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Review
. 2022 Sep;62 Suppl 1(Suppl 1):S67-S78.
doi: 10.1002/jcph.2126.

Clinical Assessment of Fetal Well-Being and Fetal Safety Indicators

Anna L David  1   2 , Rebecca N Spencer  1   3
Affiliations
Review

Clinical Assessment of Fetal Well-Being and Fetal Safety Indicators

Anna L David et al. J Clin Pharmacol. 2022 Sep.

Abstract

Delivering safe clinical trials of novel therapeutics is central to enable pregnant women and their babies to access medicines for better outcomes. This review describes clinical monitoring of fetal well-being and safety. Current pregnancy surveillance includes regular antenatal checks of blood pressure and urine for signs of gestational hypertension. Fetal and placental development is assessed routinely using the first-trimester "dating" and mid-trimester "anomaly" ultrasound scans, but the detection of fetal anomalies can continue throughout pregnancy using _targeted sonography or magnetic resonance imaging (MRI). Serial sonography can be used to assess fetal size, well-being, and placental function. Carefully defined reproducible imaging parameters, such as the head circumference (HC), abdominal circumference (AC), and femur length (FL), are combined to calculate an estimate of the fetal weight. Doppler analysis of maternal uterine blood flow predicts placental insufficiency, which is associated with poor fetal growth. Fetal doppler analysis can indicate circulatory decompensation and fetal hypoxia, requiring delivery to be expedited. Novel ways to assess fetal well-being and placental function using MRI, computerized cardiotocography (CTG), serum circulating fetoplacental proteins, and mRNA may improve the assessment of the safety and efficacy of maternal and fetal interventions. Progress has been made in how to define and grade clinical trial safety in pregnant women, the fetus, and neonate. A new system for improved safety monitoring for clinical trials in pregnancy, Maternal and Fetal Adverse Event Terminology (MFAET), describes 12 maternal and 18 fetal adverse event (AE) definitions and severity grading criteria developed through an international modified Delphi consensus process. This fills a vital gap in maternal and fetal translational medicine research.

Keywords: adverse event; clinical trial; fetal therapy; fetus; pregnancy; safety.

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Conflict of interest statement

A.L.D. receives consulting fees from Esperare Foundation, Geneva, Switzerland, a private not‐for‐profit organization, as chair of the Data Safety Monitoring Board in a clinical trial of an investigational fetal drug therapy. She is an unpaid co‐chair of the Maternal Health Project Group of the Association of British Pharmaceutical Industry (ABPI). She is a commissioner (unpaid) on the University of Birmingham's Policy Commission on Safe, Effective and Accessible Medicines for Use in Pregnancy. R.N.S. has no financial interests to disclose.

Figures

Figure 1
Figure 1
Ultrasound images of the fetal heart views used to screen for cardiac anomalies: the left‐hand image is of the 4‐chamber view and the right‐hand image is of the 3‐vessel and trachea view. Ao, aorta; IVS, interventricular septum; LA, left atrium; LV, left ventricle; MV, mitral valve; PV, pulmonary veins; RA, right atrium; RV, right ventricle; Sp, spine; SVC, superior vena cava; T, trachea; TV, tricuspid valve.
Figure 2
Figure 2
Crash sign: a first‐trimester sonographic marker of spina bifida. Schematic diagrams showing a car stationed away from a wall, representing the mesencephalon (car) and occipital bone (wall) in normal fetuses (a), and then reversed into the wall, representing the posterior displacement of the mesencephalon and deformation against the occipital bone (“crash sign”) in fetuses with open spina bifida (b). (c–h) Ultrasound images in axial view at 12 to 13 weeks of gestation, showing mesencephalon in normal fetuses (c, e, g) and the crash sign in fetuses with open spina bifida (d, f, h). (c–f) Three‐dimensional reconstructed images of 2 sets of monochorionic twins discordant for spina bifida. (g, h) Images of singleton fetuses without (g) and with (h) the crash sign (arrow). 1, thalamus; 2, aqueduct; 3, mesencephalon; 4, arachnoid space; and 5, occipital bone. Reproduced with permission from Ultrasound Obstet Gynecol. 2019;54(6):740–745 (first published: 11 April 2019); DOI: 10.1002/uog.20285.
Figure 3
Figure 3
(a) Uterine artery waveform with diastolic notch. (b) Pulsatility index (PI) above the 97th centile, indicating high‐resistance circulation with placental insufficiency.
Figure 4
Figure 4
MRI‐derived maternal and fetal perfusion fraction and fetoplacental blood oxygen saturation with gestational age using the DECIDE multimodal algorithm in early‐onset fetal growth restriction (FGR) and control age‐matched normal pregnancies. Fetal and maternal perfusion and fetal oxygen saturation were determined in women grouped according to severity of early‐onset FGR. Key: red dots, FGR with uterine and umbilical artery Doppler >95th centile (abnormal uterine and umbilical Doppler FGR, n = 4); yellow dots, FGR with uterine artery Doppler >95th centile and umbilical artery Doppler <95th centile (abnormal uterine Doppler FGR, n = 4); green dots, FGR with umbilical and uterine Doppler <95th centile (normal uterine and umbilical Doppler FGR, n = 4); blue dots, control (n = 12). There are significant differences in the fetal perfusion fraction between the groups (0.16 ± 0.02 versus 0.20 ± 0.02 versus 0.20 ± 0.01 versus 0.20 ± 0.03, P = .048, groups as described above) with post hoc analysis showing that the difference lay between the abnormal uterine and umbilical Doppler FGR group (0.16 ± 0.02) and the control group (0.20 ± 0.03). There was also a significant difference in MRI‐derived fetoplacental blood oxygen saturation (42 + 7 ± 8.5 versus 59.2 ± 20.0 versus 66.5 ± 9.9 versus 75 ± 9.6%, P = .0079, groups as described above), with a significant difference between the abnormal uterine and umbilical Doppler FGR group and the normal Doppler FGR group (P = .006) and the control group (P = .0005). Group mean values shown as plus signs. *P < .05, **P < .005; ***P < .0005. Reproduced with permission from BJOG 2020;128(2):337–345 (first published: 30 June 2020); DOI: 10.1111/1471‐0528.16387. ab, abnormal; FGR, fetal growth restriction; MRI, magnetic resonance imaging; Um, umbilical; Ut, uterine.
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