Fetal Growth Restriction: A Pragmatic Approach

Abstract

An accurate diagnosis of fetal growth restriction relies on a precise estimation of gestational age based on a carefully obtained history as well as early ultrasound, since a difference of just a few days can lead to a significant error. There is a continuum of risk for adverse outcome that depends on the certainty of dates and presence or absence of comorbidities, in addition to the estimated fetal weight percentile and the umbilical artery waveform. The results of several studies, most notably the TRUFFLE trial, demonstrate that optimal management of fetal growth restriction with an abnormal umbilical artery waveform requires daily electronic fetal heart rate monitoring, and this monitoring does not require computerized interpretation. The role of ductus venosus waveform, biophysical profile, and middle cerebral artery waveform is less clear, and the results of these three modalities should be interpreted with caution.

Key Points

• A correct diagnosis of fetal growth restriction requires a very precise estimate of gestational age.

• In the presence of abnormal umbilical artery Doppler, the cornerstone of surveillance is daily electronic fetal heart rate monitoring.

• Surveillance with biophysical profile, ductus venosus waveform, and middle cerebral artery waveform are less important than daily electronic fetal heart rate monitoring.

Keywords

fetal growth restriction - ductus venosus waveform - feta heart rate monitoring - biophysical profile - middle cerebral artery waveform

In 2020 both the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) and the Society for Maternal–Fetal Medicine (SMFM) published practice guidelines regarding the diagnosis and management of fetal growth restriction (FGR).[1] [2] The differences between these two documents, representing a primarily European versus American approach, have generated a great deal of controversy.[3] [4] The ISUOG document places a greater emphasis on the use of Doppler in fetal surveillance, relying in large part on the 2015 TRUFFLE trial.[5] However, a careful analysis of the results of this important trial leads us to conclusions that are quite different from those of its authors.

The purpose of this paper is to suggest a clinical approach based on the data presented in the TRUFFLE trial and several other studies and to address some other clinical questions that frequently arise. Our goal is to provide an evidence-based framework for management that can augment the ISUOG and the SMFM guidelines.

Definition and Diagnosis of Fetal Growth Restriction

The likelihood of stillbirth is related to the degree of growth restriction in an exponential manner. Fetuses at less than the third percentile are clearly at the greatest risk and most often present early in pregnancy, compared with those between the 3rd and 10th percentiles. However, even fetuses between the 10th and 25th percentiles are at slightly increased risk compared with larger fetuses.[6] [7] As is the case with many other diseases such as chronic hypertension and gestational diabetes, there is a continuum of risk, and rigid adherence to an arbitrary cutoff that dichotomizes patients to a diseased or nondiseased state can sometimes be disadvantageous. Titrating the response to the anticipated degree of risk may be the best approach.

SMFM defines FGR as estimated fetal weight (EFW) or abdominal circumference (AC) < 10th percentile.[2] ISUOG defines FGR as EFW or AC < 3rd percentile or between the 3rd and 10th percentile with abnormal Doppler measurements of the uterine, umbilical, or middle cerebral arteries (e.g., umbilical artery [UA] pulsatility index > 95 percentile).[1] Both documents recognize that early-onset FGR, diagnosed before 32 weeks, is more closely associated with maternal hypertensive disorders and perinatal mortality than late-onset FGR recognized after 32 weeks. ISUOG also discusses a third category of small fetuses (e.g., between the 3rd and 10th percentiles) categorized in their document as “small for gestational age” with normal Doppler findings but that are nonetheless at increased risk for various surrogates for adverse outcome, consistent with the epidemiological studies cited above.

Since fetuses between the 3rd and 10th percentiles with normal Doppler studies are identified as FGR by the SMFM criteria but not ISUOG, the SMFM criteria would be expected to have a higher sensitivity but lower specificity for adverse outcomes compared with the ISUOG criteria. This was recently confirmed by a study demonstrating the sensitivity and specificity for a composite of adverse neonatal outcomes were (only) 15 and 87%, respectively, using the SMFM criteria, compared with 10 and 95% using the ISUOG criteria.[8]

Both documents rely on assignment of a percentile for the EFW, which depends on:

1. Normative data. The Hadlock curve, based on ultrasound measurements obtained 35 years ago of 392 women from Southwestern United States,[9] is favored by SMFM, whereas the ISUOG refers to their previous document,[10] which favors carefully obtained international data from INTERGROWTH-21[11] or World Health Organization.[12] Comparison of these reference standards shows significant differences ([Tables 1] and [2]): at 24 weeks, the INTERGROWTH curve identifies a greater number of fetuses as FGR compared with Hadlock, whereas the reverse is true at 32 weeks. Use of any of these charts ignores the effect of fetal sex, maternal parity, twin pregnancy, and (more controversially) racial/ethnic variation.

2. Accurate sonographic biometry is obviously important, as is also evident in [Tables 1] and [2]. For example, according to the INTERGROWTH-21, the difference between the 3rd and 10th percentile at 24 weeks is only 27 g.

3. A very precise estimate of gestational age is of utmost importance, as an error of just a few days can make a significant difference in the weight percentile in the second and early third trimester. For example, according to the Hadlock curve, a 652 g fetus would be at the 10th percentile at 25^0/7 weeks but the 25th percentile at 24^3/7 weeks; a 589 g fetus would be at the 3rd percentile at 25^0/7 weeks but the 18th percentile at 24^0/7 weeks. Similarly, a 602 g fetus would be at the 10th percentile at 24 weeks on the INTERGROWTH-21 curve but > 50th percentile at 23 weeks. At earlier gestational ages, the need for a precise estimate of gestational age is even greater. For example, on the Hadlock curve, 398 g is the 10^th percentile at 22 weeks but the 28^th percentile at 21^3/7 weeks.

Table 1 Third percentile for fetal weight according to the Hadlock[8] the INTERGROWTH-21[11] standards, and 2.5 percentile according to the World Health Organization[12] standards

Gestational age (wk)	Hadlock 1991 (g)	INTERGROWTH-21 (g)	WHO (g)
24	503	575	523
26	685	716	707
28	908	892	929
30	1,169	1,106	1,185
32	1,465	1,357	1,473

Table 2 Tenth percentile for fetal weight according to the Hadlock,[8] the INTERGROWTH-21,[11] and the World Health Organization[12] standards

Gestational age (wk)	Hadlock 1991 (g)	INTERGROWTH-21 (g)	WHO (g)
24	556	602	576
26	758	757	780
28	1,004	951	1,026
30	1,294	1,190	1,313
32	1,621	1,473	1,635

Abbreviation: WHO, World Health Organization.

The American College of Obstetricians and Gynecologists guideline for establishing the due date[13] bases the estimate of the gestational age on the last menstrual period unless the sonographic biometry differs by >5 days prior to 9 weeks, > 7 days between 9 and 16 weeks, and by a larger amount if the first ultrasound is done later in pregnancy. This degree of accuracy is not always sufficient. Delayed ovulation is common, and therefore the menstrual history must consider changes in the timing of conception due to long or irregular cycles or the use of hormonal contraception. While some patients are unsure of the exact date of their last menstrual period, others reliably know their date of ovulation or conception, which is not always day 14. Failure to consider any of these factors can easily result in an error of a few days, potentially changing the classification between “normal” and FGR. At the time of registration, a carefully obtained history should be accompanied by a low threshold for early first-trimester ultrasound, if resources permit.

Management of Fetal Growth Restriction

Neither the ISUOG and SMFM documents discuss the importance of preexisting comorbidities such as hypertension, acquired thrombophilia, renal and autoimmune diseases, advanced age, elevated body mass index, and a complicated prior pregnancy. The presence or absence of comorbidities such as hypertension plays a major role in the likelihood that a particular EFW represents placental insufficiency and the likelihood that a given set of findings will result in stillbirth.[14]

Both documents recognize that the degree of growth restriction and evaluation of the UA waveform are of great importance in the management of FGR and recommend the use of electronic fetal heart rate monitoring (FHRM). The ISUOG document suggests that this should be every 2 or 3 days if the UA waveform demonstrates absent or reversed diastolic flow.[1] The SMFM document suggests that FHRM should be weekly if the UA waveform is normal, once or twice a week if there is decreased end diastolic velocity, at least twice a week if there is absent end diastolic flow, and at least daily if there is reversed diastolic flow.[2]

The ISUOG document prefers computerized rather than visual interpretation of FHRM, since it allows quantification of short-term variability (STV), whereas the SMFM document does not mention computerized interpretation. However, the difference between the two approaches that has generated the most controversy involves the role of Doppler evaluation of the ductus venosus (DV) and middle cerebral artery (MCA).

Ductus Venosus Waveform

The ISUOG recommendation that DV waveform should be monitored for early-onset FGR when there is an abnormal UA waveform relies heavily on the TRUFFLE trial.[5] This was a randomized controlled trial of three groups of fetuses between 26 and 32 weeks' gestation with FGR defined as AC < 10th percentile and UA pulsatility index > 95 percentile. Surveillance in one group was by computerized analysis of STV and UA Doppler velocimetry; the other two groups also incorporated evaluation of the DV waveform but used more stringent STV positivity criteria. The primary outcome was survival without neurodevelopmental impairment at 2 years of age, and the secondary outcome was survival without severe neonatal morbidity.

It is perhaps not widely recognized that there was no statistically significant difference in either the primary or secondary outcome among the three groups. The number of survivors without neurodevelopmental impairment was slightly less in the DV groups (p = 0.09), and there was an identical number of survivors without severe neonatal morbidity in each group. A post hoc analysis identified a statistically significant decrease in neurodevelopmental impairment in survivors of the two groups that were managed with DV waveform and the more stringent STV positivity criteria: 47/299 (16%) versus 33/144 (23%), which was partially offset by a small increase in stillbirths. However, it must be remembered that clinical management should not be determined by a statistically significant finding based on a post hoc analysis of the data rather than a prespecified hypothesis.[15]

The similarity in outcomes among the three groups should not be surprising, as the DV waveform had a rather limited role in management. As has been previously pointed out, only 45/205 (22%) women allocated to the DV groups with a live-born baby were delivered due to an abnormal DV waveform; 87 (42%) were delivered due to FHR abnormalities, and the remaining 73 (36%) were delivered for other fetal indications or maternal deterioration (mainly hypertension).[16]

These findings are consistent with a more recent study of 132 fetuses with FGR between 26 and 34 weeks with absent or reversed diastolic flow in the UA.[17] Only 15 fetuses (11%) were delivered due to an abnormal DV waveform compared with 81 (61%) that were delivered due to FHR abnormalities and 36 (27%) that were delivered for other fetal or maternal indications.

Furthermore, reliance on a normal DV waveform for continuing the pregnancy can result in stillbirth. In the TRUFFLE trial five of seven stillbirths had a normal DV waveform;[18] stillbirth shortly after a normal DV waveform has also been reported elsewhere.[19]

Finally, false-positive DV waveform results are possible ([Fig. 1]). This can occur if the hepatic vein, which is in close proximity to the DV and typically demonstrates reversed waves,[20] is mistakenly sampled.

Fig. 1 False positive ductus venosus waveform. This image was taken at 26 weeks. Subsequent waveforms were normal, and the patient delivered a 2,400 g (5th percentile) baby at 37 weeks with a normal course in the nursery.

Fetal Heart Rate Monitoring

Importantly, the TRUFFLE trial demonstrated an unexpectedly good outcome in all three groups.[21] The authors attribute this in part to frequent FHRM, which was daily in 17 of 20 participating centers and at least every other day in the rest.[22] The daily risk of abnormal STV and/or recurrent decelerations was 5%, and most decreases in STV occurred suddenly and unexpectedly within 24 hours of delivery.

The components of FHRM include presence or absence of accelerations or decelerations and evaluation of variability. The ISUOG document stresses the importance of STV, stating that when computerized FHRM is available, STV should be the main parameter assessed.[1] However, in the TRUFFLE trial, of the 79/165 (48%) patients who were delivered for an abnormal FHR tracing, the indication for delivery was decelerations rather than decreased STV.[16] The findings of Fratelli et al were again similar: 76/132 (58%) patients were delivered due to decelerations on FHRM compared with only 5/132 (4%) who were delivered due to decreased STV.[17]

The superiority of computerized over visual evaluation of STV is unproven.[22] [23] [24] The correlation with fetal acidemia is not robust, as there is a large overlap with normal fetuses,[25] especially if decelerations are absent,[26] and there is disagreement regarding which criterion is optimal.[24] [25] Finally, in the TRUFFLE trial the STV positivity criteria were different in the groups that were monitored by DV waveform compared with the group that was not.

It appears that frequent FHR monitoring, rather than computerized assessment, is the critical variable. This conclusion is supported by a recent study involving 367 FGR pregnancies managed by daily visual FHR monitoring who were delivered with a median birth weight of 900 g at 30 weeks. There were 347 live births and only 6 unanticipated fetal deaths.[27]

Other Modes of Surveillance

Use of the biophysical profile (BPP) is well established[28] and is the mainstay of fetal surveillance in many institutions. However, BPP was not utilized in the TRUFFLE trial, and the ISUOG recommendation regarding its use was considered a “good practice point” defined as “Recommended best practice based on clinical experience of the Guideline Development Group,” its lowest level of evidence.[1] Similarly, the SMFM document states that “further studies are required to prove the usefulness of BPP,[2] citing a series of 48 fetuses < 1,000 grams with daily BPP in which stillbirths occurred in 3/13 fetuses with a BPP score of 6/8 and in 3/27 fetuses with a BPP score of 8/8.[29]

The role of MCA Doppler, and the ratio of MCA/UA pulsatility index called the cerebroplacental ratio (CPR) is also unclear. There is uncertainty about normative data, two meta-analyses were unable to demonstrate its utility[30] [31] and it was of no benefit in fetuses less than 32 weeks in the TRUFFLE trial.[32] Nonetheless, the ISUOG gave multimodal assessment for monitoring fetuses with early FGR, including MCA Doppler, its highest grade of assessment.[1] Regarding late-onset FGR, they state that “MCA-PI and its ratios to UA-PI are the most important Doppler parameters.” However, they only recommend delivery for abnormal MCA Doppler after 38 to 39 weeks. Conversely, SMFM states that additional clinical trials are needed to evaluate the effectiveness of CPR in guiding clinical management.[2] The ongoing TRUFFLE 2 study[33] may provide these data.

Conclusion

It is imperative that all providers obtain a very careful history at the first prenatal visit that in an attempt to determine the precise date of conception. This entails inquiring about the length and regularity of the menstrual cycle, the use of hormonal contraception, and if the patient was using other methods of tracking ovulation or conception. In resource-rich settings, there should be a low threshold for an early first-trimester ultrasound.

There is a continuum of risk for small fetuses, depending on the certainty of dates, comorbidities, the EFW percentile, and the UA Doppler waveform. A greater degree of risk warrants closer surveillance. On one extreme a healthy patient whose fetus is near the 10^th percentile by less than certain dates should have at least a follow-up scan at a reasonable interval, perhaps 2 to 4 weeks. On the other extreme, fetuses at highest risk due to size or comorbidities should undergo intensive surveillance with frequent FHRM ([Table 3]). It is probably unimportant whether it is visual or computerized; what is essential is that it is frequent; daily if the UA waveform has a pulsatility index > 95 percentile. Monitoring DV waveform, BPP and MCA Doppler appears to be less important and perhaps less reliable, so both positive and negative results should be interpreted with caution.

Table 3 Recommended surveillance of pregnancies complicated by fetal growth restriction and abnormal umbilical artery waveform < 32 weeks

	Electronic FHRM	Ductus venosus waveform	Biophysical profile	Middle cerebral artery waveform
SMFM	Diminished EDV: 1–2 × per week absent EDV: at least 2 × per week reversed EDV: 1–2 × per day	Not recommended	No definite statement either for or against	Not recommended
ISUOG	Diminished EDV: no statement absent EDV: every 2–3 d reversed EDV: every 2–3 d computerized FHRM is preferred	Recommended	If computerized FHRM is unavailable; every 2–3 d for absent or reversed EDV	Useful to guide monitoring but not timing of delivery
This review	Diminished EDV: daily absent EDV: at least daily reversed EDV: at least daily	Optional; interpret with caution	Optional; interpret with caution	Optional; interpret with caution

Abbreviations: EDV, end diastolic flow in the umbilical artery; FHRM, fetal heart rate monitoring; ISUOG, International Society of Ultrasound in Obstetrics and Gynecology; SMFM, Society for Maternal-Fetal Medicine.

Note: Diminished EDV implies a pulsatility index > 95 percentile.

Finally, shared decision-making is essential. Especially in cases of extreme prematurity, it is essential to understand the value that prospective parents place on avoiding stillbirth even at the risk of neurodevelopmental impairment versus their desire to optimize long-term outcomes.

Conflict of Interest

None declared.

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Publication History

Received: 26 October 2024

Accepted: 20 November 2024

Accepted Manuscript online:
25 November 2024

Article published online:
24 December 2024