Continuing Education Activity

Placental insufficiency is a condition whereby there is a failure of placental vascular remodeling, leading to a failure of placentation resulting in acidosis and fetal hypoxemia. The most common downstream fetal consequences of this condition include intrauterine growth restriction, prematurity, or, unfortunately, fetal demise. In order to reduce the risk of fetal morbidity and mortality, especially in high-risk pregnancies, regular prenatal screening with Doppler ultrasound should be done to increase the chances of detection and diagnosis. This activity reviews the pathophysiology, evaluation, and potential treatments of placental insufficiency, and highlights the role of the interprofessional team in managing patients with this condition.

Objectives:

• Review the risk factors associated with placental insufficiency.
• Describe the typical imaging findings on Doppler ultrasound associated with placental insufficiency.
• Identify the most common adverse events associated with placental insufficiency.

Introduction

Placental insufficiency is associated with various obstetric disorders such as pre-eclampsia and intrauterine growth restriction, both of which predispose to preterm labor, a leading cause of perinatal morbidity and mortality around the world. Poor placental function is most commonly described by the term ‘placental insufficiency’ within the medical community; however, one study highlighted the problem that there is no standardized definition or consensus for the pathognomonic features pertaining to placental insufficiency.[1] 

This poses many challenges when it comes to studying placental insufficiency in the literature, but the general understanding is that placental insufficiency is a process whereby there is a progressive deterioration in placental functioning such that oxygen and nutrient transfer to the fetus via the placenta is decreased, culminating in a decompensated hypoxia and acidosis.[2][3] This process leads to fetal hypoxemia that then stimulates a downregulation of fetal metabolic demands to preserve what nutrients are already accessible, thus resulting in intrauterine fetal growth restriction. From a histopathologic view, placental insufficiency can be defined when there is chorionic villi fibrosis, uteroplacental thrombosis, placental infarcts, fibrin deposits, or a reduction in number and surface area of the villous capillary tree.[4] 

Of note, placental infarcts can be a normal finding, as they are observed in approximately 25% of normal term pregnancies; however, increasing infarction of the placenta has been shown to be associated with placental insufficiency and thus intrauterine growth restriction (IUGR). Both MRI and ultrasound studies looking for placental insufficiency have demonstrated reductions in placental area and volume as well as increased placental thickness, in addition to globular shaped placentas on MRI.[5]        

Etiology

To date, the major etiologies that may lead to placental insufficiency are poorly understood and are still being studied. There are known associated maternal risk factors, which include pre-eclampsia or other maternal hypertensive disorders, maternal cigarette use, maternal drug use including cocaine or heroin, maternal alcohol consumption, primiparity, advanced maternal age, and prior history of delivery of IUGR neonate.[2][6] 

Studies analyzing Doppler waveforms in various placental vessels of mothers who smoked cigarettes during pregnancy demonstrated reductions in the blood flow velocity waveforms, thus indicating the nicotine exposure can lead to altered placental vasculature.[6] 

Any maternal condition that can lead to a compromise in the fetal circulation puts the fetus at risk for placental insufficiency. Additionally, certain medications such as antineoplastic, anticonvulsants, or anti-coagulants can interfere with fetal growth. Extremes of maternal body mass index, including maternal malnutrition, have also been associated with the development of IUGR neonates.[7] Studies of IUGR complicated pregnancies have demonstrated that there was an incomplete transformation of the placental vasculature early in the pregnancies that can be detected by doppler ultrasound studies.[5][8]

Epidemiology

Prematurity is the leading cause of perinatal death followed by intrauterine fetal growth restriction, which complicates approximately 4% to 6% of known pregnancies. Placental insufficiency is a potential cause of preterm labor, pre-eclampsia, IUGR, and stillbirth, which can affect 10 to 15% of pregnancies. For an IUGR fetus, the risk of spontaneous preterm labor is three-fold greater when compared to a non-growth restricted fetus, and there is also a five to six times higher risk for the development of perinatal death.[2] Unfortunately, approximately 50% of newborns with IUGR are only detected following delivery.

Pathophysiology

Although the underlying etiology for placental insufficiency is unknown, there are proposed mechanisms. Placental insufficiency is associated with a reduction in blood flow across the umbilicus to the fetus, which can be secondary to increased umbilical-placental vascular resistance. This increased resistance can be visualized as abnormal umbilical artery doppler flow velocity waveforms and can be secondary to an abnormality of villi insertion into the placental membrane, a perfusion abnormality between the umbilicus and placenta, or a reduction in uteroplacental blood flow.[2] Studies of umbilical artery Doppler have illustrated that the degree of placental injury is directly related to the degree of fetal injury during pregnancy.[9]

The main role of the placenta is to serve as the interface between fetal and maternal circulations. For this to occur, placental adherence and uterine arterial remodeling must be established in order to ensure nutrients can be delivered to the growing fetus. The hallmark for successful placentation is the remodeling of the uterine arteries. Following fertilization, the blastocyst forms, which is composed of an inner cell mass that will eventually become the fetus, and an outer shell called the trophoblast that becomes the fetal portion of the placenta. To aid with placental adherence, the cytotrophoblast, which is the inner layer of the trophoblast, secretes matrix metalloproteinases that breakdown the zona pellucida, and adherence is facilitated by the formation of anchoring villi and expression of adhesion molecules.[10] This invasion of the uteroplacental arteries allows for remodeling into dilated, low-resistance, inelastic vessels that lack maternal vasomotor control that leads to increased uteroplacental perfusion such as that the requirements of the fetus can be met.[5] Any disturbance in the remodeling process can lead to an increase in uteroplacental vascular resistance, leading to hypoperfusion of the placenta and its downstream effects, including coagulation activation, endothelial cell dysfunction, placental thrombosis, and fibrin deposits, which is associated with the development of IUGR.[5][3] Furthermore, if there is a loss of focal adhesion of the endovascular trophoblasts, a reduction in placental surface area can be seen associated with placental insufficiency. This reduction in the placental surface area, along with an increase in the thickness of the placenta, creates a globular appearance to the placenta, which is postulated to act as a compensatory mechanism for placental insufficiency. 

The intrauterine environment is a low-oxygen environment, and as such fetal circulation needs to be flexible in order to adapt to any changes that occur with uteroplacental function.[9] This hypoxic environment stimulates angiogenesis whereby vascular connections are made between the maternal circulation and the intervillous space. Now that a vascular and nutritional network of support has been established, the villous trophoblast is formed, which consists of maternal microvilli and a fetal basal layer.[10] To maintain placental function requires large amounts of energy, indicated by the fact that in a regular physiologic state, the placenta consumes approximately 70% of the glucose and 40% of the oxygen that is normally supplied to the uterus. Therefore, in order to achieve optimal fetal growth and development, nutrient delivery to the uterus must exceed the placental demand such that there are residual nutrients for fetal utilization.[10] Therefore, any compromise of nutrient delivery to the uterus impacts nutrient delivery to the fetus. 

Successful placentation can be negatively affected by lateralization, which is when the placental invasion favors one side, and the placenta is not implanted centrally. If the placenta remains asymmetric until term, doppler ultrasound will demonstrate persistent notching on the non-implanted side, leading to a relative placental insufficiency. Placental lateralization has also been associated with increased risk for the development of maternal pre-eclampsia, and thus downstream placental insufficiency.[9][11]

History and Physical

As intrauterine growth restriction is one of the primary outcomes associated with placental insufficiency, most neonates that survive present either prematurely and are known as ‘extremely low birth weight’ (ELBW) neonates or depending on when the insult to the vascular supply occurred, they may present with altered body proportions at birth.[10] If there is a failure of placentation, downstream effects such as IUGR are clinically evident on Doppler studies at approximately 26 weeks gestation.[9]

When there is a concern for IUGR, whether it is secondary to placental insufficiency or another etiology, the fetus will benefit from frequent combined monitoring using both Doppler and biophysical profile screens. This combination of screening techniques allows for the recognition of the declining performance observed when IUGR is related to placental problems. Utilizing doppler studies, failed placentation can be visualized by presenting of notching in the uterine arteries as well as increased resistance in the umbilical artery with progression to either absent- or reversed end-diastolic volumes. One of the first signs seen on a biophysical profile when there is a concern for fetal compromise is a non-reactive fetal heart rate tracing. The following will either be poor or loss of fetal body movements, breathing movements, and tone. These features of declining doppler status and poor biophysical profiles are typical when there is fetal distress, which is common when there is placental insufficiency and may indicate that delivery is required.

Evaluation

Currently, the criteria to diagnose placental insufficiency lacks as there are also no standardized methods for diagnosis. Part of the problem is due to the wide variety of terminology used to describe what is known as ‘placental insufficiency.’[1] However, as technology has improved, Doppler ultrasound has proven to be a useful tool to aid in the evaluation of fetal and placental circulations in both healthy and diseased states. Four doppler techniques have been found to be fundamental in providing useful information regarding fetal-maternal circulation, including umbilical artery studies, uterine artery studies, middle cerebral artery studies, and ductus venosus studies.[9] As a fetus continues to mature during gestation towards term, there are many circulatory changes that occur that can be evaluated by Doppler ultrasound. 

Prior to the onset of pregnancy, uterine arteries show low diastolic flow, high resistance, and elastic recoil noted in the form of early diastolic notches. Successful placentation involves removal of the intimal muscle from the vasculature such that the blood vessels will have a vigorous diastolic flow, minimal resistance, and no elastic properties. When placentation is successful, Doppler ultrasound demonstrates that the remodeling occurs rapidly, such that by 12 weeks gestation, there is a loss of notching, and resistance is low by 20 weeks gestation or earlier. When there is a failure of placentation, notching persists, and resistance remains high, which has shown to be correlated with maternal-hypertensive related fetal complications, including IUGR, pre-eclampsia, and fetal demise.[9] Using the uterine artery for Doppler screening to evaluate for notching and resistance to help identify these high-risk situations has been shown to be approximately 85% sensitive for detecting severe IUGR and pre-eclampsia. 

As resistance in the placenta increases, doppler studies of the umbilical artery can demonstrate either normal, reduced, absent, or reversed end-diastolic velocities.[12][8] It is normal for placental resistance to be high in the early stages of pregnancy, and therefore it can be expected that there will be absent end-diastolic velocity on Doppler studies up to 12 to 14 weeks of gestation. When the placental successfully invades, resistance drops and doppler studies of the umbilical artery should demonstrate continuous flow by 14 to 18 weeks of gestation.[9] Persistent umbilical artery resistance over the duration of pregnancy is an indicator of increased risk of placental insufficiency.

While umbilical artery Doppler studies provide important information pertaining to possible placental compromise, a valuable adjunct is to also use the middle cerebral artery (MCA) Doppler. The MCA provides information regarding systemic circulatory responses in the developing fetus, as it represents downstream resistance in the cerebral microcirculation.  The normal MCA Doppler displays high resistance throughout pregnancy; however, the placental disease can be identified when there is increased diastolic flow along with declining pulsatility index. Therefore, MCA Doppler studies can provide important additional information when there is a concern for severe IUGR, indicating that there may be fetal compromise and intervention may be required. 

Another form of Doppler that provides insight into placental and fetal health is the venous Doppler, which relays information pertaining to cardiac data when the fetal circulation is experiencing stress. The venous waveform that has been shown to provide the best clinical data is the ductus venosus. There are many benefits of using the ductus venosus over other venous waveforms, which include its responsiveness to oxygenation changes, it is one of the primary regulators of venous return in abnormal and normal fetal circulations, it is independent of cardiac function, it serves as a direct conduit to view right atrial retrograde pulse waves, and lastly, because it has elevated and focal velocity color Doppler signal from as early as 12 weeks gestation up to 40 weeks gestation, it is very easily imaged.[9] If an abnormal ductus venosus or retrograde atrial-wave is visualized on Doppler at around 12 to 14 weeks gestation, there is an increased risk for fetal cardiac abnormalities, and it also serves as a possible precursor indicating severe placental-based IUGR. 

MRI imaging has been found to provide additional information in order to detect and diagnose placental insufficiency. Flow voids occur when there is a loss of MRI signal observed in a blood vessel where blood flows vigorously. When using T2-weighted Rapid Acquisition with Relaxation Enhancement (RARE) imaging, placental insufficiency can be detected when decreased flow voids are observed between the placenta and the uterus, as this can be considered to reflect a reduction in uteroplacental perfusion.[5] An additional advantage of MRI imaging is that it provides high soft-tissue contrast. Therefore placental vascular abnormalities, including hemorrhages and infarctions, can be detected on placental-MRI, indicating high risk for placental insufficiency and downstream IUGR.

Treatment / Management

Currently, there is no known treatment for placental insufficiency, other than delivering the fetus if it is at a viable timepoint. Low-dose aspirin and the use of antioxidant therapies, including vitamins C and E, have been shown to promote improved placentation in cases where there is uncertainty for successful placentation.[9] Studies have demonstrated that there is an approximate 38% reduction in perinatal mortality when early Doppler ultrasound is used for cases of suspected IUGR during pregnancy.[12][13] 

High-risk women, such as those with chronic hypertension, coagulopathies, or a history of pre-eclampsia, can benefit from having Doppler ultrasound screening at 12 to 14 weeks gestation because if bilateral notching is evident, then low-dose aspirin therapy should be initiated.

In vitro studies have demonstrated that heparin can stimulate neo-angiogenesis and also improve placental perfusion. Heparin’s anticoagulant properties are exhibited by its ability to mobilize tissue inhibition factor into circulation and by the fact that it also enhances antithrombin activity. Additional benefits of heparin when considering placental insufficiency and its downstream consequences are that heparin promotes trophoblastic proliferation, reduces inflammation by downregulating the complement cascade, reduces apoptosis, and it also acts indirectly as a growth factor.[3] 

Heparin has also been shown to upregulate certain proteins involved in placental angiogenesis and development. These include angiopoietin-2, which is responsible for chorionic villi vascular remodeling, leptin, which is responsible for the regulation of nutrient transfer, as well as vascular endothelial growth factor receptor-3, tissue inhibitor matrix metalloprotease-1, tumor necrosis factor-alpha, and angiostatin. Based on its properties and preliminary data, some studies have demonstrated that there may be a role for heparin as a preventive treatment for the placental disease.

Differential Diagnosis

There are many factors that can contribute to placental insufficiency, and it is known that IUGR is a major downstream complication; however, it can be difficult at times to differentiate a small-for-gestational-age (SGA) neonate versus an IUGR neonate. One of the major benefits of doppler studies, especially of the umbilical artery, is that abnormal umbilical artery Dopplers can be used to differentiate between pathologic IUGR and a small-for-gestational-age neonate, thus guiding which pregnancy would require high-level surveillance versus routine monitoring.[9][14] 

When the mean estimated fetal weight is below the 10th percentile for a specific gestational age, that fetus is SGA. Conversely, a fetus that is IUGR will not be able to achieve normal growth usually secondary to placental insufficiency, a genetic disorder, or infection.[14] Therefore, an SGA neonate will be physically small but overall healthy versus an IUGR neonate who may also be physically small but will likely have its health compromised.  

In considering differential diagnoses that contribute to placental insufficiency there are known associated diseases, including but not limited to preeclampsia, maternal hypertensive disorders as these both interfere with placental resistance and uteroplacental blood flow. Other illnesses to consider include oligohydramnios and maternal malnutrition or calorie restriction.

Prognosis

If a neonate suffered from IUGR as a consequence of placental insufficiency and survives the perinatal period, they are at higher risk compared to a non-growth restricted neonate for developing cognitive deficits in childhood, including cerebral palsy and seizure disorders. Patients who suffer from placental insufficiency often have abnormal umbilical artery doppler flow velocity waveforms (DFVWs), and when one study compared DFVWs of infants who experienced placental insufficiency in-utero versus those infants who did not, they found that the infants who had had abnormal DFVWs also had lower IQs when they were 5-years-old. There is also evidence that suffering from IUGR as an infant predisposes to chronic illness as an adult, including increased risk for developing coronary artery disease, hypertension, and diabetes.[2] 

In order to lead to a better prognosis for the neonate, the priority should be to focus on interventions that allow for maximizing gestational age at birth. It is estimated that for each week pregnancy is prolonged for fetuses between 24- and 28-weeks gestation, survival without associated sequelae is increased by approximately 10% to 15%.[3]

Complications

The downstream effects of placental insufficiency on the developing fetus are complex and multifactorial; however, the major effects tend to be a placental respiratory failure and fetal hypoxemia, both of which contribute to intrauterine growth restriction and its associated effects including prematurity.[10][14] 

The most detrimental complication is obviously a complete lack of placentation and thus miscarriage. For the developing fetus, the degree of umbilical artery abnormalities seen on doppler is correlated with acidosis, resuscitation requirements, pressor support, ventilatory support as well as multisystem organ failure, which tends to occur when there is hypoxemia as this triggers a redistribution of blood flow in the developing fetus to essential organs such the as the brain and heart at the expense of other pertinent organs, such as the bowels and kidneys.[14] Furthermore, when Doppler studies demonstrate absent or reversed end-diastolic flow, there is an increased frequency of intraventricular hemorrhage in the neonate.[9] 

With increasing placental resistance during pregnancy, the already IUGR fetus is at further risk for hypoglycemia, hypoxic-ischemic encephalopathy, thrombocytopenia, leukopenia, and anemia.[8] Furthermore, there is evidence indicating that infants are at risk for developing cognitive deficits in childhood, and later developing chronic illness as an adult.

Deterrence and Patient Education

It is imperative that regular prenatal screening and ultrasound monitoring occur when a woman is pregnant to provide the best possible outcome for the neonate. Although there are no definitive preventive measures for placental insufficiency, once it has been recognized either via ultrasound, MRI, BPP, or any combination of these methods, interventions such as heparin therapy can be initiated with the hopes to prolong gestation with the hopes of minimizing acidosis and hypoxia and resultant  IUGR, prematurity or fetal demise. Further studies need to be done on interventions and treatments, and when during pregnancy, they will provide the most benefit to the developing fetus.

Pearls and Other Issues

There is no definite cure for placental insufficiency, but the consequences can be minimized if diagnosed early, and the mother receives adequate prenatal care. Recent metanalysis revealed that heparin might promote fetal growth and prolong pregnancy if heparin is initiated in whom there is a high suspicion of placental insufficiency, but no benefit in reducing adverse outcomes in the neonates.

Enhancing Healthcare Team Outcomes

Based on Doppler studies, the earliest signs of failed placentation are likely not to be detected until at least after 12 weeks gestation, which correlates with a prospective cohort study that demonstrated screening placental function in high-risk pregnancies in the second versus first trimester was a better predictor for adverse perinatal outcomes.[15] 

When discussing placental insufficiency, there are going to be at least two teams, if not more, contributing to the care of the patients, as one team will be responsible for monitoring the mother and the fetus prenatally, and another team that will care for the neonate post-natally. Managing both mother and an IUGR-baby requires an interdisciplinary team composed of Ob/Gyn’s, neonatal intensivists, both Ob and NICU nurses, respiratory therapists, pharmacists, pulmonologists, and sometimes other specialties including surgery, infectious disease, or genetics.

For the IUGR neonate, they often develop chronic lung disease secondary to their prematurity and may require multiple medications as well as home oxygen management, or they may develop multiple infections including necrotizing enterocolitis or late-onset sepsis, all of which requires coordination between the above-mentioned teams to provide improved outcomes for the patient. At times, depending on the outcome of the pregnancy, it will be important to involve an ethics committee or a palliative care team. Often it is easier for the families if family meetings can be organized where at least one member from each specialty team is present, as this improves communication between all teams and affords families the chance to ask their questions from all the specialists at once.