University of Groningen Hypertensive disorders of pregnancy Pereira Bernardes, Thomas Patrick Custodio Heinrich

Hypertensive disorders of pregnancy

Pereira Bernardes, Thomas Patrick Custodio Heinrich

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10.33612/diss.99788387

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Pereira Bernardes, T. P. C. H. (2019). Hypertensive disorders of pregnancy: occurrence, recurrence, and

management. University of Groningen. https://doi.org/10.33612/diss.99788387

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GENERAL INTRODUCTION

In science it often happens that scientists say, “You know that’s a really good argument; my position is mistaken,” and then they actually change their minds and you never hear that old view from them again. They really do it. It doesn’t happen as often as it should, because scientists are human and change is sometimes painful. But it happens every day.

- Excerpt from “The burden of skepticism”, Carl Sagan

Hypertensive disorders of pregnancy

Of the estimated 213 million pregnancies that occur worldwide annually, hypertensive

disorders are present in 3 to 10%.

_{These disorders remain important causes of maternal}

and perinatal morbidity and mortality. It is estimated that 14% of maternal deaths as well as

up to 10% of stillbirths can be attributed to hypertensive disorders.

_{This thesis describes}

studies that focus on their prevention and management.

Hypertensive disorders of pregnancy are classified under four major categories: gestational

hypertension, eclampsia, chronic or preexisting hypertension and superimposed

pre-eclampsia.

_{Figure 1 provides an outline of their worldwide distribution.}

Figure 1. Worldwide distribution of hypertensive disorders of pregnancy. Reproduced with permission (Khan

KS et al 2006)11

Pre-eclampsia is defined as the development of new onset arterial blood pressure levels

equal or above 140 mmHg systolic or 90 mmHg diastolic measured twice with a minimum

interval of 4 hours between measurements, after completion of 20 weeks of gestation with

1

either proteinuria (300mg/dL or more in a 24h sample, a protein/creatinine ratio of 0.3

or more, or a dipstick reading of 2+ if quantitative methods are not available) or severe

features present (American College of Obstetrics and Gynaecology 2019, Table 1).

Pre-eclampsia has a prevalence of 3 to 5% and it is more common in the 1st pregnancy, with

prevalences approximately twice higher than that of subsequent pregnancies.

_The

presence of severe features or early onset of presentation, i.e. before 34 weeks, increases

morbidity and mortality risks.

_{Progression to eclampsia, the occurrence of grand mal}

seizures inexplicable by a more compelling neurological cause, may occur in 0.6% of women

who present pre-eclampsia with severe features despite magnesium sulfate prophylaxis.

Differences in availability of magnesium sulfate may partly explain the wide difference

in eclampsia prevalence found in the comparison between developing and developed

countries, range of 90—157 and of about 6 in 10,000 pregnancies, respectively.

_{It is of}

note though that the relative proportion of maternal deaths attributable to hypertensive

disorders in developing and developed regions is comparable at 14 and 12.9%, respectively.

Table 1. Severe features of hypertensive disorders of pregnancy - ACOG 201912

a. Systolic blood pressure of 160 mm Hg or more, or diastolic blood pressure of 110 mm Hg or more on two occasions at least 4 hours apart (unless antihypertensive therapy is initiated before this time);

b. Thrombocytopenia (platelet count less than 100,000 x 109_/L);

c. Impaired liver function as indicated by abnormally elevated blood concentrations of liver enzymes (to twice the upper limit normal concentration), and severe persistent right upper quadrant or epigastric pain unresponsive to medication and not accounted for by alternative diagnoses;

d. Renal insufficiency (serum creatinine concentration more than 1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of other renal disease);

e. Pulmonary edema;

f. New-onset headache unresponsive to medication and not accounted for by alternative diagnoses;

g. Visual disturbances.

Gestational hypertension is defined by the new onset arterial blood pressure levels equal

or above 140 mmHg systolic or 90 mmHg diastolic measured twice with a minimum interval

of 4 hours between measurements, after completion of 20 weeks of gestation without

proteinuria or severe features.

The prevalence in nulliparous women ranges from 6 to 17% and, as with pre-eclampsia, it is

less common in multiparous women who present a prevalence between 2 and 4%.

_Up

to half of the women who present gestational hypertension may progress to pre-eclampsia,

with higher rates of deterioration being associated with earlier onset of hypertension during

the pregnancy.

_{The absence of proteinuria does not preclude progression to adverse}

outcomes as there are reports of increased perinatal mortality, thrombocytopenia and liver

dysfunction in women with nonproteinuric hypertension.

Chronic or preexisting hypertension is characterized as hypertension diagnosed preceding

the pregnancy, or hypertension present at a minimum of two evaluations before completion

of 20 weeks of gestation, or hypertension that persists longer than 12 weeks postpartum.

In the latter case, a previous diagnosis of gestational hypertension is updated to reflect its

chronicity. Estimates to its prevalence in pregnancy vary from 0.9% up to 5%.

_{Progressively}

higher maternal ages and rates of obesity are reflected in an increase of 67% in the period

of 2000 to 2009 in the prevalence of chronic hypertension during pregnancy in the US.

Although most women who present chronic hypertension have uncomplicated pregnancies,

some cases progress to hypertensive crises that are difficult to control, increasing maternal

and neonatal risks.

_{Low birthweights, preterm births as well as perinatal mortality are}

more common in pregnancies complicated by chronic hypertension.

Finally, women with chronic hypertension may experience

superimposed pre-eclampsia,

which involves new onset proteinuria or end-organ dysfunction characterized by severe

features after completion of 20 weeks of gestation. Rates of progression to superimposed

pre-eclampsia are estimated to be up to 20 to 50%.

_{Maternal and fetal outcomes}

in superimposed pre-eclampsia tend to be more severe when compared to outcomes in

pregnancies complicated by either pre-eclampsia or chronic hypertension alone.

Complications associated with hypertensive disorders in pregnancy

Incomplete or dysfunctional spiral artery remodeling that culminates in diminished blood

flow to the fetus provides the pathophysiological link between hypertensive disorders of

pregnancy – early onset pre-eclampsia in particular – and

intrauterine growth restriction

(IUGR).

_{About a third of pregnancies complicated by pre-eclampsia are also affected by}

IUGR.

_{Fetal distress, impaired immune function, cerebral palsy, cardiovascular disease and}

perinatal mortality risks are all increased in pregnancies complicated by intrauterine growth

restriction. Neonatal hypoglycemia and polycythemia are increasingly more frequent with

greater growth restriction.

_{Conditions such as aneuploidies, congenital infections, and}

some umbilical cord are also associated with intrauterine growth restriction and need to be

considered as possible causes or aggravating factors.

Pregnant women that present

HELLP syndrome, i.e., hemolysis, elevated liver enzymes, and

1

disorders of pregnancy. Although there is some controversy in the inclusion of HELLP

syndrome as a distinct entity within the spectrum of hypertensive disorders, it is undisputed

that the vast majority of women who develop this serious complication also present with

hypertension, proteinuria or both.

The usual although not consensual diagnostic criteria are: lactate dehydrogenase (LDH)

equal or over 600 IU/L, aspartate aminotransferase (AST) and alanine aminotransferase

(ALT) higher than twice the normal upper limit of the particular test used and platelet count

below 100,000 x 10

_{/L. Progression to HELLP syndrome increases the risks of mortality and}

of serious maternal complications such as placental abruption, disseminated intravascular

coagulation, pulmonary edema, and also the need for blood products transfusion.

HELLP syndrome is also associated with lower birthweights and increased rates of stillbirth

when compared to pregnancies complicated by pre-eclampsia only. As progression to HELLP

syndrome after 34 weeks of gestation prompts immediate delivery by current guidelines,

long and short-term risks associated with preterm birth are also elevated. The associated

perinatal mortality rates range from 7.4% to 20.4%, the latter being associated with earliest

preterm deliveries.

Prevention of hypertensive disorders of pregnancy

Considerable effort has been put forth in the search for preventive interventions that

may benefit women at risk of hypertensive disorders of pregnancy. Supplementation with

calcium, folic acid, vitamins E and C and the use of aspirin were all promising candidates,

with plausible biological mechanisms. Although beneficial effects were found in small

studies most of them were later found to be of either limited or no benefit.

_Exceptions

are calcium and aspirin, which are now part of standard antenatal care focused on the

prevention of hypertensive disorders of pregnancy for specific groups of women.

In 2013 the WHO released a guideline that recommends

calcium supplementation for

the prevention of pre-eclampsia, in particular to women at high risk of hypertension, in

populations with low calcium intake.

_{This recommendation was based on a 2010}

meta-analysis of 13 trials, updated in 2018 without inclusion of new trials, that showed

pre-eclampsia risk was halved and gestational hypertension risk reduced by 35% with high-dose

calcium supplementation. However, the authors of the meta-analysis recommend caution

in the interpretation of these large effects. They suggest that potential small-study effect

or publication bias may have occurred, in view of funnel plot asymmetry. Moreover, a

considerably smaller 8% pre-eclampsia risk reduction with a confidence interval that crossed

unity was observed in the largest study included.

Aspirin use to prevent pre-eclampsia has now been extensively studied, with more than

18,000 women over 16 trials included in a 2018 meta-analysis.

_{Authors found it reduced}

preterm pre-eclampsia risk by 38% but also that there was no effect on the risk of term

pre-eclampsia. Administration should be started at the latest in the 16th week of gestation

in women who are at high-risk for pre-eclampsia. There is no current consensus on what

constitutes this high-risk group. Current guidelines have so far resorted to listing known

risk factors and recommend aspirin use either in the presence of a single factor highly

associated with pre-eclampsia, such as occurrence in a previous pregnancy, or a combination

of two or more moderate risk factors, such as nulliparity and BMI over 30. Figure 2 shows

a comparison of pre-eclampsia occurrence rates in women presenting with and without

numerous risk factors.

Figure 2. Risk of pre-eclampsia among women with and without individual clinical risk factors determined

by 16 weeks’ gestation.

IUGR: intrauterine growth restriction; SLE: systemic lupus erythematosus; ART: assisted reproductive technology; BMI: body mass index; aPL: antiphospholipid antibody syndrome. Reproduced with permission (Bartsch 2016)69_.

Management

Although the use of anti-hypertensive drugs and magnesium sulfate in the management of

hypertensive disorders of pregnancy is critical for the reduction of morbidity and mortality

risks, the only definitive treatment is delivery of child and placenta.

_{However, maternal}

1

are potentially more severe if hypertension occurs away from term as its management may

involve delivery and consequently result in preterm birth, increasing rates of respiratory

distress syndrome, intraventricular hemorrhage and neonatal mortality.

_Furthermore,

induction of labor was long held to be associated with an increased risk of cesarean section

although recent meta-analyses of randomized clinical trials have shown otherwise.

_The

alternative of delaying delivery is not a solution as extending a pregnancy complicated by

hypertensive disorders increases maternal morbidity and mortality risks.

The dilemma posed by increased maternal and neonatal risks in both delivering too soon

or too late suggests that an optimal timing may exist. Several randomized controlled trials

have evaluated management strategies for hypertensive disorders of pregnancy covering

different gestational age ranges and different subgroups.

_{The succession of the trials that}

were performed so far should be viewed in the light of developing evidence over the last 15

years. Uncertainty regarding the effectiveness and potential harm of the intervention, also

regarding an unwanted potential increase of cesarean sections, prompted ethical concerns.

Because of this, researchers independently approached these challenges in a gradual way.

To circumvent the problem of the rarity of severe adverse neonatal and maternal outcomes

associated with high mortality rates or long-term morbidity, which would require large

sample sizes, composite adverse outcomes were constructed for the individual trials.

Although initially informative, with time the need arose for more conclusive evidence for

specific rare outcomes and for subgroup analyses in this diverse but interrelated group of

disorders.

The

HYPITAT trial randomized 756 women between October 2005 and March 2008 with

gestational hypertension or pre-eclampsia without severe features and a gestational

age from 36 weeks to either immediate delivery or expectant management, choosing at

the start not to include women with chronic hypertension or earlier gestational ages.

To tackle the rarity of very severe outcomes, the chosen primary outcome measure was

a composite consisting of maternal mortality, eclampsia, HELLP syndrome, pulmonary

edema, thromboembolic disease, placental abruption, major post-partum hemorrhage or

progression to severe hypertensive disease (systolic blood pressure 170 mmHg, diastolic

blood pressure 110 mmHg, or proteinuria 5 g per 24 h).

The

“Deliver or Deliberate” trial focused instead on pre-eclampsia only, which resulted in a

predictable longer recruitment period (March 2002—June 2008) and a smaller recruitment

target of 220 women. Women presenting pre-eclampsia with gestational ages of 34+0 – 36+6

weeks were randomized to immediate delivery or expectant management until 37 weeks.

Results favored delivery because of lower rates of progression to severe pre-eclampsia with

no significant difference in neonatal morbidity.

Superimposed pre-eclampsia was studied by Hamed et al. by randomization of pregnant

women with mild to moderate chronic hypertension recruited between 24-36 weeks. This

trial compared planned delivery at 37 weeks to expectant management until spontaneous

labor, completion of 41 weeks of gestation, or development of superimposed pre-eclampsia

without severe features after the 37

_{week of gestation or with severe features at any time.}

They found no significant differences in maternal outcomes, but more NICU admissions and

unsurprisingly smaller babies in the planned delivery group

_.

Finally, the

HYPITAT II trial followed the same design of “Deliver or Deliberate” but allowed

for the inclusion of women presenting with gestational hypertension in addition to those

presenting with pre-eclampsia. Women were randomized between 34 and 36+6 weeks of

gestation to immediate delivery or expectant management until planned delivery at 37

weeks of gestation. Immediate delivery showed a not significant tendency towards less risk

of maternal complications whereas respiratory distress syndrome risk was increased. The

authors concluded that results favored a policy of expectant management up until 37 weeks

of gestation or until the clinical situation deteriorates.

1

OUTLINE AND AIM OF THIS THESIS

The body of work composing this thesis was directed towards two main aspects of

hypertensive disorders of pregnancy: their prevention and their management. However

unclear the extent of the prevention potential of aspirin, it is now well established that

women at high risk of developing hypertensive disorders benefit from its early introduction

in pregnancy. Nonetheless, the uncertainty regarding what exactly constitutes this high-risk

group naturally leads to the question of whether more women would benefit from this

intervention if a better evaluation of their individual risk profile could be established. The

first part of this thesis focuses on providing evidence that contributes towards this goal.

This part is comprised of

Chapters 2 and 3, with both studies based on large

population-based cohort Dutch registry data. In

Chapter 2, the impacts of max diastolic arterial pressure

and gestational age at delivery in the first pregnancy were evaluated as risk factors for

the occurrence and recurrence of pre-eclampsia in the following pregnancy.

Chapter 3 is

focused on the relationship between pre-eclampsia and delivery of small for gestational age

infants across subsequent pregnancies.

The second part of this thesis uses randomized controlled trial data to tackle the dilemma

of optimal delivery timing for women that have a potential indication for delivery in two

scenarios. First,

Chapter 4 doubles as a call-to-arms highlighting the value of individual patient

meta-analyses (IPDMA) and as a protocol for their use in the study of the management of

hypertensive disorders of pregnancy near term.

Chapter 5 describes the IPDMA itself, which

encompasses all available trial data that has so far been generated. Second, in so far as

timely delivery may be beneficial in preventing maternal morbidity for women presenting

with hypertensive disorders at term,

Chapter 6 shows if for women with low Bishop scores

any potential benefits are countered by potential increases in cesarean section and neonatal

morbidity rates.

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1

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