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Consequences of in-utero exposure to antihypertensive medication: the search for definitive answers continues

Boesen, Erika I.

doi: 10.1097/HJH.0000000000001486
EDITORIAL COMMENTARIES

Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska, USA

Correspondence to Dr Erika I. Boesen, Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, 985850 Nebraska Medical Center, Omaha, NE 68198-5850, USA. Tel: +1 402 559 6055; fax: +1 402 559 4438; e-mail: erika.boesen@unmc.edu

Hypertension during pregnancy is a leading risk factor for maternal and foetal morbidity and mortality, with a recent systematic analysis conducted by the WHO attributing 14% of maternal deaths globally to hypertensive disorders [1]. Estimates of the prevalence of hypertension in pregnancy, irrespective of cause, commonly range from 5 to 10% in Western countries. Hypertension during pregnancy may present in the form of preexisting hypertension, as gestational or pregnancy-induced hypertension (onset after 20 weeks, no proteinuria) or as the more hazardous condition of preeclampsia (onset after 20 weeks with development of proteinuria). Risk factors for hypertension include obesity, which is rising amongst women who go on to become pregnant [2]. Hypertension itself increases the risk of developing preeclampsia [3]. Accordingly, it is likely that the population of pregnant women exhibiting preexisting hypertension or preeclampsia will grow rather than shrink in the coming years.

In addition to immediate health concerns for the mother and unborn child, maternal hypertension may confer long-term, complex effects on physical and behavioural health through foetal programming, with outcomes that may not manifest until later in childhood or even in adult life. For example, in 2009 an analysis of the Helsinki Birth Cohort Study, which included singletons born between 1934 and 1944, provided evidence of a doubling of risk for stroke in offspring of preeclamptic mothers, with heightened stroke risk also found for exposure to gestational hypertension [4]. Intrauterine growth restriction, premature delivery and being born at low birthweight for gestational age are all associated with maternal hypertension, particularly with preeclampsia. Although not specific to hypertensive disorders of pregnancy, these markers of an adverse intrauterine environment have been associated with increased risk of later development of hypertension [5], cardiovascular disease [6], chronic kidney disease [7] and metabolic disorders [8]. Reduced nephron endowment has been proposed as a possible contributing factor to some of these outcomes [9], although additional mechanisms no doubt also contribute and require further investigation. Nomura et al. [10] recently reviewed evidence associating preeclampsia and gestational hypertension with impaired neurobehavioural development in children, and discussed possible mechanisms by which this might occur. A 2017 meta-analysis also identified gestational hypertension along with a number of other prenatal factors associated with autism risk [11]. Accordingly, hypertension during pregnancy could carry a wide range of long-term health implications for the unborn child.

The known antenatal/perinatal risks associated with hypertension, to both mother and child, together with mounting evidence regarding potential life-long foetal programming effects on the offspring provides impetus for efforts to control maternal blood pressure (BP) during pregnancy. However, where pharmacological interventions are concerned, this raises the question of what effect in-utero exposure to antihypertensive medications might have in terms of maintaining a viable pregnancy, normal foetal development, and incidence of future physical or behavioural problems. Teratogenic effects are known to be associated with the use of certain classes of antihypertensive and other medications by pregnant women. Renin–angiotensin system blockers are contraindicated in pregnancy; however a variety of other classes of antihypertensive medications are not, and remain in use for the management of hypertension in pregnant women. For these agents, determining whether adverse effects of maternal hypertension are mitigated or whether the treatments themselves pose new risks is an important yet complicated task. A comprehensive understanding of the risks and potential benefits of antihypertensive medications to the unborn child, both during in-utero exposure and any subsequent impact on postnatal life would aid in appropriate clinical decision-making with a view to preventing lifelong complications and give peace of mind to expectant parents.

In this issue of Journal of Hypertension, Fitton et al. [12] present a systematic review of the health outcomes of in-utero exposure to antihypertensive medications. In bringing together the current state of the literature, the need for more high quality, well designed studies becomes apparent. Despite spanning a broad period of time, from 1950 until October 2016, and casting a wide net, only 47 studies ultimately met the authors’ inclusion criteria for review. Of these, only five were deemed to be of excellent quality, based on a modified version of the Critical Appraisal Skills Programme (CASP) quality assessment tool, and still with significant criticisms. Together with the level of heterogeneity in studies, meta-analysis was not a viable option, and instead the authors provided a narrative account of child outcomes.

The systematic review's findings [12] include that for studies evaluating the effects of antihypertensive exposure, the odds of adverse effects such as preterm birth, low birthweight and congenital malformations may have been higher in treated mothers compared with normotensive untreated reference groups. However, the same combinations of adverse effects were not uniformly seen between studies, even within the same class of medication, and similar adverse findings were also frequently observed in offspring exposed to untreated maternal hypertension. As an example of the level of uncertainty despite a substantial number of investigations, 24 studies included beta-blockers but ultimately only six of 13 reported increased risk of preterm birth, being small for gestational age, increased perinatal mortality and low birthweight when controlling for underlying hypertension. As such, Fitton et al. were frequently forced to caution that the study designs did not permit determination of the relative importance of hypertension versus exposure to the antihypertensive medication in question.

Building a consensus view of which adverse perinatal outcomes or types of malformations might occur more frequently with a particular class of medication is highly desirable to inform clinical practice and understand the mechanisms involved. However, such efforts were largely thwarted by heterogeneity and shortcomings in study design, including inadequate comparison with untreated hypertensive control groups and the sheer variety of outcomes evaluated, and conflicting results between studies. This being said, the authors provide Forest plots of odds ratios for preterm delivery, perinatal mortality and congenital cardiovascular defects. Together, the overall trend is for an increased risk of these outcomes across different classes of antihypertensive agents, although this interpretation still needs to be made cautiously given the limitations and inconsistencies between studies.

Given the recognized potential for foetal programming to have long-term health consequences, it was disappointing that only four of the included studies investigated effects of in-utero exposure to antihypertensive medication on later childhood development. Although two reported no detrimental effect on intelligence quotient at age 7, the other two hinted at increased risks of sleep disorders and attention deficit hyperactive disorder. However, none of the studies were rated as excellent, were limited in scope and involved relatively small study populations. Clearly more work is needed to draw firm conclusions on behavioural and neurodevelopmental outcomes of antihypertensive drug exposure in utero. Despite the literature search dating back to 1950, it appears that no studies addressed adult health outcomes such as risk of hypertension or cardiovascular disease, representing a significant gap in our knowledge.

Strengths of the approach taken by Fitton et al. include designing a systematic review protocol in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, searching multiple data bases as well as reference lists, utilization of CASP quality analysis and evaluation of inclusion/exclusion and quality analysis by two reviewers independently. In addition, the authors have registered their review with the International Prospective Register of Systematic Reviews. Overall, the review provides a useful summary of what has been reported in the literature, together with important caveats regarding the quality and limitations of this information, and the need for further research to ensure that robust data is available and used to inform treatment decisions.

As mentioned above, teasing out whether adverse outcomes are related to in-utero exposure to antihypertensive medications or are attributable to the complex pathological mechanisms prompting antihypertensive treatment in the first place is difficult and requires appropriately-powered randomized controlled trials. Whether the risks or benefits of antihypertensive medications differ due to differences in cause of hypertension also remains an open question. A notable limitation of the design of this study [12], and frequently of the source material itself, was that hypertension of all causes was included, rather than separating out preeclampsia, gestational hypertension and preexisting chronic hypertension. Each of these carries a different risk profile and underlying mechanistic basis, and the interaction between these factors and the pharmacological agents selected for use could have complex outcomes. As an added layer of complexity, timing of in-utero exposure may also differentially affect development. Currently, insufficient data exists in the literature to draw conclusions regarding these nuanced but important issues.

Most of the exclusion terms selected by Fitton et al. [12] were appropriately geared towards discarding animal studies and nonrelevant material. However, it remains possible that some informative studies may have been overlooked, for example by using the term ‘ambulatory’ to exclude studies. At the time of writing, a PubMed search combining the terms ‘ambulatory’, ‘pregnancy’ and ‘hypertension’ yielded 366 search results. The use of ambulatory BP monitoring (ABPM) allows differentiation between masked, nocturnal, white-coat and chronic hypertension. Detection of white-coat hypertension using ABPM helps to avoid unnecessary antihypertensive treatment of pregnant women and consequent in-utero exposure to antihypertensive medications. As many as half of the pregnant women suspected to have new onset or chronic hypertension based on office BP measurements may instead be shown by ABPM to have white-coat hypertension [13,14]. As discussed elsewhere [15], white-coat hypertension in pregnancy may not be altogether benign and could portend subsequent development of gestational hypertension or preeclampsia. On the other hand, a study recently published in this journal [16] reported that of 87 women with high-risk pregnancies who were thought to be normotensive based on office evaluation, one-third had masked hypertension and almost half had nocturnal hypertension. Together, these data argue in favour of more extensive monitoring of maternal BP in future clinical studies to ensure that patients are correctly allocated to study groups and that hypertension, if present, is treated appropriately.

Of potential relevance to the use of antihypertensive medication, ABPM also allows for more accurate assessment of BP control or detection of hypotension in patients undergoing treatment. Fitton et al. [12] pointed out that data on whether BP was adequately controlled by antihypertensive drug exposure was largely lacking in the reviewed studies. Inadequate control of hypertension or overcorrection could have distinct health implications for the as-yet unborn child, both in utero and long-term. The extent of overtreatment of pregnant women with antihypertensive medication such that hypotension occurs is unknown. Regardless, the potential adverse effects of maternal hypotension, whether drug-induced or spontaneous, have received scant attention in the literature. A 2011 study reported that no evidence of increased risk of congenital abnormalities or low birthweight was seen in association with hypotension [17]. In contrast, an often-cited 2000 meta-analysis of 14 studies found a relationship between antihypertensive treatment-induced falls in mean arterial pressure and reduced birthweight for gestational age [18]. A number of investigators have since raised concerns that several factors complicate the authors’ overall conclusion [18] that treatment-induced falls in maternal BP may adversely affect foetal growth. These often include that only 16% of birthweight was attributable to mean arterial pressure, and that there is potential for larger falls in BP being observed in more severely hypertensive patients who might be expected to produce low birthweight babies anyway [19]. Whether appropriate use of antihypertensive medication in terms of maternal BP control creates an unfavourable haemodynamic environment for the developing foetus is also unclear but would provide a plausible mechanism for adverse outcomes such as reduced foetal growth. To better understand the issue, measurements of foetoplacental perfusion are necessary, but not all studies incorporate such measurements. Further, the term ‘ultrasound’ was used as an exclusion term in the current systematic review [12]. Again, these findings highlight the difficulty in parsing out contributions of underlying disease processes from possible side effects of treatment and highlight the need for more rigorous and detailed studies to be performed.

To unravel the complex interactions and effects of different hypertensive conditions and antihypertensive medications, animal studies may be informative and alleviate some of the ethical and safety concerns associated with human studies. Indeed, studies relating to maternal and foetal outcomes of pregnancy-associated hypertension is an active area of ongoing research and a number of models are available, as reviewed recently [20]. Animal models do however carry a number of limitations, including differences in placentation and underlying cause of maternal disease, with additional consideration needed regarding the ability to recapitulate complex long-term outcomes of clinical interest in the offspring. Although translating behavioural phenotypes may present some challenges, some animal models of maternal hypertension and preeclampsia-like disease have already been shown to induce programming of cardiovascular phenotypes in offspring (e.g. [21,22]) and may be of use in determining which currently-used antihypertensive medications best ameliorate programming effects in offspring without conferring additional adverse effects.

Despite the efforts of the authors [12], and of the authors of the studies reviewed, there remains a number of critical questions that the current literature fails to definitively answer regarding the outcomes of in-utero exposure to antihypertensive medications. Is controlling maternal BP sufficient to prevent both immediate and more long-term health risks in offspring, irrespective of maternal hypertension's cause? Or, do particular classes of antihypertensive agents provide superior risk/benefit profiles? Does this change depend on the type of hypertensive disorder? In terms of offspring effects, are the mechanisms underlying responses primarily of a haemodynamic nature, or something else? Should additional pathological mechanisms be targeted to provide better outcomes for mother and child? Clearly, there is a further need for well designed, appropriately powered, high-quality studies to be performed in this area, and understanding the long-term outcomes in offspring represents a key step towards reducing the future burden of noncommunicable diseases.

Treatment of pregnant women with antihypertensive medications is not a new phenomenon, nor are the medications used to do this. Shouldn’t we have enough data by now to know more? The search for answers continues.

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ACKNOWLEDGEMENTS

E.I.B. receives grant support from the Lupus Research Alliance, American Heart Association and an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health, grant number P30 GM106397.

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Conflicts of interest

There are no conflicts of interest.

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