In South Africa, the main cause of perinatal death is unexplained stillbirths (twenty five percent). Twenty five percent of the unexplained stillbirths have intrauterine growth restriction (IUGR); with amniotic fluid and umbilical artery Doppler abnormalities as determined by ultrasound [1]. Furthermore, the highest number of perinatal deaths (of which more than 50% are stillbirths.) occur in Black Africans (75%). The number of stillbirths have been increasing over the years; 8 per 1000 in 1998 and 17 per 1000 births in 2013 [1]. Foetal death remains a major challenge in obstetrics, and the precise aetiology is difficult to determine in many cases. The cause of stillbirth is unknown in 25 to 60% of cases of foetal death. Unexplained stillbirth is a mystery. Numerous population-based studies have identified risk factors for this condition, but extensive research efforts over the last two decades have not resulted in a reduction in the incidence [2].  The majority of the reports deal with population-based strategies for the primary prevention of unexplained stillbirth. Unfortunately, many of the risk factors, such as lower socioeconomic status, maternal age, and race, are not easily modifiable. During antenatal care, other risks such as maternal obesity, smoking, and diabetes are routinely addressed. Because the rate of stillbirth is not decreasing, the most common issue that antenatal care providers face is deciding what to offer women in their next pregnancy [3]. Failure to identify growth restriction appears to be a common factor in many unexplained stillbirths [4], with failure to identify growth restriction being a common factor [5].  Although almost universal, antenatal measurement of symphysio-fundal height has limited utility in screening for growth restriction [6]. Because growth restriction is a final common pathway for many pathological processes, it would seem advisable to provide routine fetal ultrasound for the detection of abnormal fetal growth. Up to 32 weeks of gestation, uterine artery flow measurement by Doppler has been shown to be a useful predictor of stillbirth due to growth restriction, but such testing is of limited value in later pregnancy [7]. Risk factors for stillbirths have been identified by numerous population-based studies (nulliparity, advanced maternal age, smoking, obesity and low socioeconomic status) and small gestational age is one of the risk factors. Prevention strategies that target the risk factors can play a role in reducing the rate of stillbirths during the antenatal care [3]. Unexplained stillbirth is a challenging subject to research because of the paucity of clues. In addition, several of the above factors are likely to be heterogeneous. The incidence of intrauterine growth restriction is between 3 and 9% of pregnancies in high resource settings, but in low-resource settings, rates as high as 30% of pregnancies have been reported¹. Less than 30% of infants with a birth weight <10th percentile is detected during pregnancy [2]. Prenatal diagnosis of fetal growth restriction is made by either physical examination (symphysis fundal height) or ultrasonography. Aetiology of intrauterine fetal death is complex; making it difficult to find the cause especially in resource constraint countries. There are not enough studies done on other causes of unexplained stillbirths, and none exists in Kwa-Zulu Natal. Furthermore, data on intrauterine growth restriction is limited in South Africa. In primary care, district and regional hospitals, poor technique and expertise to detect IUGR has resulted to stillbirths. However, to improve prediction and prevention of stillbirth, specific modifiable risk factors should be aimed at. Clinical trials and research focus on known risk factors including maternal smoking, obesity, and medical conditions. Problems with the placenta have also been implicated in the occurrence of stillbirths in the past. IUGR is also an established risk factor for stillbirth. However, few studies have examined specific factors that may increase stillbirth risk, like fetal fragility and stressors. Unexplained fetal fatalities are those when no harmful factor has been found. Therefore, the aim of the study was to determine the association between missed intrauterine growth restriction and unexplained intrauterine deaths.

This observational descriptive study was conducted over one year, in two hospitals serving the Pietermaritzburg metropolitan area. All booked women from the age of 18 with singleton pregnancies, gestational age of 28 weeks or more (or weight of 1000 g or more)- determined by last normal menstrual period; clinical examination or early ultrasound were recruited, and their records reviewed. The exclusion criteria included patients below the age of 18 years, multiple pregnancies, documented cause of death on the Perinatal Problem Identification Program (PIPP) form, and un-booked patients.

Data Collection

Demographic, socioeconomic, obstetric and antenatal data was collected following record reviews using a data extraction sheet. We also collected data on weight gain during pregnancy, nutritional status and any co-morbidities. Serial plotting of the symphysis-fundal height growth curve was analysed.

Data Analysis

Data was entered into SPSS version 25 for analysis. A descriptive statistical analysis of the data was conducted. The Chi-square test of association and the Fisher exact test was used to assess any associations between categorical variables. A p value of < 0.05 was regarded as statistically significant.

Regulatory approvals

Provincial and Institutional approval was obtained from the relevant authorities prior to commencing data collection. The principal investigator was responsible for capturing all data. The study was approved by the Biomedical and Research Ethics Committee (BE038/18).

There were 305 stillbirths over the study period, of which 165 met the inclusion criteria. All parturients were Black African (100%) and of low socioeconomic status (64.2% were single, 77.6% had secondary education, and 81.8% were unemployed with varying levels of skills) (Table 1). Although 48.5% of parturients were overweight and was and 10.9% obese, maternal weight gain in pregnancy had no significant impact on fetal growth (Table 2). The study included 36.4% primiparous and 63.6% multiparous women. Most patients (65.5%) booked for antenatal care between 16-28 weeks but the visits were irregular. A majority (67.3%) of the patients started antenatal care at the clinic and were attended by midwives and professional nurses. Forty-six (27.9%) were HIV infected with 12.7% of patients having CD4 counts more than 500 cells/mm3. Of the HIV infected, only 20(12.1%) were associated with fetal growth restriction (Table 2). Patients with Anemia during pregnancy were not at increased risk of fetal growth restriction compared to those without Anemia (Table 3). Smoking was prevalent in the study population with 1.8% of women indicating that they were smoking in pregnancy, 2.4% of patients consumed alcohol and there was no associated fetal growth restriction in both groups (Table 3). Gestational age was determined by calculating the dates from the last menstrual period, early ultrasound and clinical palpation.  The median gestational age was 34 weeks (28-41 weeks) and a median birth weight of 1812.50g (570-4200 g). Seventy-nine infants (47.9%)) were preterm (born before 34 weeks), and twenty-nine (17.6%) had fetal growth restriction.40 (24.2%) were late-preterm at (34–36 weeks), and 46 (27.9%) were term at (≥37 weeks) with 13(7.9%) growth restricted. In 40% of cases the birth weight was below the tenth centile for gestation. Obstetric ultrasounds done did not detect fetal growth (only done for estimating gestational age). The measurement of symphysis fundal height was not done in 69(41.8%) and 38(23%) had growth restricted foetuses (Table 4). The study showed 40% of unexplained stillbirths were probably growth restricted.

 Table 1: Demographic characteristics of the study population.

Table 2: Obstetric history.

Table 2: Obstetrics history (continued).

Table 3: Maternal risk factors.

Table 4: Tools used to detect intrauterine growth restriction and outcome of pregnancy.

The proportion of stillbirths in this study was notably higher than 0.42% reported in a well-resourced setting such as the United Kingdom but less compared to countries like India and Pakistan which are also low resource areas [9]. However, it was lower than the 4.0% reported by Avachat and colleagues in India [10]. 3.26% reported by Kidanto and colleagues in Tanzania [11], and 2.59% reported by Chalumeau and colleagues in urban West Africa [12]. These differences in proportions are likely attributable to population health differences between developed and developing countries, as well as the availability of prenatal quality care. In our study, 40% of unexplained stillbirths had fetal growth restriction, which was slightly higher to the findings of Lavin et al in 2016¹. The avoidable factors for these unexplained stillbirths were both patient and health worker related. A study by Vais et in 2012 showed that age below 20 and above 35 was associated with high perinatal death rates [13]. A recent meta-analysis by Flenady et al concluded that age >35 increases the odds of stillbirth by 65%. Also, the risk of stillbirth increased by 23% in overweight women and by 60% in obese [14], our study did not show these differences Flenady et al identified four studies which investigated the relationship between smoking and the risk of stillbirth and those studies concluded that smoking could contribute to as many as 20% of stillbirths in low-income countries, this was not the case in this study. It has been shown previously that unexplained stillbirth is much more prevalent in patients with a poor socioeconomic background [15]. A significant proportion of unexplained stillbirths occur in low-risk women with an apparently uncomplicated pregnancy [16]. Maternal HIV disease with CD4 < 200 in the first trimester was strongly associated with FGR in the study by Iqbal 2010; one of the three women who had CD4 <200 in our study had growth restricted foetus, however this was not statistically significant. NICE and the RCOG recommend that SFH measures be taken at each prenatal appointment beginning at 24 weeks (ensure empty bladder). It discovers fetuses that are too small for gestational age (SGA) with a sensitivity of 21% and a specificity of 96%. With a sensitivity and specificity of 27% and 88 percent, respectively, SFH measurement improves prediction of IUGR very somewhat, however the predictive accuracy varies widely depending on the study cited. A Cochrane review by Peter et al. of 1639 women comparing SFH and abdominal palpation for detection of IUGR, noted no significant difference in incidence of SGA or perinatal death between the groups. Our study did not show any clinical difference whether the SFH was plotted or not, in keeping with the Cochrane review. Despite reservations on its robustness, SFH measurement remains a simple, low cost, non-invasive screening tool that can be used in a variety of clinical settings and socioeconomic environments. Foetal growth restriction is not only associated with maternal risk factors but also fetal aneuploidies and fetal infection, as a result in high income countries investigations are done to exclude these [19]. The investigations include fetal autopsy, gross and histologic evaluation of placenta, umbilical cord, membranes and genetic testing, this is not routinely done in low resource countries due to cost and lack of expertise. The results of IUFD in our study was lower than the reported variation of 14- 47% [17,18], and may be due to our small sample size and the duration of the study. Our study has several limitations, this was a small retrospective study, not representative of the whole population of Pietermaritzburg, done over a short period of time. We were unable to compare the potential risk factors and to analyse the effect on birth weight because of the small number of patients included in the study. Secondly the weight gain was fixed for the entire pregnancy. The results need to be interpreted with caution; more research is still required.

There is an association between missed IUGR and unexplained intrauterine deaths. Fetal Growth restriction remains the highest contributor to antenatal fetal deaths, and at present cost-effective screening has not been identified. Primary health care capacitation for quality antenatal care and early referral to higher level of care is important in preventing the risk factors associated with stillbirth and its social and economic implications, but these interventions are difficult to achieve at present due to lack of resources especially in resource constraint countries. It should be remembered that birth weight can be reduced by the duration of intrauterine death. The investigations (histology, microbiology and genetic studies) for the cause of the death are still not performed.

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