Reproductive Sciences
1-13
Adolescent Preeclampsia: Pathological ª The Author(s) 2018
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Drivers and Clinical Prevention DOI: 10.1177/1933719118804412
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Abstract
Preeclampsia is an important cause of maternal and perinatal morbidity, especially in first-time pregnant adolescent women. Although
prevention of preeclampsia has been attempted for many decades, effective intervention can only be achieved upon the full eluci-
dation of the risk factors and mechanisms of disease. As the pathogenesis of preeclampsia during adolescence may differ from that in
older women, preventive interventions should be tailored accordingly. During adolescence, 4 putative drivers of preeclampsia can be
identified. First, uterine immaturity in very young teenagers is likely a major cause of defective deep placentation and adverse
reproductive outcome, underscoring the importance of educational programs and public health initiatives focused on teen pregnancy
prevention. Second, the association between adolescent obesity and preeclampsia merits further studies on the benefits of weight
loss and dietary interventions to improve pregnancy outcome. Third, there is a need for greater awareness of the link between
cardiovascular risk factors in young women and early-onset preeclampsia associated with atherosclerosis of the uteroplacental
arteries. Finally, infrequent menstruations may prolong uterine immaturity because of lack of “menstrual preconditioning.” This risk
factor may be amenable to pharmacological/hormonal preconditioning prior to conception.
Keywords
preeclampsia, hypertension, adolescent pregnancy, obesity, progesterone resistance, defective deep placentation, cardiovascular
disease risk, preterm birth
Figure 1. Forest plots of adjusted odds ratios of preeclampsia and preterm birth in adolescents stratified by age. The y-axis indicates the
frequency of preeclampsia (left panel) or preterm birth (right panel) in each age group. The age range of control patients in the studies of
Leppalahti et al, Blomberg et al, and Kawakita et al was 25 to 29, 25 to 29, and 20 to 24.9 years, respectively.
studies on uterine development and maturation led us to con- First-time pregnant adolescent girls are at increased risk of
clude that the pathological triggers of PE in adolescents may obstetrical disorders, including preterm birth (PTB) and PE
differ from that in adult women.7 Since the consequences of a (Figure 1). For example, a recent population-based epidemio-
pathological pregnancy are especially troublesome for logical study by Leppalahti et al in Finland found that the
teenage girls, we expand here on the biological processes that youngest group of teenagers (13-15 years) is at increased risk
make adolescence a vulnerable developmental period for of PE and PTB compared to 16-year-olds.12 The study con-
pregnancy and explore which preventative interventions cluded that the younger the expectant mother, the greater the
should be considered to mitigate the risk of poor reproductive risks of neonatal and maternal complications, including PE.
outcome in young and very young women. Another study carried out in a tertiary center in Greece showed
significantly higher incidence rates of PTB, preterm premature
rupture of the membranes, PIH, and PE among teenage mothers
Adolescent Pregnancy and Risk of PE aged 12 to 19 years.13 The authors stressed that obstetricians
The global adolescent birth rate has declined from 65 births per should be aware of these increased risks in order to improve
1000 women in 1990 to 47 births per 1000 women in 2015.8 obstetrical outcome of childbearing teenagers. A retrospective
Although these figures suggest overall progress, the overall investigation from Turkey and a prospective study from India
population of adolescents continues to grow and projections also reported a higher incidence of PE in young first-time
indicate that the number of adolescent pregnancies will mothers, aged 12 to 19 and 13 to 19 years, respectively.14,15
increase globally by 2030, with the greatest proportional Further, Kawakita et al reported a retrospective cohort study
increases in first-time pregnant adolescent women in Africa.9 from 19 hospitals in the United States with 43 537 first-time
Adolescent pregnancy is not a problem confined to low- and pregnancies in women younger than 25 years, which included
middle-income countries. For example, in the United States 1189 young adolescents (age <16 years), 14 703 older adoles-
alone, a total of 229 715 babies were born in 2015 to women cents (age 16-19.9 years), and 27 645 young adults (age 20-
aged 15 to 19 years, for a birth rate of 22.3 per 1000 women in 24.9 years). Again the authors found that young adolescents are
this age-group.10 Although the rates are declining across all at increased risk of a range of adverse pregnancy complica-
ethnic groups in the United States, they still remain much tions, including PE and PTB.16 On the other hand, Blomberg
higher compared to many other developed countries. In the et al found no increased risk of adverse neonatal outcome in
European Union, the United Kingdom continues to have a high teenagers, except for PTB before 32 weeks.17 In this Swedish
birth rate in 15- to 17-year-olds (6.8 per 1000), especially when study, very young teenagers were grouped with the older teen-
compared to countries such as Denmark (1.1 per 1000) or the agers, which may have masked the effect of age on the inci-
Netherlands (1.3 per 1000).11 dence of PE.
Brosens et al 3
in pregnancy is not yet known, sufficient progenitor cells are Uterine Maturation and Spontaneous Decidualization
arguably essential to ensure that the endometrium has the
During childhood, the uterus remains an immature organ, both
adaptive capacity (ie, plasticity) for rapid expansion in preg-
physically and in terms of hormone responsiveness, as outlined
nancy and to accommodate trophoblast-mediated spiral
previously.21 Maturation commences some years before the
artery remodeling.43
menarche with marked uterine growth in response to rising
In view of the multitude of functions exerted by decidual
estradiol levels. The onset of regular ovulatory menstrual
cells, perturbations in this differentiation process may not only
cycles sometime after the menarche could be considered as
render the fetomaternal interface vulnerable to various stres-
evidence of uterine maturity. The term “perimenarche” has
sors but also compromise vascular remodeling in pregnancy.
been coined to describe this lag period between the menarche
A recent study provided direct evidence of impaired decidua-
and the onset of regular ovulatory menstrual cycles.51 The
lization in PE. Using laser microdissection to isolate the perimenarcheal stage varies tremendously; it may be as short
decidua from tissue sections of the fetomaternal interface, as a few months or as long as 5 years or more.21 This variability
Garrido-Gomez et al demonstrated that decidual gene expres- is explained by the fact that regular cycles depend on conver-
sion is profoundly abnormal in preeclamptic pregnancies.44 gence of 2 processes: (1) establishing robust feedback loops
Furthermore, the authors examined the decidualization poten- that control the hypothalamic–pituitary–ovarian (HPO) axis
tial of cultured endometrial cells isolated from biopsies follow- and (2) acquisition of endometrial responsiveness to progester-
ing a normal or preeclamptic pregnancy. Based on the severely one signaling and other deciduogenic cues. Socioeconomic
blunted secretion of prolactin and insulin-like growth factor factors and metabolic variables, such as nutritional status and
binding protein 1 in primary cells differentiated in culture, the body mass index (BMI), exert a strong influence on the matura-
authors concluded that decidualization defects in the endome- tion of the HPO axis.52 This raises the possibility that metabolic
trium may persist for many years after an affected pregnancy.44 disorders, especially child obesity, cause asynchrony between
the maturation processes in the uterus and HPO axis, thus
increasing the likelihood of a pregnancy occurring in an as yet
Intrinsic Decidual Resistance immature uterus.21
Under a progesterone-dominant environment, endometrial
A blunted response of primary endometrial stromal cells to cellular “stress” has emerged as an evolutionary conserved,
deciduogenic signals is not specific to PE. The same phenom- obligatory trigger for decidualization.53 For example, scratch-
enon, commonly referred to as “progesterone resistance,” ing the endometrium in progesterone-primed mice, or exposure
has been associated with various reproductive disorders, most of the uterine lumen to an oil drop, is sufficient to trigger a
prominently endometriosis. 45 It has been argued that massive decidual response.54,55 Furthermore, neonatal uterine
“progesterone resistance” is a misnomer as these endometrial bleeding is more prevalent following preeclamptic or postterm
stromal cells are also unresponsive to other essential cues for pregnancies,56,57 indicating that in utero stress also sensitizes
decidualization, including cyclic adenosine monophosphate the fetal endometrium to decidualization. A recent study high-
(cAMP) signaling and human chorionic gonadotropin.46,47 Fur- lighted the importance of rapid estradiol-mediated growth and
ther, the term “progesterone resistance” implies that “normal” proliferation stress prior to ovulation on the sequence of events
endometrial stromal cells are intrinsically progesterone respon- after ovulation that renders the endometrium receptive to
sive but lose this ability under pathological conditions. In fact, embryo implantation during the midluteal phase of the cycle.58
the opposite is true; human endometrial cells are not innately Following menstruation, rapid proliferation not only increases
responsive to differentiation signals but acquire the ability to the endometrial thickness multifold over in approximately 10
decidualize at some point following the menarche.21,48 The days but also imparts replication stress on some but not all
most compelling evidence for intrinsic or ontogenetic stromal cells. After the ovulatory rise in circulating progester-
“decidual resistance” of human endometrium at birth has come one levels, increasing intracellular cAMP levels in endometrial
from an autopsy study published by Ober and Bernstein in stromal cells impose a cell cycle block at G0/G1. Cell cycle
1955.49 Despite exposure to very high concentrations of exit is a prerequisite for differentiation. However, prestressed
unbound estrogens and progesterone in utero, Ober and Bern- stromal cells do not differentiate into specialized decidual cells
stein found that the endometrium was either inactive or weakly but instead undergo acute cellular senescence (Figure 3).
proliferative in 68% of neonates and term fetuses. Evidence of Unlike chronic senescence associated with aging, acute senes-
secretory changes in the glandular compartment was observed cence is a tightly orchestrated biological process implicated in
in 27% of cases, but the incidence of decidual or menstrual wound healing, tissue repair, and development.59 Typically,
changes was only 5%. These findings are corroborated by the acute senescent cells secrete tissue-specific inflammatory med-
observation that overt neonatal uterine bleeding affects approx- iators with defined paracrine functions and self-organize their
imately 4% to 5% of female babies during the first week of elimination by various immune cells. This is also the case in the
life.50 Thus, the human endometrium can already be responsive human uterus; acutely senescent endometrial cells during the
to deciduogenic signals at birth, but in the vast majority of midluteal phase mount a transient inflammatory response that
newborn girls, it is not. renders the human endometrium receptive for implantation.60
Brosens et al 5
Figure 4. Schematic illustrating the production of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) via the nutrient-sensing hexosa-
mine biosynthetic pathway (HBP) in decidualizing endometrial stromal cells and subsequent protein O-GlcNAcylation by EOGT (EGF domain-
specific O-linked GlcNAc transferase; left). The EOGT controls the expression of the peptide hormone adropin, which promotes indices of
vascular health including migration, angiogenesis, and proliferation in endometrial endothelial cells (top right) of the emerging spiral arteries
(bottom right). Fructose-6-P indicates fructose 6-phosphate; glucosamine-6-P, glucosamine 6-phosphate; N-acetylglucosamine-6-P, N-acetyl-D-
glucosamine-6-phosphate; OGA, O-GlcNAcase; O-GlcNAC, O-linked b-N-acetylglucosamine; OGT, O-linked b-N-acetylglucosamine trans-
ferase; UDP-GlcNAc, uridine diphosphate N-acetylglucosamine; uNK, uterine natural killer.
glucose with amino acid-derived amine, lipid-derived acetyl, 60 years later, a Cochrane review of 49 randomized controlled
and the nucleotide uridine, thus sampling all core cellular meta- trials involving 11 444 women yielded high-quality evidence,
bolism in the process (Figure 4). The EOGT uses UDP-GlcNAc confirming that diet, exercise, or both during pregnancy are
to modify specific cell surface and proteins earmarked for effective in lowering the risk of excessive GWG, in reducing
secretion. Strikingly, knockdown of EOGT in decidualizing the incidence maternal hypertension, and in improving preg-
endometrial stromal cells abolishes the expression of adropin,39 nancy outcome, particularly in high-risk women.72
a recently discovered peptide hormone that promotes various
indices of vascular health, including endothelial cell prolifera-
tion, migration, and angiogenesis.68 By suppressing monocyte– Transgenerational Hypertension and Early-Onset CVD
endothelial cell adhesion, adropin also exerts important anti- In the absence of physiological spiral artery remodeling, the JZ
atherosclerosis actions.69 Expression of EOGT and adropin in uterine vessels are prone to developing acute atherosis, char-
midluteal endometrial biopsies correlates inversely with BMI, acterized by changes in lipid metabolism, intravascular inflam-
suggesting a direct pathway that links obesity to uteroplacental mation, macrophage infiltration, and endothelial cell
disease in pregnancy.39 Moreover, low circulating adropin lev- dysfunction.73 The term “atherosis” refers to vascular disease
els have been associated not only with high BMI, insulin resis- at the fetomaternal interface in PE. When affecting the JZ
tance, endothelial dysfunction, and coronary atherosclerosis arteries, these lesions are indistinguishable of atherosclerosis,
but also with severe PE.70,71 the primary driver of CVD. Autopsy studies on young people
Thus, the incontrovertible link between obesity and PE who died of accidental causes established that atherosclerosis
should provide additional impetus to implement public health begins as early as 10 years of age.74 By the age of 15, a majority
measures and educational programs to tackle the current epi- of adolescents have evidence of early atherosclerotic lesions
demic. In pregnancy, the focus should be on strict prevention of and subsequent progression is determined by the conspicuous
excessive GWG—as advocated by Hamlin in 1952.2 More than determinants of cardiovascular health: BMI, non–high-density
Brosens et al 7
interventions that mitigate the risk of PE and other obstetrical medroxyprogesterone acetate or norethisterone) for a period
disorders in young mothers, whether or not the pregnancy was of time prior to conception, to mitigate the risk of placental
planned. In addition to tackling comorbidities (obesity and disorders in pregnancy and improve long-term health out-
other cardiovascular risk factors) as already outlined, there is comes for both the mother and her baby.
a need to reflect on the role of drug interventions, either prior to
pregnancy to accelerate uterine maturation or in pregnancy to
reduce the risk of adolescent PE.
Drug Prevention in Pregnancy
Since the publication of the first clinical trial in 1985,4 aspirin
has become the drug of choice for the medical prevention of
Pharmacological Preconditioning PE. However, its efficacy has been debated ever since. More
Compared to other organs, the adult uterus is unique in many than a decade after the initial successful trials, Sibai pointed out
aspects: It is imbued with seemingly unlimited capacity to that while early single-center trials demonstrated an average
regenerate and repair, it is capable of accommodating a semi- reduction of PE of 70% with low-dose aspirin, 7 large multi-
allogenic conceptus without triggering immune rejection, and it center trials (>27,000 women) showed minimal benefit.91 A
can form, repeatedly, an uteroplacental vascular tree that systematic review and meta-analysis published in 2010 seemed
accommodates *20% of cardiac output by late pregnancy. to settle the debate.92 Based on analysis of 34 randomized
As outlined before, none of these critical uterine functions are controlled trials, the study concluded that low-dose aspirin
programmed at birth but acquired gradually after the onset of started at 16 weeks or earlier significantly reduces the risks
cyclic menstruations through a process coined “menstrual pre- of PE (relative risk [RR] 0.47, 95% CI, 0.34-0.65), FGR (RR
conditioning.”20 The term “preconditioning” refers to the para- 0.44, 95% CI, 0.30-0.65), PIH (RR 0.62, 95% CI, 0.45-0.84),
doxical but ubiquitous biological phenomenon that a brief and PTB (RR 0.22, 95% CI, 0.10-0.49). However, low-dose
exposure to a harmful stimulus at a dose below the threshold aspirin was ineffective in preventing either PE or FGR when
for tissue injury provides robust protection against, or tolerance initiated after 16 weeks.92 A subsequent study by the same
to, the injurious effects of a subsequent more severe insult. In team showed that the protective effect of low-dose aspirin is
recent years, different preconditioning strategies (ie, ischemic, dose responsive. Meta-analysis of 45 randomized controlled
pharmacological, remote, and local) have been studied inten- trials with a total of 20 909 pregnant women randomized to
sively because of their promise in preventing ischemia–reper- between 50 and 150 mg of aspirin daily showed that the higher
fusion injury in a variety of organs, including the brain, heart, dosages of aspirin are associated with greater reduction of
kidney, and lung.84,85 At a cellular level, inflammation has both PE and FGR, but only when initiated 16 weeks. 93
been shown to trigger epigenetic memory of injury by main- Another report using individual participant data meta-
taining chromosomal accessibility to key stress response genes, analysis on a larger sample size (32 217 women and 32 819
enabling a more rapid and heightened response to subsequent babies) promptly challenged the assertion that treatment
challenges.86 There is ample clinical evidence of endogenous needs to be initiated early in pregnancy and concluded that
uterine preconditioning after the menarche. As aforemen- low-dose aspirin and other antiplatelet agents consistently
tioned, gynecological age is a better predictor of adverse preg- lower the incidence of PE and its complications, regardless
nancy outcome in adolescent mothers than chronological age.21 of whether treatment is started before or after 16 weeks’
A prior birth confers a strong protective effect against PE, gestation.94 A recent trial highlighted the effectiveness of
whereas a prior induced abortion confers a weaker protective aspirin (150 mg daily) in preventing preterm PE (ie, before
effect.87,88 However, analysis of 20 846 primiparous women 37 weeks of gestation) in women deemed at high risk (based
participating in the Norwegian Mother and Child Cohort algorithm that combines maternal factors, mean arterial pres-
Study demonstrated that the protective effect of 2 prior sure, uterine artery pulsatility index, and maternal serum
induced abortions is similar to that of one birth.89 The latter pregnancy-associated plasma protein A and placental growth
observation is important as it demonstrates the cumulative factor),95 although there is also evidence that aspirin may be
effect of injury on uterine memory and subsequent ability to less effective in women with chronic hypertension.96
cope with hyperinflammation imposed by deep trophoblast Over the past 3 decades, tens of thousands women have been
invasion in pregnancy. randomized in various clinical trials, making aspirin one of the
Recently, we expressed the opinion that young adolescent most intensively studied drug in obstetrics.6 And yet we were
women and patients with polycystic ovary syndrome (PCOS) unable to identify a single study evaluating the efficacy of low-
share a number of reproductive features, including frequent dose aspirin in preventing adolescent PE and other obstetrical
anovulation, infrequent menstrual shedding and repair, per- disorders. While clinical studies may or may not be forthcom-
sistent decidual resistance, and increased risk of defective ing, there are no obvious reasons to assume that vascular adap-
deep placentation as manifested by the higher incidence of tation in pregnancy differs substantially between adults and
major obstetric syndromes.90 We also argued that there is a teenagers. In order words, serious consideration should be
role for pharmacological preconditioning of the uterus in given to the routine use of low-dose aspirin prophylaxis in
these women, either by inducing ovulation (eg, with clomi- first-time pregnant adolescents, especially before the age of
phene citrate) or cyclic withdrawal bleeds (eg, with 16 when the risk of PE and PTB is highest.
Brosens et al 9
It is important to emphasize that that the overall reduction of risk reduction interventions, although such sustained programs
PE with low-dose aspirin is estimated to be 10%,6 rendering it are often considered beyond the scope, as well as financial
imperative that other preventative strategies are developed. means, of many health-care systems.81
Several drugs are currently under evaluation, including metfor- From a biological perspective, the increased incidence of
min,97 pravastatin,98 esomeprazole,99 and sildenafil.100 Need- placental disorders in adolescence, especially very young
less to state that there is insufficient evidence of safety or women, lays bare several aspects of uterine physiology that are
efficacy to recommend usage of these drugs in adolescent preg- virtually unexplored. Concepts such as “uterine immaturity,”
nancies. One exception is metformin, which is increasingly “decidual resistance,” “menstrual preconditioning,” and “acute
used for weight management in children and adolescents. A endometrial senescence” are likely also relevant to the patho-
recent systematic evidence review of the US Preventive Ser- genesis of other intransigent reproductive disorders, including
vices Task Force concluded that the use of metformin in chil- endometriosis.48 A number of common themes underlie that
dren and adolescents results only in very modest reductions in these emerging physiological concepts, including that endome-
BMI (8 trials; n ¼ 616; 95% CI, 1.44 to 0.29), which trial responses to steroid hormones, are determined by the
represents approximately 2% reduction from baseline BMI. cumulative impact of repeated tissue “injury” associated with
Furthermore, pharmacotherapy with metformin in this age- menstruation, miscarriage, and parturition. Another emergent
group (6-19 years) was shown to confer little or no benefit theme centers on prepregnancy origins of obstetrical disorders,
on cardiometabolic parameters, including fasting glucose as illustrated elegantly by recent studies.43,44 Defining the
level.101 Nevertheless, there is evidence that metformin may molecular, epigenetic, and cellular mechanisms underpinning
be effective in optimizing the peri-implantation endometrial uterine maturation and tissue plasticity is a prerequisite for
environment. For example, 3-D power Doppler ultrasonogra- effective preconception interventions that mitigate the risk of
phy has shown that metformin treatment for 6 months signifi- placental disorders in pregnancy. Finally, it is increasingly
cantly increases endometrial thickness, endometrial volume, apparent that the developmental origins of health and disease
and endometrial and subendometrial vascularity indices (vas- hypothesis, based on the influential epidemiological studies of
cularization index, flow index, vascularization flow index) in Baker and Osmond,105 also apply to the uterus. In this respect,
women with PCOS.102 Another study reported that metformin evaluation of neonatal uterine bleeding, which likely reflects a
reduces soluble fms-like tyrosine kinase 1 and soluble endoglin prior fetal uterine stress response, as a putative biomarker of
secretion from primary endothelial cells, villous cytotropho- poor reproductive outcome later in life, is warranted.7,50
blast cells, and preterm preeclamptic placental villous explants,
suggesting a role for this multifaceted drug in the prevention or Authors’ Note
treatment of PE.103 Clinically, the efficacy of metformin in PE All authors significantly contributed to the preparation and write-up of
prevention remains unclear. Although a recent systematic this manuscript.
review and meta-analysis reported that metformin use in preg-
nancy is associated with a nonsignificant reduction of PE (RR: Declaration of Conflicting Interests
0.74, 95% CI, 0.09-6.28), the authors concluded that further
The author(s) declared no potential conflicts of interest with respect to
trials are warranted given the low quality of evidence and the
the research, authorship, and/or publication of this article.
clinical heterogeneity of current data.97
Funding
Perspective The author(s) disclosed receipt of the following financial support for
Globally, teenage pregnancies are more likely to occur in mar- the research, authorship, and/or publication of this article: J.M. and
J.J.B are funded by Tommy’s National Miscarriage Research Centre.
ginalized communities, often driven by poverty, poor educa-
tional attainment, and lack of employment opportunities. In
pregnancy, adolescents have less access to antenatal care than References
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