Identifying the High-Risk Fetus in the Low-Risk Mother Using Fetal Doppler Screening

FGR as a Major Cause of Antenatal Stillbirths

A fetus who does not reach its full genetic growth potential is defined as having FGR.¹³ This definition implies that a growth-restricted fetus is not necessarily small but still at risk of adverse outcomes. The fact that a growth-restricted fetus is not always small explains why current techniques such as symphysis-fundal height measurements or measuring fetal size on conventional ultrasound have failed to reduce perinatal mortality. Placental insufficiency is the most common cause of FGR and occurs when the placenta is damaged to such an extent that it cannot provide the fetus with sufficient nutrients and oxygen, ultimately leading to starvation.³⁴ As the placental insufficiency progresses, the fetus initially loses fat and glycogen stores, detected by a reduced liver size, followed by a reduction in muscle mass and later in bone mass, with ultimately death (stillbirth) as the most severe consequence. As previously mentioned, AEDF is a measure of end-stage placental disease and, left unmanaged, usually results in a stillbirth. If the prevalence of AEDF is high in a low-risk pregnant population, then FGR is an important cause of stillbirth.

When one extrapolates the South African AEDF prevalence to all births in the country per year and assumes, conservatively, that half of the 1 million births annually are from low-risk pregnancies and 1% have undetected AEDF and assumes, conservatively, that half of these fetuses die, then 2,500 stillbirths per year [(500,000 × 0.01) × 0.5)] could be ascribed to AEDF.²⁹ Unexplained stillbirths account for approximately 25% of the 20,000 stillbirths annually in South Africa (approximately 5,000 stillbirths),¹⁰ therefore, approximately 50% (2,500) of the unexplained stillbirths in South Africa could be due to undetected AEDF and could be prevented by CWDU screening.

Postnatal Diagnosis of FGR

The Umbiflow International study found that fetuses with abnormal UmA-RI were significantly smaller at birth than their normal UmA-RI counterparts, across all birth weight centiles and after correction for sex and gestational age at birth, leading the research team to the conclusion that CWDU has the potential to diagnose FGR before birth.³⁰ After birth, FGR due to placental insufficiency can be assessed by studying the infant's body composition, in particular, the fat-free mass (FFM), which is a measure of muscle and bone mass. Unfortunately, this measure is not routinely available, but body composition can be measured in infants by air displacement plethysmography, dual-energy X-ray absorptiometry, or deuterium dilution. A follow-up study of infants of LRMs who were screened with CWDU at 28–34 weeks' gestation reported a significant association between an abnormal UmA-RI in pregnancy and lower infant FFM at 6 weeks, 10 weeks, 14 weeks, and 6 months, pointing toward a starved fetus.³⁵ Furthermore, more than 75% of these infants were classified as appropriate-for-gestational age at birth. Interestingly, those infants who were classified at birth as being SGA (see below) but who had a normal UmA-RI during pregnancy had a higher FFM than those infants who were classified as appropriate-for-gestational age with an abnormal UmA-RI, although the numbers were small. This illustrates that screening with CWDU has the ability to detect fetuses with FGR irrespective of their size and birth weight, across all birth weight-for-gestational age centiles.

Difference Between SGA Babies and FGR

An SGA baby is defined as a baby whose birth weight is less than the 10th centile for its gestational age. Using this definition, 10% of normal babies will classify as SGA. This definition does not satisfy the requirement of a growth-restricted fetus, as, for example, a fetus who is genetically destined to have a birth weight on the 75th centile but who is born on the 25th centile and is not reaching his/her growth potential does not fulfill the criteria of being SGA. This growth-restricted fetus has a much greater risk of adverse outcomes than a fetus who is born on the 8th centile, is SGA, and is not growth-restricted (constitutionally small). The advantage of Doppler ultrasound of the umbilical artery is that it tests placental function rather than fetal size and can detect poor placental function irrespective of the fetal growth centile. This gives screening with Doppler ultrasound a big advantage over screening by measuring size that requires serial measurements to determine the growth pattern, which is much more expensive and difficult for a health system to manage. Thus, the Delphi consensus on defining FGR includes Doppler abnormalities in their definition.³⁶ Furthermore, the dropping of centiles (even though not less 10th centile) is included in their definition as contributory parameters in diagnosing FGR supporting the definition of a fetus not reaching its genetic growth potential.

Impact of CWDU Screening on Low-Risk Pregnancies

Having determined that CWDU screening is potentially worthwhile in geographic locations that have a high prevalence of FGR, the next step was to assess if the knowledge of an abnormal UmA-RI within the clinical care setting actually reduced the stillbirth rate. A cohort analytic study of women attending primary health care antenatal clinics in 9 different geographical areas in diverse settings in South Africa compared a group of LRMs who were between 28 and 34 weeks of gestation and were screened with CWDU to a group of LRMs who were not screened.

Among the CWDU group of 7,088 women, with pregnancy outcomes recorded in 6,536 (92.2%), 66 women had stillbirths, resulting in a stillbirth rate (SBR) of 10.1/1,000 births. Among the control group of 10,832 women, the SBR was 17.8/1,000 births. Hence, screening LRMs with CWDU followed by referral and further management according to the study protocol (Figure) resulted in a decrease in the SBR of 43% (risk ratio [RR]: 0.57, 95% confidence interval [CI]=0.29, 0.85). If all women in the control group who developed subsequent antenatal complications were excluded, there were 9,811 women and 152 stillbirths, giving an SBR of 15.5/1,000 births, which was 35% higher than the CWDU-screened group (RR: 0.65, 95% CI=0.36, 0.94). The cesarean delivery rate was similar between the groups, but there was an increase in the number of low birth weight infants in the CWDU-screened group. However, despite the increase in the use of neonatal services, the neonatal mortality rate did not increase, thus the fetuses who were at risk of stillbirth were not transferred to neonatal deaths (T Hlongwane, unpublished data, 2022).

Nkosi et al. reported similar results where 2,868 women had CWDU screening and the pregnancy outcomes were available for 2,539 fetuses (88.5%).²¹ There were 29 perinatal deaths in the CWDU group. The perinatal mortality rate for 12,168 women attending primary health care antenatal clinics and their referral hospitals who did not have a CWDU screening was 21.3/1,000 births, significantly higher than in the CWDU group (11.4/1,000 births, RR: 0.58, 95% CI=0.42, 0.81).

Thus, UmA-RI screening using CWDU is an effective tool that detects FGR, and, when the information is used, it prevents stillbirths.

Additional Effects

There are several known maternal and infant factors that result in FGR, but just as many unknowns; hence, it is currently not feasible to prevent FGR from occurring primarily. However, early detection of FGR and appropriate management of pregnancies enable close fetal monitoring and prevention of stillbirths. If the fetuses survive, these infants can then be further monitored and interventions put in place to optimize postpartum growth and development since it is known that infants who were growth-restricted in utero are at greater risk of stunting, obesity, and cardiovascular diseases (e.g., stroke and hypertension) later in life.^37–39 A study done on infants from low-risk pregnancies who had FGR reported that these infants had reduced cognitive ability at 12 years.⁴⁰

Since the “first 1,000 days” are known to be a critical period for growth and development, a simple and effective screening and intervention during this period could play a major role in terms of improved health outcomes, not only in the growing fetus but further into infancy, childhood, and adulthood.

Potential Negative Effects

The immediate effect of implementing the screening system will be the increased pressure on the local antenatal and neonatal services.

• There will be approximately 10% more referrals of women classified as having low-risk pregnancies to high-risk antenatal clinics for evaluation. This will increase the clinicians' time at the receiving facility. In the previous studies done, a separate clinic was set up for women with an abnormal UmA-RI. Less than 1 of 10 referred women will have a false positive screening test and be referred back to the primary antenatal clinic.

• Furthermore, there will also be more premature and/or growth-restricted neonates requiring clinical management, increasing the use of neonatal services. However, this can be interpreted as positive, as without the screening a number of these neonates would have been stillbirths.

The major concerns are: (1) Are the fetuses that are potential stillbirths being transferred to neonatal deaths? and (2) Are there unnecessary interventions that increase maternal and neonatal morbidity? Hlongwane et al. and Nkosi et al. reported no increases in neonatal mortality when the CWDU-screened group was compared to the unscreened group—neither was the cesarean delivery rate significantly different.²¹ Further, Alfirevic et al. did not find a difference in interventions in HICs when those women with normal pregnancies who had a screening Doppler ultrasound were compared to those who did not.²⁷ However, as with any new intervention, this aspect will have to be carefully monitored.

Another potential negative effect is that women referred for more intensive evaluation will be more anxious about their pregnancy. Any fetus with an abnormal UmA-RI probably has some degree of FGR, and that infant's FFM will be reduced.³⁵ This infant might then be at risk of developing childhood malnutrition or obesity and the woman, knowing this, can then apply appropriate infant feeding practices.