

Women where we could define the pre-pregnancy BMI: N = 965/1162 (83.0%) LOP; N = 456/574 (79.4%) EOP; N = 64,102/71,078 (90.1%) controls.

Discussion

The results of this large retrospective cohort clearly demonstrate that (a) chronic hypertension is the strongest risk factors for preeclampsia, but mainly linked with EOP, b) nulliparity at booking is linked rather with LOP than with EOP, although OR in the multivariate analysis are similar (Table 2), c) previous preeclampsia is strongly linked with EOP, e) pre-existing medical conditions such as thyroid disease are linked with both EOP and LOP, f) advanced maternal age is both linked with the occurrence of EOP and LOP, but in a paralleled and coupled rise (see Table 3 and Fig 4) f) pre-pregnancy maternal BMI is also linked with the EOP and LOP, but the paralleling and coupling is with LOP (see Figs 1–3) and no clear correlation with EOP, and finally, g) gestational diabetes is not an independent risk factor for preeclampsia when controlling for maternal ages and maternal pre-pregnancy BMI (ppBMI). Pre-conceptional weight and weight gain during pregnancy were found to be associated with pregnancy complications in a recent meta-analysis of European, North American and Australian cohorts although the correlation between preeclampsia and ppBMI was not investigated in detail [16]. Furthermore, pre-existing diabetes is a well-established risk for diabetes, and several studies previously proposed GDM as a risk factor (risk X by 2 or 4 [17]). Reports associate diabetes and preeclampsia [18-20], especially with LOP [20]. However, a few studies [21,22] do not find such an association when controlling for maternal weight and age, as in a very recent study, in a cohort of 15,000 pregnant women in Beijing, China [23]. In our prospective cohort also, after controlling for maternal pre-gestational BMI and maternal ages, gestational diabetes is no longer an independent risk for preeclampsia, and especially for late onset PE. These findings suggest that a certain degree of mild hyperglycaemia per se does not adversely affect maternal-placental homeostasis.

In our experience, growth retardation in newborns is higher in EOP pregnancies (33% of newborns), but remains relatively high (25%) in LOP infants (OR 1.47, [1.17–1.85], p = 0.001 for EOP, Table 1), which was not the case in the SCOPE study (LOP babies were mainly normal weighted) [10]. This 18-year cohort confirms that chronic hypertension and previous history of preeclampsia are paramount risks for PE and notably EOP. Prior preeclampsia and chronic hypertension have been ranked first and second in a meta analysis recalling some 25 million pregnancies [24]. However, it should be noted that while in this cohort 178/1736 (10.3%) women had PE superimposed on chronic hypertension, and 131 (7.6%) preeclamptic multiparous women had a preeclampsia in an earlier pregnancy (representing 15% of our preeclamptic multiparae [25]), 1459 (84%) of our preeclamptics did not present any of these two risks, highlighting the major importance of other major risk factors. Advancing maternal age is usually assumed as a risk factor for preeclampsia [22,26-27], while some studies contest that advanced age is involved [14, 28–29]. In this study, there is a rise in preeclampsia incidence with maternal ages (Fig 4), but it is exactly the same parallel rise for EOP and LOP.

It is important to note that the distinction EOP vs LOP, albeit important’ is arbitrary. Over the past decade the pivotal role of syncytiotrophoblast (STB) stress [30-32] and the resulting anti-angiogenic state have been recognised as the ‘final common pathway’ to endothelial dysfunction and as such the maternal syndrome PE. Poor spiral artery remodelling is typically associated with IUGR [33] and therefore EOP. Lack of spiral artery remodelling with subsequent STB damage by damaging ‘pulsatile’ flows [34] and subsequent ischaemia reperfusion event clearly represent an important pathway leading to STB stress. One can easily hypothesize why chronic hypertension with the stiffer, thicker arterial walls will lead to EOP. The biology of adverse factors like maternal age per se are not directly evident, STB stress leading to PE has also been proposed as reflecting premature STB aging. Would advanced maternal age associate with premature STB aging? LOP is mostly not associated with inadequate spiral artery remodelling, other factors are required to trigger STB stress, with BMI clearly representing a very important player, both the status of chronic inflammation as increased triglyceride levels but also increased sympathetic stress [35] being possible adverse vectors.

High BMI, especially obesity, increase the risk of preeclampsia as extensively documented in multiple studies [6,15,36]. But several studies investigating preeclampsia subtypes (EOP and LOP) reported specifically that being overweight/obese increased the risk of LOP and not the risk of EOP [14,23, 37–39]. The SCOPE consortium had reported that obesity was both a similar risk factor for EOP and LOP [10], but using a binary definition of obesity (30+/-, yes/no). In this study, we demonstrate that using the BMI as a continuum, we find in both cases that increasing BMI is linearly associated with the incidence of LOP. Further, we wanted to double check this BMI effect over time: as a matter of fact, in Reunion island, we have a major public-health problem of a secular rise of obesity (≥ 30 kg/m²). As epidemiologists, both obstetricians and neonatologists, we witness with some helplessness this regular rise of obesity year after year in our context. Interestingly, the preeclampsia incidence is quite a twin curve of that of LOP during these 18 years (Fig 3).

Obesity has been shown to represent a definite risk for the development of preeclampsia during pregnancy [40]. Obese patients present a metabolic syndrome (MS) characterized by insulin resistance with excessive flux of fatty acids and a proinflammatory state that contribute to disrupt the equilibrium between immunology, metabolic alterations and systemic inflammation that are necessary for a healthy pregnancy.

The SCOPE study demonstrated that all variables making up the metabolic syndrome, so not only obesity, are risk factors for PE [41]. In clinically evident preeclampsia, an exacerbated MS occurs, and this may represent the major risk of cardiovascular and metabolic disease in later life [42,43]. In fact, a close relationship between hypertension, endothelial and kidney damage (features shared between preeclampsia and MS) hold a pivotal role for long term complications [43,44] as demonstrated by interventions to improve insulin sensitivity that reduce the risk of both hypertension in pregnancy and later life cardiovascular complications [45,46]. Metabolic and inflammatory intracellular pathways share some mediators like the insulin receptor substrate, phosphatidyl inositol 3-kinase, and the protein kinase B [47] that are also involved in the immunological activation of natural killer cells [48] and in the angiogenic imbalance that was demonstrated in preeclampsia [49,50]. The association between the MS and preeclampsia is supported by evidence of increased hyperinsulinemia [48], abnormal placental accumulation of glycogen [51] and unusual insulin mediators [52] with subsequent impaired placental insulin signaling. Certainly, insulin resistance act synergistically with impaired angiogenic factors [49,50] that lead to the preeclamptic syndrome (hypertension, proteinuria, and organ damage) [53-54].

A strength of this study is the fact that it represents a true population study. The Centre Hospitalier Universitaire Sud-Reunion’s maternity (Level 3, European standards of care) is the only public hospital in the southern part of Reunion Island (Indian Ocean, French overseas department). It serves the whole population of the area (ap. 360,000 inhabitants, and 5100 births per year). With 4,300 births per year, the university maternity represents 82% of all births in the South. But, as a level 3 (the other maternity is a private clinic, level 1), we are sure to have had ALL the preeclampsia of the south of the island during the 18 year period. During all the 18-year period, definitions of preeclampsia and HELLP syndrome have been the same. The weakness of this study is that the available data base does not provide data on length of sexual relationship and/or primipaternity.

Conclusions

“Getting rid” of diabetes in preeclampsia, while recognising that late onset preeclampsia is linearly associated with rising maternal pre-pregnancy body mass index (and not early onset PE) may narrow the beam toward future researches on carbohydrate/lipid metabolism explaining the maternal inflammation syndrome at the 3rd trimester of pregnancy. This problem of corpulence may also explain the discrepancy we are facing nowadays on this planet where high-income countries report 90% of their preeclampsia being LOP [55], while it is only 60–70% in medium-low income countries (unfortunately, still the great majority of humankind) [56] as well as the reports of the 20th century’s scholars [57,58], where, for example, our masters did not emphasized at all obesity.

EOP BMI: Calculations of BMI and EOP in the whole population.

(DOC)

Click here for additional data file.

LOP BMI: Calculations of BMI and LOP in the whole population.

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Click here for additional data file.

EOP vs LOP 19: Main calculations EOP vs LOP.

(DOC)

Click here for additional data file.

EOP vs LOP singletons: Complementary calculations EOP vs LOP.

(DOCX)

Click here for additional data file.

Logistic regression age BMI: Calculations of logistic regression.

(DOCX)

Click here for additional data file.

Logistic regression EOP LOP: Cal culations logistic regression.

(DOCX)

Click here for additional data file.

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29 Aug 2019

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PONE-D-19-21680

LATE ONSET PREECLAMPSIA IS LINEARLY ASSOCIATED WITH RISING MATERNAL PRE-PREGNANCY BMI. A POPULATION-BASED STUDY of 1,700 CASES of PREECLAMPSIA IN SINGLETON PREGNANCIES.

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b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

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4. Please upload a copy of Figure 5, to which you refer in your text on page 8. If the figure is no longer to be included as part of the submission please remove all reference to it within the text.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: In this paper, authors did a 18 year-observational cohort study to analyse the parameters related with EOP and LOP and compared their different effects on these two preeclampsia. It is a relatively comprehensive research based on so large number of cases. And authors got the interesting findings that increment of 5 years for maternal age rising and incidence of preeclampsia were strictly parallel for EOP and LOP, while increment of 5kg/m² for BMI was only associated with LOP. That can give us some clues on the different mechanism of EOP and LOP.

There are some problems need to be modified:

1, In the method, authors quoted the levels of maternity, like level 1, level 3, but didn't give some background of the definition of the levels for maternity. They need introduce the division of levels.

2, In the findings, authors found that increment of 5 (years for age, 5kg/m² for BMI) rising maternal ages and incidence of preeclampsia were strictly parallel for EOP and LOP, while increment of BMI was only associated with LOP. It is hard to understand when put 5kg/m² for BMI with 5 years for age to explain the relationship between maternal ages and incidence of preeclampsia. It would be better if they put the information of 5kg/m² for BMI down when concluded that BMI was only associated with LOP.

3, Some abbreviations, like LDW, VLDW, GDM, ppBMI need to write their full names when first using them in this manuscript. And authors should make the whole paper be more organised.

Reviewer #2: Pierre-Yves Robillard et al. investigated the effect of BMI (body mass index) on EOP (early onset preeclampsia) vs LOP (late onset) by a long term observational cohort study. And they found that increment of maternal BMI was only associated with LOP during pregnancy. This was a great job. However, there were some issues in the manuscript.

And the suggestion of the manuscript followed:

1. The authors did not highlight the significance of BMI for preeclampsia such as EOP or LOP in the introduction, and there was some confusions in the logical structure in the part;

2. The maternal BMI analysis of the cohort study was not enough in the Results. It was suggested to set a time point for maternal BMI before and during pregnancy.

3. The format of Table 4 needs to be revised to meet the requirements of article publication; Table 1-2 has too many entries and needs to be re-integrated and revised;

4. Figures 1-4 should be illustrated with brief annotations;

5. The limitations of the paper need to be explained in detail;

6. The conclusion of the paper did not match the title, so the conclusion should be written around the center of the paper.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

12 Sep 2019

[PONE-D-19-21680] - [EMID:49f54e1ae9a6df0f]

After comments of the reviewers, we have shortened the title which is now:

Increased BMI has a linear association with late-onset

preeclampsia: a population-based study

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Verified

2. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

We did not understand at first, we will send all the anonymized calculations

3. Please include a separate caption for each figure in your manuscript.

Figures will be added separately in TIFF format

4. Please upload a copy of Figure 5, to which you refer in your text on page 8. If the figure is no longer to be included as part of the submission please remove all reference to it within the text.

It was a typing mistake, in fact it is Figure 4, corrected

****************************************************************************

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: In this paper, authors did a 18 year-observational cohort study to analyse the parameters related with EOP and LOP and compared their different effects on these two preeclampsia. It is a relatively comprehensive research based on so large number of cases. And authors got the interesting findings that increment of 5 years for maternal age rising and incidence of preeclampsia were strictly parallel for EOP and LOP, while increment of 5kg/m² for BMI was only associated with LOP. That can give us some clues on the different mechanism of EOP and LOP.

There are some problems need to be modified:

1, In the method, authors quoted the levels of maternity, like level 1, level 3, but didn't give some background of the definition of the levels for maternity. They need introduce the division of levels.

Sentences have been added page 4 (in blue in the text):

“Level 1 maternities are allowed to manage pregnancies after 35 weeks of gestation, without severe risk factors (preeclampsia, multiple pregnancies, in utero fetal deaths, medical termination of pregnancies, complicated gestational diabetes). Level 2 maternities are allowed to manage deliveries of 33 weeks onward; there are never been level 2 maternities in South-Reunion. Level 3 maternities take care of all pregnancies delivering after 21 weeks gestation and all complicated pregnancies (see level 1 exclusions).

Pregnancies are well followed (an average of 9 prenatal visits and 4 ultrasonographies. The mean gestational age at first (“datation”) ultrasonography being 11 weeks.”

2, In the findings, authors found that increment of 5 (years for age, 5kg/m² for BMI) rising maternal ages and incidence of preeclampsia were strictly parallel for EOP and LOP, while increment of BMI was only associated with LOP. It is hard to understand when put 5kg/m² for BMI with 5 years for age to explain the relationship between maternal ages and incidence of preeclampsia. It would be better if they put the information of 5kg/m² for BMI down when concluded that BMI was only associated with LOP.

Increments by 5 years of age, and by 5 kg/m² indeed look similar on the graphs and therefore may be confusing. We have added in the different figures clearly in abscissa years of ages or kg/m².The statistical comparison using 5-unit intervals (BMI and years of age) allows to evaluate more homogeneous data than continuous variables with lower intergroup variability.

Further, we have added in Table 3 a Logistic bivariate regression analysis between maternal ages and pre-pregnancy BMI showing their respective interactions. We have added, page 7 the sentence:

“Also Table 3 shows the bivariate interaction between maternal ages and BMI both together. Adjusted Odds ratios for maternal ages and BMI are similar in EOP women (1.035 [1.02-1.05], 1.039 [1.03-1.05] respectively. This is not the case for LOP: aOR for maternal ages is 1.015 [1.006-1.024] while it raises at 1.056 [1.05-1.06] for maternal pre-pregnancy BMI. In all preeclamptic women, there is a higher increment for BMI, aOR 1.05 (i.e. an increment of 5% for each increment of 5kg/m²) than for maternal ages aOR 1.03 (an increment of 3% for each increment of 5 years of age). But this effect is concentrated only in LOP. Fig 1-2 and Fig 4 show geometrically that indeed, in one case (pre-pregnancy BMI) the two curves diverge by an angle of ap. 30°, while it is a parallel rise when we consider maternal ages”.

3, Some abbreviations, like LDW, VLDW, GDM, ppBMI need to write their full names when first using them in this manuscript: corrected page 4

And authors should make the whole paper be more organised.

The introduction and the conclusions have been completely re-written (in blue in the revised text)

Reviewer #2: Pierre-Yves Robillard et al. investigated the effect of BMI (body mass index) on EOP (early onset preeclampsia) vs LOP (late onset) by a long term observational cohort study. And they found that increment of maternal BMI was only associated with LOP during pregnancy. This was a great job. However, there were some issues in the manuscript.

And the suggestion of the manuscript followed:

1. The authors did not highlight the significance of BMI for preeclampsia such as EOP or LOP in the introduction, and there was some confusions in the logical structure in the part;

The introduction and the conclusions have been completely re-written (in blue in the revised text)

2. The maternal BMI analysis of the cohort study was not enough in the Results. It was suggested to set a time point for maternal BMI before and during pregnancy.

All data are pre-pregnancy BMI. The study focuses on pre-pregnancy BMI only, not on weight gain during pregnancy. We have added in material and methods, page 5 the sentence:

“Pre-pregnancy BMI (ppBMI),was calculated on the recalled pre-pregnancy weight by patients themselves in the majority of cases, controlled by the booking weight at first visit (average 6-8 weeks), always written down in the maternity booklet.”

3. The format of Table 4 needs to be revised to meet the requirements of article publication; Table 1-2 has too many entries and needs to be re-integrated and revised

- Table 1-3 have been deleted and replaced by a synthetic Table which is now Table 1.

- Table 4 (logistic regression analysis), now Table 2 and 3 have been revised to meet the requirements

Figures 1-4 should be illustrated with brief annotations.

We have added in the different figures clearly in abscissa years of ages or kg/m².

5. The limitations of the paper need to be explained in detail;

The paragraph is the last one of page 10 (in blue in the text)

6. The conclusion of the paper did not match the title, so the conclusion should be written around the center of the paper.

THE TITLE has been highly shortened and is now:

Increased BMI has a linear association with late-onset preeclampsia: a population-based study

The introduction and the conclusions have been completely re-written (in blue in the revised text)

________________________________________

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

25 Sep 2019

PONE-D-19-21680R1

Increased BMI has a linear association with late-onset

preeclampsia: a population-based study

PLOS ONE

Dear Dr. Robillard,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

We would appreciate receiving your revised manuscript by 10/25/2019. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.

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Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Linglin Xie

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This article analyzed the relationship between BMI and LOP or EOP. And can give us some useful information from the conclusion.

Reviewer #2: Although the tables had been revised according to the reviewer's opinions, there are still some problems in the format, which do not meet the requirements of publication. It is suggested that the author read the form requirements of this journal carefully.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

27 Sep 2019

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

________________________________________

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

________________________________________

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This article analyzed the relationship between BMI and LOP or EOP. And can give us some useful information from the conclusion.

Reviewer #2: Although the tables had been revised according to the reviewer's opinions, there are still some problems in the format, which do not meet the requirements of publication. It is suggested that the author read the form requirements of this journal carefully.

We have carefully made changes in Table 1 and Table 2 (in red in the manuscript track changes). We hope that the modifications fit with the Plos requirements

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

Submitted filename: Answer reviewers 2.docx

Click here for additional data file.

2 Oct 2019

Increased BMI has a linear association with late-onset

preeclampsia: a population-based study

PONE-D-19-21680R2

Dear Dr. Robillard,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

With kind regards,

Linglin Xie

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

8 Oct 2019

PONE-D-19-21680R2

Increased BMI has a linear association with late-onset preeclampsia: a population-based study

Dear Dr. Robillard:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Linglin Xie

Academic Editor

PLOS ONE