Examining Proposed Causes of Fetal Growth Restriction to Pinpoint Risk Factors and Potential Preemptive Therapies for Preterm Birth

ABSTRACT

Background     Preterm birth (PTB), or birth before 37 weeks of gestation, is the leading cause of death in children. Neonatal deaths comprise 44% of all deaths of children under the age of 5 years. Knowledge of the disease processes involved in PTB is limited. As such, further research into the molecular mechanisms of disease progression is necessary to give insight into predispositions and preventative therapies for PTB. In this review, I propose possible causes of PTB based on known causes of fetal growth restriction (FGR), in which fetal growth rate is significantly slowed due to placental insufficiency. FGR is the second most common cause of perinatal death and affects about 10% of all pregnancies. PTB is commonly observed to occur with FGR, which is why I hypothesize that the two pathologies may share developmental mechanisms. 

Methods     The PubMed database was utilized to acquire relevant articles. Keywords and their variants were used to expand the search. From the results, 46 articles are referenced in this review.

Results     The following were found to be the most pertinent FGR risk factors for my study of PTB causes and therapies: compromised vascular proliferation, faulty invasion of extravillous trophoblasts (EVTs), hypoxia associated with inadequate fetal nutrient supply systems, vascular oxidative stress, and misregulation of the renin-angiotensin-aldosterone system (RAAS).

Conclusion     In this review, I investigate conjunctions of the physiological processes contributing to FGR and PTB. I propose risk factors, potential therapies, and areas of further research in preventing and treating PTB. 

Keywords: preterm birth, fetal growth restriction, placental insufficiency, vascular health

INTRODUCTION

PTB is a leading cause of severe neurological complications and developmental delays in children (Lackritz et al., 2013). Annually, 15 million infants are born preterm worldwide, 1 million of whom die before the age of 5 years (Walani, 2020). Modern neonatal care permits preterm infants to survive to adulthood; however, babies born preterm have higher incidences of chronic disease later in life, and therefore diminished quality of life (Crump, 2020). Because of its detrimental impact on population health, PTB is an urgent area of study. However, understanding is limited about the mechanisms regulating the gestational clock, making it difficult to design therapies targeting a singular cause.

Because FGR is frequently observed with PTB (see, e.g., Malhotra et al., 2019; Colella et al., 2018; Siqueira et al., 2007), I hypothesize that the two conditions may share physiological origins. In this review, I examine various processes that are associated with both conditions in hopes of elucidating the mechanism of PTB development. 

FGR is a condition in which fetal growth is significantly slowed as a result of placental insufficiency (Colella et al., 2018; Nardozza et al., 2017). In a normal pregnancy, EVTs establish the maternal-placental vascular connection by invading maternal uterine spiral arteries (Malhotra et al., 2019; Moser & Huppertz, 2017). Defects in the invasive process prevent adequate fetal nutrition from blood supply. This causes pregnancy complications such as FGR and PTB (Pollheimer et al., 2018; Lyall et al., 2013).

This review is organized into five sections, each of which explores a cause of FGR that contributes to PTB. The following are the FGR risk factors hypothesized to contribute to PTB: compromised vascular proliferation, inadequate invasion of EVTs, hypoxia, oxidative stress, and misregulation of the RAAS. I propose risk factors, potential therapies, and areas of further research in this subject. 

METHODS

To evaluate the physiological connections between FGR and PTB, I performed a systematic literature review. The academic database PubMed was used. The following keywords and their variants were used to search for relevant articles: “preterm birth,” “fetal growth restriction,” “endothelial damage,” “oxidative stress,” “spiral arteries,” “extravillous trophoblasts,” “placental invasion,” “preeclampsia,” and “hypoxia.” From all the articles obtained in the search results (n=528,160), I chose the relevant articles (n=26). Articles were excluded if irrelevant (n=528,134). If slightly irrelevant articles provided insights into my paper’s proposed sub-questions, I expanded the focus of my literature review by searching for additional key terms found in these articles. The articles obtained from this search (n=20,877) were sifted through to compile the remaining articles referenced in my paper (n=20). This resulted in a total of 46 articles being included in this review. This workflow is diagrammed in Figure 1.

One shortcoming of my method is that I didn’t consider authorial repetition as I compiled articles to include in my review. As a result, my discussion of hypoxia is majorly evidenced by a single author, M. Wareing. Bias may have been introduced into that section since many other scientific perspectives on hypoxia were not considered. This review otherwise utilizes a diversity of credible studies to support my reasoning.

RESULTS

Compromised Vascular Proliferation

The physiological connection between maternal vasculature to FGR is as follows: because maternal blood provides nutrients essential to fetal growth, inadequate vascular proliferation causes insufficient nutrition supply, thereby restricting growth (Phipps et al., 2019). Early-onset preeclampsia, or preeclampsia of preterm birth, is associated with inadequate vascularization and therefore FGR from fetal malnutrition (Rasmussen et al., 2014). 

One mechanism by which vascular proliferation is compromised in preterm preeclamptic patients is by a decrease in vascular endothelial growth factor (VEGF) levels. Serum levels of the soluble FMS-like receptor (sFlt), which acts as a VEGF antagonist, control VEGF bioavailability in vivo. Increased serum sFlt is characteristic of preeclampsia (PE), more so for early-onset PE, which is the PE subtype coinciding with PTB (Raymond & Peterson, 2011; Bonagura et al., 2008). Therefore, a potential therapy to be researched for PE-associated PTB is the sFlt antagonist.

We must also consider estrogens as therapies to target inadequate vascular proliferation. It has been observed that the high serum estrogen levels characteristic of pregnancy are associated with increased uterine vascular proliferation. Additionally, the lowered estrogen levels associated with a preeclamptic FGR outcome are suggestive of estrogen’s involvement in the vascular proliferation process (Mandalà, 2020). It has been found that administration of exogenous estrogens relieves the symptoms of PE, which makes estrogen a promising therapy to explore for the diseases of pregnancy associated with compromised vascular proliferation (Shu et al., 2021).

Inadequate Invasion of EVTs

Related to the discussion of inadequate vascularization is the phenomenon of faulty placental invasion into uterine maternal spiral arteries. Inadequate EVT invasion has been associated with FGR and PTB (Pollheimer et al., 2018; Lyall et al., 2013). Invasive processes are key to establishing placental-vascular connections, which are integral for maternal-fetal nutrient exchange. It follows that a deficiency in this process can cause fetal undernourishment, which is a precondition to FGR and therefore PTB (Malhotra et al., 2019).

Using Doppler sonography, it has been found that significantly increased maternal uterine fluid shear stress (FSS) is indicative of an undernourished FGR placenta. This relationship has also been confirmed using computational models. In a normal pregnancy, the maternal-fetal vascular connections formed result in optimal placental perfusion. Increased perfusion relative to FGR cases causes nitric oxide (NO) release by the endothelium, triggering vasodilation. This prevents FSS in a normal pregnancy. In FGR cases, where blood flow is restricted, vasodilatory mechanisms involving NO signaling are similarly activated; however, responsivity is low and thus the regulatory mechanism has no effect. This causes uterine endothelial damage, which results in reduced perfusion and therefore FGR and PTB (Morley et al., 2021).

Additionally, VEGF may play a role in the NO pathway (Morley et al., 2021). Studies have shown that VEGF-assisted vascular proliferation requires use of the NO pathway (Crump, 2020; Cooke & Losordo, 2002). Studies have also shown a VEGF receptor (VEGFR) subtype being important in the mechanosensing pathways that ultimately trigger NO production to prevent FSS. However, both mechanisms are incompletely understood and therefore warrant further research (see, e.g., Chatterjee, 2018; Rodríguez & González, 2014; Tzima et al., 2005). Because VEGF also promotes EVT invasion, the decreased invasion of FGR may be attributed to the decreased VEGF levels observed in FGR pregnancies. This again points towards sFlt antagonists as important potential therapies to be studied (Raymond & Peterson, 2011). A study on baboon EVT invasion points toward estrogens being involved in negative regulation of the VEGF pathway, by increasing sFlt levels (Bonagura et al., 2008). This suggests that estrogen worsens symptoms of PTB. Because current knowledge of estrogen’s effects on vascular proliferation and trophoblast invasion offers opposing information on estrogen’s promise as a therapy for growth restriction-associated conditions, further research is needed on this topic.

Hypoxia

Hypoxia is characteristic of FGR-associated diseases because of the connection to undernourishment of the fetus. Based on perfusion data, hypoxia has been associated with vascular resistance of uterine arteries, which is also associated with FGR. The physiological mechanism for this association is not understood but may have a basis in voltage-gated potassium (Kv) channel activity of the uterine arteries (Wareing, 2013; Wareing, Bai et al., 2006).

One process by which Kv channels participate in uterine artery function is in hypoxic fetoplacental vasoconstriction (HFPV), wherein blood flow is diverted to well-oxygenated cotyledons, or perfusion chambers. The association of HFPV to Kv channels was demonstrated upon observing that both HFPV and the presence of 4-aminopyridine, which inhibits the Kv channel, cause increased blood vessel pressure. This suggests that HFPV is connected to faulty Kv channel activity. Other ion channel inhibitors did not have major effects on vascular tone, suggesting that Kv channels are majorly responsible for uterine blood vessel vasoconstriction indicative of the somatic response to hypoxia (Hampl et al., 2002). 

Hypoxia, which is characteristic of FGR pregnancies, induces homeostatic vasoconstriction by inhibiting Kv channels, since Kv channels regulate vascular tone (see, e.g., Wareing, Greenwood, Fyfe et al., 2006; Hampl et al., 2002). Uterine vasoconstriction is a local homeostatic mechanism with the objective of carrying the limited amount of oxygenated blood available to the fetus (see, e.g., Wareing, Greenwood, Taggart, et al., 2003). However, maximal vasoconstriction in response to hypoxia has harmful effects on endothelial health. Constriction increases vascular resistance index, which is associated with FGR. Therefore, Kv channel misregulation can increase vascular resistance. It has been found that blocking Kv channels in chorionic plate vasculature increases vascular tone (Su, 2015), thus increasing resistance index (RI) (Wareing, Greenwood, Fyfe et al., 2006). Regardless of the current focus being maternal vasculature, the concept of Kv channel misregulation increasing RI is still relevant, even if in the chorionic plate. RI is relevant because FGR is associated with a high RI (van Zijl et al., 2020). By utilizing Doppler sonography to observe waveform notching patterns, one group found that PTB risk is higher in women with a high RI; however, predictive ability of PTB using only a Doppler ultrasound is low. FGR is associated with a high RI (see, e.g., Satoh et al., 1989; McCowan et al., 1987; Fleischer et al., 1985; Giles et al., 1985). Vascular tone, which is regulated by Kv channels, is a major determinant of RI. So, substances that act upon Kv channels may be important in disease progression of FGR pregnancies (Jackson, 2000). Further research is needed about the clinical effects of these compounds.

Progesterones have been found to have significant effects on RI and therefore birth outcomes. Progesterones decrease uterine vascular RI, and thus seem to be a logical therapy to explore in clinical trials (Maliqueo et al., 2016). Boelig et al., 2019 reported success with oral progesterone administration in the prevention of recurrent PTB, while Meis & Aleman, 2004 claimed progesterone to be completely ineffective, both as a short-term tocolytic and a long-term preventative therapeutic. Because of this contradiction, further research is needed on the efficacy of progesterone in preventing and managing preterm birth.

Oxidative Stress

Substances that interfere with Kv channels and therefore increase RI include reactive oxygen species (ROS), which are elevated in FGR placenta (Morley et al., 2021). Increased vascular oxidative stress from the presence of ROS causes vasoconstriction. This necessitates vascular obtainment of NO to carry out the vasodilatory pathway. Failure of vasodilation causes poor perfusion and therefore FGR from diminished blood supply (Care et al., 2015).

ADVANCED MATERNAL AGE

A risk factor for oxidative stress and therefore FGR is advanced maternal age. Rat studies showed that delaying pregnancy significantly increased FGR frequency (Care et al., 2015). This can be attributed to age-associated weakening of maternal vascular defenses against oxidative stress. Increased age is associated with downregulated NF-E2-related factor-2 (Nrf2) expression, which is a key transcription factor involved in activating antioxidant genes to mitigate oxidative damage (Ungvari et al., 2011). Therefore, diminished Nrf2 expression from aging provides a plausible explanation of the physiological relationship between FGR and advanced maternal age. However, more research is needed on this topic, considering that the results obtained from the rat study did not conclusively point to oxidative stress as the main cause of FGR development in advanced maternal age pregnancies.

PE is a disorder characterized by faulty trophoblast invasion, leading to improper establishment of the maternal-fetal interface. It has been observed that preeclampsia is associated with increased oxidative stress from less oxidative defenses, thus providing a potential explanation for the strong association between advanced maternal age and PE incidences. Superoxide dismutase (SOD) is integral to defense against oxidative stress. It follows that low SOD levels are one significant causative of diseases associated with oxidative stress. Indeed, proteomic analyses assessing SOD activity found significantly lower SOD levels in preeclamptic placental tissue than in a control. This furthers the notion that oxidative stress is significant to the development of pregnancy complications (Thompson et al., 2015; Wang & Walsh, 2001).

Directly associated with advanced maternal age (40 years and over) in pregnancy is PTB (see, e.g., Esposito et al., 2022; Fuchs et al., 2018). Advanced maternal age causes weakened vascular defenses to oxidative stressors (Ungvari et al., 2011). The resulting vascular damage is associated with PTB (Menon, 2014). 

Misregulation of the RAAS

The elevated progesterone levels of pregnancy, which exist to prevent endometrial shedding during gestation, have important effects on the RAAS. Specifically, progesterone decreases the sensitivity of maternal vasculature to angiotensin II (ANG II). Because pregnant women are refractory to ANG II, increased compensatory levels of ANG II are observed. Additionally, the elevated estrogen level in pregnancy, made for the same purpose as progesterone, increases liver angiotensinogen production, further compensating for low RAAS activity in the pregnant woman (Irani & Xia, 2011).

During pregnancy, future preeclamptic mothers are hypersensitive to the RAAS due to ANG II receptor (AT1) heterodimerization with the bradykinin receptor (B2). Although ANG II levels markedly decrease in this condition to prevent overstimulation of these dimerized and therefore hypersensitized receptors, preeclamptic patients still experience symptoms suggestive of continued overstimulation of these receptors, including high blood pressure from increased vasopressive effects. The resulting compromised endothelial health has been linked to FGR and PTB. Reasons for continued stimulation remain elusive; however, one hypothesis proposes that the presence of agonistic autoantibodies promotes stimulation. Therefore, it is worth exploring therapies targeting these autoantibodies to prevent high maternal blood pressure and the resulting endothelial damage (Irani & Xia, 2011).

Using pregnant transgenic mice, it was found that human angiotensinogen increased the stimulation of mouse AT1 receptors and ultimately contributed to FGR. However, when the AT1a subtype of AT1 receptors was removed, elevated blood pressure was not observed. This reveals the clinical importance of the AT1a receptor, and how AT1a antagonists could potentially be a treatment for the high blood pressure characteristic of certain pregnancy complications (Saito et al., 2004).

Understanding pregnancy’s effect on the RAAS is key to elucidating the underlying cause of preterm birth (Wiegel et al., 2022). Overstimulation of the RAAS during pregnancy increases the risk of PTB, FGR, and PE.

DISCUSSION & CONCLUSION

By examining various physiological connections between FGR and PTB, this review has identified risk factors, potential therapies, and areas for further research of this topic.

sFlt antagonists and estrogens are promising therapeutic agents to ensure adequate vascular proliferation via the VEGF pathway to supply blood to the maternal-fetal vascular interface. Both compounds also affect EVT invasion into the maternal spiral arteries; however, estrogens seem to have a negative effect on EVT invasion, thus necessitating further research on the effects of estrogen administration on diseases of pregnancy. Additionally, the mechanism by which VEGF acts on the NO pathway to cause homeostatic vasodilation is not understood and is a relevant area of further study.

Compounds that improve Kv channel activity also have therapeutic potential because excessive Kv channel inhibition is hypothesized to cause homeostatic hypoxic vasoconstriction, which slows maternal blood supply to the fetus.

Progesterones have potential as PTB therapies because they decrease uterine vascular RI. However, varying results have been reported in clinical trials, suggesting that progesterones as therapies for PTB warrant further study.

Oxidative stress is a major risk factor of FGR and therefore PTB because of the resulting compromised vascular health. As such, advanced maternal age is a risk factor for PTB because of increased vascular susceptibility to oxidative damage. This susceptibility results from age-associated lowering of the expression of SOD and other antioxidant-related proteins.

Therapeutics targeting AT1 receptor autoantibodies may successfully prevent maternal endothelial damage characteristic of abnormal sensitivity to the RAAS during pregnancy. Additionally, AT1a receptor antagonists may be worthwhile targets to prevent high blood pressure.

Of note is the truth that superficial interventions are not viable long-term solutions to disease. Tocolytics and neonatal care, while effective in the short term, do not address the root cause of PTB, subjecting both mother and child to compromised health. Hence, solutions to PTB must target the fundamental underlying physiological processes of disease development.

This review investigated major junctions between FGR and PTB in hopes of furthering the knowledge of connections between these diseases of pregnancy. Using published research, I compiled information about FGR to elucidate clinically significant information about PTB. This was possible because of the intimate association between the two conditions. Future analyses purposefully connecting multiple areas of translational reproductive science will revolutionize medicine.

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