Safety of contrast-enhanced ultrasound using microbubbles in human pregnancy: A scoping review

Abstract

Introduction Successful placentation is crucial for fetal development and maintaining a healthy pregnancy. Placental insufficiency can cause a variety of obstetric complications. Despite the many efforts to enhance diagnosing placental insufficiency, no imaging technique has proven satisfactory. A promising imaging technique is contrast-enhanced ultrasound (CEUS) using microbubbles which has proven capable of (micro)vascular imaging. Its use for placental vascularization assessment in human pregnancies remains constrained by limited evidence and safety concerns. This scoping review aims to demonstrate the safety of CEUS used in human pregnancy in the published literature to date.

Material and Methods A systematic search using PubMed, Medline, Embase, and Cochrane databases was performed. All studies where contrast-enhanced ultrasound was used in pregnant humans were included. Studies, where there was a planned termination of pregnancy, were excluded. To assess the safety of CEUS during pregnancy, relevant outcomes were divided into the following 3 categories; fetal outcome, maternal outcome, and pregnancy and neonatal outcomes.

Results A total of 13 articles were included, in which 256 women underwent CEUS during pregnancy. No clinically significant maternal or fetal adverse events or negative pregnancy or neonatal outcomes associated with CEUS were described.

Conclusion Based on our findings, we consider expanding the knowledge of this promising diagnostic technique in future larger clinical studies to be safe and relevant.

Zusammenfassung

Einleitung Eine erfolgreiche Plazentation ist entscheidend für die fetale Entwicklung und die Aufrechterhaltung einer gesunden Schwangerschaft. Eine Plazenta-Insuffizienz kann eine Reihe von geburtshilflichen Komplikationen verursachen. Trotz zahlreicher Bemühungen, die Diagnose der Plazenta-Insuffizienz zu verbessern, hat sich keine Bildgebungstechnik als zufriedenstellend erwiesen. Ein vielversprechendes bildgebendes Verfahren ist der kontrastverstärkte Ultraschall (CEUS) mit Microbubbles, der sich für die (mikro-)vaskuläre Bildgebung bewährt hat. In der Schwangerschaft ist sein Einsatz zur Beurteilung der Plazenta-Vaskularisation durch eine geringe Evidenz und Sicherheitsbedenken erschwert. Diese Übersichtsarbeit zielt darauf ab, die Sicherheit von CEUS in der Schwangerschaft in der bisher publizierten Literatur zu untersuchen.

Material und Methoden Es wurde eine systematische Suche in den Datenbanken PubMed, Medline, Embase und Cochrane durchgeführt. Eingeschlossen wurden alle Studien, in denen kontrastverstärkter Ultraschall bei schwangeren Frauen eingesetzt wurde. Ausgeschlossen wurden Studien mit geplantem Schwangerschaftsabbruch. Um die Sicherheit von CEUS in der Schwangerschaft zu bewerten, wurden relevante Ergebnisse in die folgenden 3 Kategorien eingeteilt: Fetales Outcome, maternales Outcome, Outcome der Schwangerschaft und des Neugeborenen.

Ergebnisse Es wurden insgesamt 13 Artikel eingeschlossen, in denen sich 256 schwangere Frauen einer CEUS-Untersuchung unterzogen. Im Zusammenhang mit CEUS wurden keine klinisch bedeutsamen maternalen oder fetalen unerwünschten Ereignisse und kein negativer Outcome der Schwangerschaft oder des Neugeborenen beschrieben.

Schlussfolgerung Aufgrund dieser Ergebnisse halten wir es für sicher und wichtig, das Wissen in Bezug auf diese vielversprechende Diagnosetechnik durch zukünftige größere klinische Studien zu erweitern.

Keywords

ultrasonography - contrast-enhanced ultrasound - microbubbles - safety - pregnancy

Introduction

The placenta is vital for fetal development, maintaining a healthy pregnancy, nutrient delivery, gas exchange, and immune regulation [1]. Successful placentation is crucial and achieved by trophoblast invasion. Defective placentation could ultimately lead to placental insufficiency, causing obstetric complications like fetal growth restriction (FGR) and preeclampsia (PE), impacting 3–5% and 2–8% of all pregnancies, respectively [2] [3]. The FGR definition is consensus-based and ultrasound diagnosis is often inaccurate [4]. Furthermore, it is challenging to differentiate FGR from small-for-gestational-age (SGA) cases [4]. Roughly 70% of all small-for-date fetuses are healthy (SGA), while 30% are FGR and prone to complications [5]. Despite the many efforts to enhance the diagnosis of placental insufficiency, no imaging technique has proven satisfactory.

A promising imaging technique is contrast-enhanced ultrasound (CEUS), which employs ultrasound contrast agents (UCAs), microbubbles encapsulating a non-toxic gas in a (phospho)lipidic shell [6] [7]. UCAs remain metabolically inert, immuno-neutral, and stay within the intravascular space rendering them suited for (micro)vascular imaging [8] [9] [10]. With a half-life averaging between 2 to 15 minutes, they are rapidly eliminated through renal or pulmonary clearance [11] [12] [13]. Contrast-specific imaging sequences, exploiting the highly nonlinear acoustic response of UCAs compared to tissue, improve the visualization of the UCA-perfused (micro)vasculature [14]. CEUS has been widely used for various non-obstetric indications including cardiac diagnostic imaging [15]. Its safety profile for these indications is well-established, with minimal adverse events (AE) reported. In a cohort study of 49.100 patients, the incidence of AE was found to be merely 0.088%, with no fatalities [16]. Adverse events include anaphylaxis, nausea, dizziness, headache, chest discomfort, back pain, and injection site reactions [17]. CEUS is more accessible when compared to other contrast-enhanced imaging techniques and entails no radiation. Most importantly, it has proven capable of identifying intervillous space perfusion, suggesting its potential to identify compromised villous tree architecture leading to placental insufficiency [8] [18] [19]. Yet, its use for placental vascularization assessment in human pregnancies remains constrained by limited evidence and safety concerns. Safety encompasses maternal complications, placental tissue integrity, and fetal development interference [20].

Though CEUS’s safety is not firmly established, prior research has already explored its use during pregnancy. However, this mostly entails studies in animals or pregnancies with planned termination [8] [9] [21] [22] [23] [24] [25] [26] [27] [28]. These studies yield reassuring findings regarding the effect of CEUS on maternal and fetal safety, and perinatal outcomes [29]. For example, studies describe that microbubbles, used during CEUS, do not interfere with the permeability nor cross the placental barrier [9] [30]. However, data on ongoing pregnancies and postnatal effects remain scarce. Consequently, it has not yet been approved for use in pregnancy by the FDA.

The objective of this scoping review is to comprehensively examine all studies utilizing CEUS during ongoing human pregnancies, for both obstetric and non-obstetric indications, to evaluate fetal and maternal safety.

Methods

We conducted this scoping review to identify and review all published literature to date on the safety of using microbubbles in human pregnancy, adhering to the PRISMA-ScR guidelines checklist.

The inclusion criteria involved original studies employing CEUS with microbubbles as UCAs in pregnant subjects with both obstetric and non-obstetric indications. Exclusions were made for studies involving planned termination of pregnancy, as well as review articles and study protocols. Language restrictions were not applied.

To identify relevant literature, a structured literature search was performed in December 2022 across databases including Medline, Embase, and Cochrane, with an update conducted on July 19, 2023. Additionally, we conducted a free text term search in PubMed and examined reference lists of both included and excluded publications to identify any additional relevant studies.

The search terms used were: Pregnancy, contrast-enhanced ultrasound, and microbubbles (and synonyms). Search terms were applied to all fields using MeSH and Emtree terms were used in the database searches (Appendix I, supplementary table 1.1–1.3).

All papers generated by the searches were screened for titles, abstracts, and keywords by two independent reviewers (referred to as A and B) labeling them as “include”, “exclude”, or “maybe”. Reviewers were able to leave comments if needed. Articles were reviewed in full text by both reviewers in the case of a disagreement or ambiguity, followed by discussion leading to inclusion or exclusion. All included studies were reviewed in full text.

The study quality assessment tools by the National Heart, Lung, and Blood Institute (NHLBI) were used to assess the quality of the case series, case-control studies, pre-post studies, and observational studies [31]. However, quality assessment was not performed for case reports, as is common in scoping reviews. The quality and risk of bias were assessed by the two researchers by answering the predefined quality checklist questions and stating the degree of quality as “high”, “moderate”, or “low”. Any discrepancies were resolved through discussion and, if necessary, consultation with a third expert (C) (Appendix II, supplementary table 2.1–2.6).

To assess the safety of CEUS during pregnancy, outcomes were categorized into fetal, maternal, and pregnancy/neonatal outcomes. Relevant fetal effects seen during or shortly after the CEUS examination included microbubble uptake in fetal compartments or the umbilical cord, alteration in the fetal cardiovascular system (indicated by changes in cardiotocography (CTG), fetal heart rate, or umbilical cord blood flow), alterations in fetal movements, impairment of fetal growth and/or development, and fetal death. Maternal adverse events that were considered relevant included nausea, abdominal/ flank pain, headache, pruritus, rash, allergic reactions, or anaphylaxis. Lastly, relevant pregnancy outcomes were: the mode of delivery (vaginal or cesarean section (CS)), gestational age at the time of delivery, the indication in case of termination of pregnancy, and subsequent neonatal outcomes (live birth, neonatal death, and neonatal condition postpartum). Study characteristics were noted before data extraction in a data extraction form in which the results from all included studies were systematically presented.

Results

The literature search was carried out in July 2023 and yielded 1166 results. After resolving duplicates, 1097 studies remained. Screening of titles and abstracts excluded 1066 studies primarily unrelated to the topic of interest, CEUS used in a non-ongoing pregnancy or involving animal subjects, or those concerning review articles or study protocols. Following full-text review and discussion, 22 articles were excluded for similar reasons. Thus, 9 studies were eligible for inclusion. The additional PubMed search and reference list review provided another 4 eligible studies. A total of 13 studies, including 256 women undergoing CEUS examination during pregnancy, were included in the scoping review ([Fig. 1]).

Fig. 1 Flowchart of study selection.

The studies, published between 1997 and 2022, were predominantly from northwestern European countries (10), with two from Asia, and one from North America. They all utilized quantitative methods, with various study designs: six case reports, three case series, two diagnostic studies, one observational study, and one experimental study. Sample sizes ranged from one to 137 women with both uncomplicated and complicated singleton or twin pregnancies. The contrast agents SonoVue, Levovist, and Definity were used across all trimesters for both obstetric and non-obstetric indications ([Table 1]). The various agents utilized, type of UCA, and the number of patients involved are illustrated in [Table 2].

Table 1 Study characteristics of studies using CEUS in pregnancy.

Reference & country	Year of publication	Study type	Population	Total number of participants	Number of participants eligible	Number of CEUS examinations	Contrast agent	Indication for use of CEUS	Exposure period
Roberts et al. USA [32]	2017	Experimental study	Pregnant women, uncomplicated pregnancies	35	35	35	Definity	Assessment of placental perfusion	1st trimester
Mengjia et al. Japan [33]	2023	Case report	Pregnant woman, uncomplicated pregnancy	1	1	1	Perflubutane	Diagnosing liver metastasis during pregnancy	3rd trimester
Götzberger et al. Germany [34]	2020	Case report	Pregnant woman, uncomplicated pregnancy	1	1	1	SonoVue	CEUS-guided ERCP for treatment of common bile duct stones	3rd trimester
Geyer et al. Germany [35]	2020	Case series	Pregnant women, uncomplicated pregnancies	5	5	11	SonoVue	Assessment of various intra-abdominal conditions during pregnancy	2nd & 3rd trimester
Ordén et al. Finland & Sweden [36]	1998	Diagnostic study	Pregnant women. 16 uncomplicated pregnancies, 7 FGR, 1 PE & FGR, 1 case of gestational diabetes (GDM)	25	25	25	Levovist	Examination of uteroplacental circulation	3rd trimester
Ordén et al. Finland [37]	2000	Case-control	Pregnant women. 45 uncomplicated pregnancies, 8 FGR, 1 PE & FGR, 5 PE, 4 GDM, 4 cases of vaginal bleeding, 1 fetal Down’s syndrome, 1hypothyreodism	69	69	69	Levovist	Examination of uteroplacental circulation and umbilical artery blood flow	3rd trimester
Schwarze et al. Germany [38]	2019	Case series	Pregnant women, uncomplicated pregnancies	6	6	6	SonoVue	Assessment of hepatic lesions during pregnancy	2nd & 3rd trimester
Schwarze et al. Germany [39]	2021	Case series	Pregnant women, uncomplicated pregnancies	5	5	6	SonoVue	Evaluate safety and value of CEUS during pregnancy to investigate non-obstetric conditions	1st, 2nd, & 3rd trimester
Schwarze et al. Germany [40]	2020	Case report	Pregnant woman, uncomplicated pregnancy	1	1	1	SonoVue	Diagnosing liver echinococcosis during pregnancy	1st trimester
Denbow et al. England [41]	1997	Case report	Pregnant woman, twin-pregnancy. Uncertainty regarding chorionicity.	1	1	1	Levovist	Assess chorionicity and placental vascularization	3rd trimester
Kirkinen et al. Finland [42]	1997	Case report	Pregnant woman with 2 previous cesarean sections	1	1	1	Levovist	Imaging of abnormal placental adherence	2nd trimester
Pintault et al. France [43]	2021	Case report	Pregnant woman with incomplete uterine rupture and repair in current pregnancy	1	1	1	Not stated	Imaging of placenta adherence	2nd trimester
Yin et al. China [44]	2022	Diagnostic study	Pregnant women with an ovarian tumor	137	105	105	Not stated	Assessment of ovarian tumors in pregnancy	1st, 2nd, & 3rd trimester

Table 2 Results of included studies on the safety of CEUS in pregnancy.

UCA*	Type of microbubble agent	Pharmacokinetics
		t1/2 #	Clearance
* UCA: ultrasound contrast agent. #: half-time
SonoVue	Sulphur hexafluoride microbubbles	12 minutes (range 2–33 minutes)	Pulmonary
Levovist	Galactose – Palmitic Acid microbubbles (no longer in use)	Galactose: 10–15 minutes Palmitic acid: 1–4 minutes	Renal
Definity	Phospholipids-encapsulated perfluoropropane microspheres	1.68 minutes	Pulmonary

For all studies, except the case reports, a risk of bias assessment and critical appraisal of methodological quality was performed. After reviewer discussion, one study was rated as “high” quality, four as “moderate”, and one study as “low” (Appendix II). Two studies had only abstracts available but were included since a significant number of participants underwent CEUS for placental vascularization imaging and the information in the abstract was considered sufficient for inclusion [32] [33].

Charted data

To determine the safety of CEUS in human pregnancy, the following outcome measures were charted: fetal and maternal outcome during or directly after the use of CEUS, pregnancy outcome, and neonatal outcome postpartum ([Table 3]).

Table 3 Results of included studies on the safety of CEUS in pregnancy.

Reference & country	Fetal outcome	Maternal outcome	Pregnancy and neonatal outcomes
Roberts et al. USA [32]	Not stated	Not stated	Not stated
Mengjia et al. Japan [33]	Not stated	Not stated	Planned cesarean section at 34 weeks of gestation after antenatal corticosteroids
Götzberger et al. Germany [34]	Not stated	Transient mild elevation of lipase post-ERCP	Not stated
Geyer et al. Germany [35]	No fetal adverse events. No fetal contrast uptake detected during CEUS.	No maternal adverse events	One vaginal delivery of a healthy neonate at 38 weeks of gestation after 5 consecutive CEUS examinations. Four cases with unknown pregnancy outcome.
Ordén et al. Finland & Sweden [36]	No fetal adverse events. Acute fetal distress excluded using CTG analysis before, during, and after CEUS.	No maternal adverse events	Not stated
Ordén et al. Finland [37]	No fetal adverse events. Similar increase in short-term variation, accelerations, and fetal movements in CEUS and control group after the procedure. No changes in umbilical artery blood flow velocity waveform.	No maternal adverse events	6 premature deliveries (8.7%), 17 cesarean sections (24.6%). Five premature neonates with a 1 and 5-min APGAR score of below 7 and 6 respectively, 17 NICU admissions
Schwarze et al. Germany [38]	No fetal adverse events	No maternal adverse events	Two cesarean sections at 32 and 35 weeks of gestation, one vaginal delivery at 35 weeks of gestation, rest with delivery of unknown route. Neonatal outcome not stated.
Schwarze et al. Germany [39]	No fetal adverse events	No maternal adverse events	Two vaginal births at 37 and 40 weeks of gestation, Three deliveries of unknown route. All healthy neonates.
Schwarze et al. Germany [40]	No fetal adverse events	No maternal adverse events	Not stated
Denbow et al. England [41]	No fetal adverse events. Fetal heart rate and Doppler unaltered	Not stated	Uncomplicated pregnancy. Delivery by cesarean section at 30 weeks of gestation. Post-natal supportive neonatal care for prematurity.
Kirkinen et al. Finland [42]	Not stated	Not stated	Immature rupture of membranes at 22 weeks of gestation. Induction of labor. Vaginal delivery. Neonatal death 14 minutes post-partum due to immaturity.
Pintault et al. France [43]	Not stated	Not stated	Planned cesarean section at 32 weeks of gestation after repaired incomplete uterine rupture. Live birth.
Yin et al. China [44]	Not stated	Not stated	72 full-term deliveries, 27 preterm deliveries. 105 live births, 52 healthy neonates after CEUS in the 3rd trimester.

Maternal outcomes

Seven studies addressed maternal adverse events post-CEUS, of which only one case report showed a transient mild lipase elevation after the CEUS-guided endoscopic retrograde cholangiopancreatography (ERCP) in a third-trimester pregnant woman. CEUS was used during the ERCP procedure to visualize the common bile duct during cannulation as an alternative to fluoroscopy [34]. This elevation, common after ERCP, was not clinically significant nor related to CEUS. Furthermore, six studies reported the absence of maternal adverse events without further elaboration [35] [36] [37] [38] [39] [40]. The remaining six studies did not report on maternal outcomes after CEUS [32] [33] [41] [42] [43] [44].

Fetal outcomes

Seven out of thirteen studies stated fetal outcomes during or directly after CEUS without any adverse events. A 1997 case study used CEUS to determine chorionicity in a twin pregnancy with discordant fetal growth at 30 weeks because chorionicity was not assessed accurately at 16 weeks of gestation. The procedure was uncomplicated. Fetal heart rate and Doppler measurements of the umbilical artery remained unchanged post-CEUS [41].

Another case series described 11 CEUS examinations in 5 pregnant women evaluating non-obstetric intra-abdominal conditions including renal angiomyolipoma, pyelonephritis, and uterine fibroids. The absence of fetal adverse events and fetal contrast uptake is described in this article [35].

Furthermore, in a 1998 diagnostic study, 25 pregnant women (29–42 weeks of gestation) underwent power Doppler ultrasound with and without contrast agent enhancement to evaluate uteroplacental circulation. Seventeen pregnancies were uncomplicated, while eight pregnancies were already complicated with FGR. No fetal adverse events occurred and acute fetal distress was excluded before, during, and after CEUS using computerized CTG analysis [36].

In a 2019 case-control study, 69 high-risk patients, based on their general or obstetric history or current obstetric problems, received CEUS in the third trimester. A subset received computerized CTG analysis shortly before and after CEUS (n=25). They were compared to a control group who received a physiological saline injection during the ultrasound examination (n=15). Both CEUS and control groups showed a statistically significant increase in short-term variability, accelerations, and fetal movements after injection. There were no significant changes detected in the umbilical blood flow velocity waveform 5 minutes after UCA administration. This study stated that there were no signs of immediate deterioration of fetal well-being related to the CEUS examination [37].

Of the seven studies remaining, three reported the absence of fetal adverse events without elaborating on it [38] [39] [40] and four did not report the presence or absence of fetal adverse events [32] [33] [34] [42] [43] [44].

Pregnancy and neonatal outcome

Nine out of 13 studies assessing pregnancy and neonatal outcomes after CEUS found no direct negative effects. In a recent case report, published as an abstract in 2023, CEUS was employed during the 32^nd week of gestation to diagnose liver lesions suspected of malignancy. The urgency to accurately confirm or rule out a malignancy during pregnancy was crucial due to potential consequences for the mother and child. CEUS confirmed liver metastasis derived from colon cancer. The pregnancy was terminated by a planned CS at 34 weeks of gestation, after antenatal corticosteroids. Neonatal outcomes were not stated [33]. The remaining four studies did not explicitly report pregnancy or neonatal outcomes [32] [34] [36] [40]

In a recent case series examining non-obstetric intra-abdominal conditions using CEUS, pregnancy and neonatal outcomes were reported for one of the five pregnant participants. This patient, diagnosed with renal angiolipoma, underwent five consecutive CEUS examinations to monitor tumor growth and delivered a healthy neonate at 38 weeks. The outcomes for the remaining four participants were not stated [35].

In the 2019 case-control study with 69 high-risk pregnancies, as described above, CEUS was used. No immediate complications were seen post-procedure. Six patients delivered prematurely. Two of these were already known to have FGR, two had placenta abruption and/or vaginal hemorrhage 5 and 9 days after CEUS, and one had an abnormal CTG 10 days after CEUS. The sixth pregnancy was not described specifically. The remaining 63 patients delivered at term. Seventeen patients delivered by CS, where the indication for CS was not reported. A total of seventeen neonates were treated in the neonatal intensive care unit (NICU) for different indications. This study concluded no direct harmful effects, attributing unfavorable outcomes more to high-risk aspects of the pregnancy. They also stated that UCAs for the examination of maternal circulation are safe in the third trimester [37].

In a case series with 6 participants, CEUS and MRI were compared for visualizing various liver abnormalities (i.e., hepatic metastases, atypical hemangioma, and arteriovenous malformation) during pregnancy. Two CEUS examinations were performed: one confirmed hepatic metastases of rectal cancer at 24 weeks of gestation, followed by delivery at 32 weeks of gestation, and the other was performed to diagnose an unknown hepatic mass at 19 weeks of gestation. Four months later, progressive hemorrhages in the liver prompted an immediate CS at 35 weeks of gestation. One vaginal delivery occurred spontaneously at 35 weeks. The mode of delivery was not described for the other participants [38].

In a German case series, 5 pregnant women underwent CEUS for different non-obstetric conditions. In one case, CEUS was used initially to diagnose rhabdomyosarcoma in the rectus abdominis muscle and secondly to perform a CEUS-guided biopsy of the lesion. Furthermore, CEUS was performed in a patient 33 weeks pregnant for identification of a hepatic hemangioma. Both patients gave birth vaginally to a healthy term neonate. The other indications included diagnostic workup for a liver abscess at 5 weeks of gestation, diagnostic workup for intra-abdominal bleeding after a high-speed car accident at 21 weeks of gestation, and analysis of a renal cyst in a pregnant woman with recurrent urinary tract infections at 12 weeks. Further pregnancy and neonatal outcomes were not described in these last 3 cases. Despite this, coupled with the absence of fetal and maternal adverse events, the researchers concluded that CEUS is safe for these indications during pregnancy [39].

In a case study, using CEUS to determine chorionicity in a twin pregnancy, monochorionicity was confirmed prompting delivery due to discordant fetal growth. Both infants required supportive neonatal care after CS at 30 weeks due to prematurity [41].

One case report used CEUS to visualize the invasion of the placenta into the cesarean scar tissue at nineteen weeks gestation after 2 previous CSs. It showed an invasion of the placenta through the myometrium into the bladder wall. At 22 weeks of gestation, premature rupture of the membranes occurred simultaneously with vaginal bleeding. Labor was induced prematurely with oxytocin. The neonate passed away 14 minutes after vaginal delivery [42]. It is unlikely that CEUS was the luxating factor for this premature rupture of membranes. Placenta accreta together with vaginal bleeding is a more plausible explanation for this event and the subsequent pregnancy outcome.

In a case report, a patient with two prior term CSs experienced an incomplete uterine rupture at 17 weeks of gestation. After the rupture was repaired in the ongoing pregnancy, MRI and CEUS were used and indicated placenta increta as the underlying cause for this complication. The pregnancy progressed without complications until the planned CS at 32 weeks, when the patient gave birth to a live-born neonate [43].

Lastly, a diagnostic study published in 2022 used CEUS to differentiate between benign and malignant ovarian tumors during pregnancy. The study involved 105 subjects in the live birth group. Among them, 52 cases were diagnosed with malignant tumors using CEUS in the 3^rd trimester. They all gave birth to a healthy baby. This article also reported that 72 women delivered at term, while 27 had preterm deliveries. However, the reason for preterm delivery was not specified, nor whether it was iatrogenic. In addition, further information on the neonatal outcome was not provided. Pregnant women who were diagnosed with an ovarian tumor early in pregnancy opted more often for elective abortion [44].

Discussion

Overall, the results of this scoping review provide reassurance regarding the safety of CEUS during human pregnancy. Safety was assessed based on maternal adverse effects, fetal outcomes impacted by CEUS, and interference with the pregnancy and neonatal outcome. Across all trimesters, a considerable number of pregnant individuals received CEUS for both obstetric and non-obstetric indications without any complications, regardless of the type of UCA used. The majority of the included articles described pregnancy and neonatal outcomes after using CEUS with no apparent negative outcomes directly attributed to CEUS. Similarly, no maternal adverse events linked to the CEUS procedure were observed. Moreover, research investigating the direct effect of CEUS on fetuses indicated that the UCAs do not enter the fetal circulation and therefore cannot adversely affect fetal health or development [8] [30].

These findings are consistent with prior research in animal models and human pregnancies where termination of pregnancy was planned. In recent years, CEUS has found application in pregnant animal models for several indications, consistently confirming that UCAs remain confined to the maternal circulation, preserving placental integrity and presenting no risk to the fetus [8] [9] [20] [27] [28] [45]. In addition to these findings, a recent study in animal models featuring FGR demonstrated CEUS’s potential in estimating and quantifying placental perfusion [18].

Comparable outcomes emerged from studies conducted in non-ongoing human pregnancies, which showed no detection of UCA’s on the placenta’s fetal side, umbilical vein, or fetal compartments during the CEUS procedure [25] [30]. Moreover, one of these studies demonstrated the absence of maternal adverse events such as nausea, abdominal pain, headache, itching, rash, or allergic reactions [30]. Additionally, in a subset of human cases who underwent CEUS in the first trimester right before TOP, placental tissue was obtained one hour after this procedure for histological examination of tissue integrity using electron microscopy, revealing no signs of microvascular hemorrhage, lodging of microbubbles in the intervillous space, nor damage to the syncytiotrophoblast microvilli [19].

Various microbubble types have been commercially available for years [46] [47]. Sulfur hexafluoride microbubbles, also known as Lumason or SonoVue, and Perflutren microbubbles like Definity are categorized as pregnancy category B by the Food and Drug Administration (FDA), meaning animal studies show no harm to the fetus, but no adequate studies have been done in pregnant women [48] [49]. This suggests that this drug should be used only if clearly needed. Other microbubble agents are FDA-approved for human use but not yet for use in pregnancy.

This scoping review is the first to structurally assess the maternal and fetal safety of CEUS during pregnancy. Combining all published reports results in a relatively large number of pregnant women who underwent CEUS. Overall, reassuring pregnancy, maternal, and fetal outcomes were reported. However, it is important to consider that the degree of evidence was notably variable, and the included studies were not all specifically designed to investigate the safety of CEUS during pregnancy. Therefore, no meta-analysis could be performed. In addition, different contrast agents were used by different research groups, at different moments in pregnancy for different indications, which makes it more difficult to compare the results. Finally, publication bias could be a limitation, although no specific signs of publication bias were identified after the quality assessment.

Conclusion

CEUS has demonstrated effectiveness in visualizing the placental microvasculature and assessing maternal blood flow in the placental intervillous space (IVS) [6] [8] [9] [20] [24] [47]. It is a promising, relatively straightforward technique that can be used during pregnancy for a wide range of (non-)obstetric indications [50]. In the future, CEUS might be an imaging modality of great added value for diagnosing (non-)obstetric complications during pregnancy, for instance, the distinction between SGA and FGR fetuses based on the placental microvasculature.

So far, clinical data on CEUS using microbubbles in pregnancy is still limited. However, this scoping review suggests that there is evidence of CEUS being safe during pregnancy. Furthermore, theoretical knowledge and previous animal and human studies show no harmful effects of CEUS during pregnancy. In conclusion, we recommend expanding the knowledge of this promising diagnostic technique in future, larger clinical studies to establish the additional value and safety of CEUS during ongoing human pregnancies.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Received: 20 February 2024

Accepted after revision: 10 May 2024

Accepted Manuscript online:
24 June 2024

Article published online:
06 September 2024