Identification of Risk Factors for Preterm Birth in a Regional Hospital in Northern Region of Sudan—A Prospective Study

1. Introduction

Preterm birth defined as delivery < 37 completed weeks is the leading cause of neonatal morbidity and mortality world-wide, accounting for 18% of deaths among children less than 5 years old and 35% of deaths among those aged less than 28 days [1]. The rate PTB varies from country to country with the highest rates in low-income countries and the lowest in high income countries. [2] It is estimated that there are approximately 15million preterm births every year for an average PTB rate of 11% [3]. The rates vary from 5%-9% in high income countries to about 18% in some low-income countries [4,5,6]. In sub-Sahara African the rate of PTB is high being for example 13.3% in Ethiopia [7] and 18.3% in Kenya [8]. In addition to negative health outcomes, the cost of PTB is exorbitant to families, society and governments [9]. The long-term health consequences include chronic lung diseases, cognitive impairment and cardiovascular disease [10].

Increasingly, PTB is not regarded as a single entity, but a complex condition best described as a syndrome caused by an interaction of multiple factors where these are known but in many cases these factors are unknown. There is now an acknowledgement that to better understand its pathophysiology, prevention and management, PTB should be phenotyped based on conditions present in the mother and conditions of the fetus and placenta at the time of birth [11]. Two classical phenotypes have been proposed [12,13]. Prevention of PTB can only be effective if its multifactorial aetiology is better understood.

Although the causes of PTB are known in some cases, they are poorly defined in many cases, but various risk factors have been identified [14]. Most of these risk factors are modifiable [15] and it has been estimated that more than 75% of PTB deaths are preventable without intensive care [16]. In sub-Sahara Africa and some South-East Asia [17,18] with limited resources, therefore a more pragmatic approach to reducing PTB would be identifying the modifiable factors and taking appropriate steps to mitigate them. These factors vary from individual, social and medical, to care provided antenatally. Identification of these factors and addressing them either pre-pregnancy or during pregnancy may significantly reduce the risk of PTB. Some of these factors which if addressed have been shown to reduce the rate of PTB include smoking [10], short interpregnancy intervals, maternal age (<20years and >35 years) [19,20], anaemia, urinary tract infections, previous preterm birth and medical disorders of pregnancy [11,20] and infections [21].

That the WHO and the United Nations' 2010 goal of reducing mortality due to PTB by 50% before 2025 has unfortunately not been achieved in most countries is reflective of failure of multidisciplinary concerted efforts to address modifiable factors that increase the risk of PTB. In Sudan for example, a country that is currently experiencing one of the most destructive civil strife, most studies on PTB have been retrospective and few have investigated modifiable factors such as nutritional status, periodontitis [22] number of antenatal clinical visits and regularity of iron and folate supplementation during pregnancy [23]. In a previous study from Omdurman, Sudan, the rate of live preterm birth was surprisingly 3.8%, significantly lower than rates reported from all of the region. The study did identify a few preventable factors (interpregnancy interval of <18 months and low or high BMI), hence was not comprehensive, and furthermore the economic changes in the country partly because of the civil strife and poverty have undoubtedly increased the number and prevalence of preventable factors [24]. That study [24] could be criticised on many counts, the most important being that the cohort was not reflective of the country (the rate was too low). In another study in North Ethiopia, age, rural residency, lack of antenatal care, multiple pregnancy and malaria infections were identified as preventable factors associated with PTB [7]. The aims of this study were therefore to comprehensively investigate and identify the modifiable/preventable factors (including intrinsic maternal factors like nutrition and extrinsic factors) and determine whether they are similar to those reported from other sub-Sahara countries and middle- and high-income countries in the hope of overcoming the weaknesses in the previous and retrospective studies. Identifying these factors should provide healthcare policy makers a list to address in any multidisciplinary attempt to reduce the rate and burden of PTB in Sudan.

2. Materials and Methods

Study design and setting

This was a prospective study at Omdurman Maternity Hospital, located in Khartoum State for the period June to December 2022 - a period of political instability and population displacement that preceded the ongoing civil war. All pregnant mothers who received antenatal care and their pregnancies progressed beyond 26 weeks of gestation and delivered in the hospital were recruited. We excluded those who miscarried or had an elective caesarean section (normally performed at term). For each woman studied, a set of variables were extracted from their records onto a spread sheet. These included age, family income, level of education, antenatal folic acid and iron supplementation, number of antenatal visits, obstetric history (including previous deliveries, miscarriages and gestational age at delivery), medical history, social variables (smoking, alcohol and drugs) and any complications during pregnancy. All information was collected on a spreadsheet.

The family income was estimated from the combined earnings of the woman and her husband. Education level was categorised into

The women who delivered before 37 weeks were analysed as the preterm group while those whose pregnancies progress to at least 37 weeks of gestation were analysed as the term group.

Preterm birth was defined as delivery between before 37 completed weeks of gestation. 26 weeks is the gestational age cut-off for fetal viability in viability in Sudan.

Nutritional status was assessed at the first antenatal visit using Mid-Upper Arm Circumference (MUAC). Status was categorized as 'poor' (MUAC < 23 cm), 'normal' (MUAC 23-28 cm), or 'good/excellent' (MUAC > 28 cm) [25,26].

Iron and folate supplementation was categorized as 'regular' if the woman reported taking prescribed supplements for more than 75% of her pregnancy days, and 'rare' if taken for less than 50%.

Antenatal care (ANC) attendance was considered 'regular' if the woman attended at least 4 scheduled antenatal visits prior to delivery, as per WHO recommendations. Attendance of fewer than 4 visits was deemed 'inadequate'.

Data analysis

The IBM Statistical Package for Social Sciences software, version 27of 2019, was used for analysis. Data are presented as means and standard deviation if normally distributed and median and range if not. Normal distribution was tested by the Kolmogorov Smirnov test. Comparisons between the groups were made using Chi square Test or Fisher’s Exact Test. Binary logistic regression Test was used to identify risk factors associated with PTB. The statistical analysis was undertaken by a statistician (Dr Rami Yousif Hasabelrasul Mohamed)

Ethical consideration

Ethics approval for the study was obtained from the Sudan Medical Specialization Board (SMSB), council of family medicine, Khartoum state ministry of health research department on 25th May 2022. Each woman who was included in the study gave a signed informed consent to participate in the study. Each study participant was assigned a study number, and the data were extracted and analysed anonymously.

3. Results

Over the study period, a total there were a total of 411 deliveries, and 384 pregnant women were recruited (20 excluded as these were elective term CSs and 11 delivered between 24 and 26 weeks) and followed up. Table 1 shows the demographics of the cohort. The mean (SD) age was 27 (6) years (range 16-45 years). Most of the women were housewives (88.8%) and more than three quarters were from families that owned their houses (75.5%). 177 (46.1%) of the women were primigravida. In the multigravida group (207), 31 (8.1%) had previously delivered preterm. There were 50 (13%) multiple pregnancies. The education level of the women varied. 62% had secondary school, university or postgraduate education and 32% were either illiterates or had only completed primary schooling. 69.5% of the husband's had either secondary, university or postgraduate education and 30.5% were either illiterates or had only primary schooling. Approximately, two-third (66.7%) of husband's were self-employed and non-smokers (75.8%). With regards to the income of the household from which the women came, 4.4% had a total monthly income of <30.000-50.000 Sudanese pound (SDG)[50-85 USD], 18.0% >50.000-70.000 SDG[85-120 USD], 46.1% >70.000-100.000 SDG[120-170 USD], and 31.5% >100,000 SDG[>170 USD].

Table 2 shows the inter-pregnancy interval, nutritional status at first visit, regularity of antenatal visits and micronutrient supplementation. The inter-pregnancy interval was less than 6 months in 21 (10.1%) of cases, 6–12 months in 34 (16.4%), >1-2 years in 57 (27.5%) and more than 2 years in 95 (46.0%) cases. About 64.1% (246) of mothers received folate and iron supplementation regularly while 60.4% (232) attended antenatal care regularly. More than half of the mothers' nutrition during pregnancy was judged as either excellent or good in 63.3% (N=243) of cases and poor in 6.8% (N=26) of cases.

The complications reported in the pregnancy are shown in Table 3. The most common were hypertensive disorders of pregnancy (15.6%), diabetes mellitus (17.4%) and urinary tract infections (16.9%). Malaria was diagnosed in 3.9% of cases.

In this cohort there were 30 preterm deliveries for a rate of 7.8% and 4 neonatal deaths. A comparative analysis (Table 4) was undertaken of variables in the cohort - divided into those who had preterm birth and those who delivered at term. Sociodemographic factors that were significantly more common in the preterm group included younger mothers age (P=0.017), area of residence (P=0.013), and poor housing (P=0.007).

Table 5 shows the relationship between pregnancy complications and preterm and delivery. Multiple pregnancy, hypertensive disorders of pregnancy, diabetes mellitus, and toxoplasmosis in pregnancy were all associated with a statistically increased risk of preterm birth. Of all the antenatal complications, urinary tract infection had the highest impact on the risk of preterm birth (P=0.000001 OR - 5.685 (95%CI 1.752-18.447) followed by previous preterm birth (P=0.0001, OR=35.094, (95%CI 5.983-205.856) and antepartum haemorrhage (P=0.002; OR 29.085 (95%CI 3.325-254.431). Interestingly malaria infection was not a risk factor for preterm birth, but the number of confirmed infections was very small.

A logistic regression was undertaken to predict which factors had the greatest impact on the risk of preterm birth. Mother's age <25 years (P=0.04; OR 2.5; 95% CI 1.042-6.003) and interpregnancy interval of <6 months (P=0.04, OR 0.59; 95% CI 0.356-0.997) were associated with an increased risk of preterm birth while excellent or good nutrition (P=0.003; OR 4.069; 95%CI 1.631-10.151) was associated with a decreased risk of PTB. Table 6 shows the association between timing of delivery and family income, regularity of antenatal attendance, nutritional status at first visit to the hospital and interpregnancy intervals. Low family income was significantly associated with an increased in the risk of preterm birth (P=0.005) while regular iron and folate supplementation in pregnancy (P=0.00001), regular attendance of antenatal clinics (P=0.013) and having an excellent or good nutrition (P=0.0000001) were factors that significantly reduced the risk of preterm.

4. Discussion

The preterm delivery rate in our cohort was 7.4%. Factors which were more prevalent in those who delivered preterm included maternal age <20 years, low levels of maternal education, interpregnancy interval of <6 months low family income, inadequate folate and iron supplementation throughout pregnancy, irregular antenatal visits, poor nutritional status at booking, and previous preterm delivery. Pregnancy complications such as antepartum haemorrhage, diabetes mellitus, hypertensive disorders of pregnancy, multiple pregnancy and, and urinary tract infections increased the risk of preterm birth. An interpregnancy interval of at 1-2 years was associated with the lowest risk of PTB.

The PTB rate of 7.4% in this cohort is much higher than that from previous studies in Sudan which were 3.8% in 2010 and 4.7% in 2012 [27,28]. By using a cut-off of 26 weeks, we might have under-estimated the PTB rate. Including the 7 deliveries between 24 and 26 weeks would have given a much higher PTB rate of 9.0%. The problem of variable cut-offs for defining viability are well recognised when comparing not only perinatal mortality but PTB rates across the globe [29]. Lack of high-level neonatal care facilities mean survival before 26 weeks is almost impossible in Sudan and indeed most low-income countries compared to high-income countries with viability varying from 22-24 weeks. [30,31]. There has been a consistent rise in the PTB rate in Sudan, and this is most likely to have risen exponentially with the ongoing civil war. For low and middle-income countries, this rate is in the middle of the range (5% to 19%) [3,32]. Our rate is however, comparable to those from some middle and high-income countries such as the USA with the latest reported rate of 9.6% and 5%-9% in European countries [4]. We feel that this rate does not truly reflect the magnitude of the problem in the country for two reasons - firstly, our numbers are very small and secondly, the population that comes this this hospital may be skewed toward the middle/higher income category. In our cohort, about two thirds of the women and the men had either received secondary, university or postgraduate education and just over 90% of the men were either self-employed or employed. This reflects the income for the household and therefore better nutritional status, more compliance with antenatal visits and supplementation.

Maternal age < 20 years old was found to be significantly associated with an increased risk of preterm birth. This finding is similar to that from other studies (high income and low/middle income countries). In Taiwan for example this was significantly associated with PTB [33]. Age above 35 years was not a risk factor for PTB in our series. This finding is at odds with findings from other studies especially from high income countries such as Taiwan and Canada [33,34]. Several reasons could be responsible for this - our numbers are small and furthermore our older women were multiparous having previously delivered at term which, in itself lowers the risk of PTB.

Central to maternal health is availability of not only healthcare resources but also ensuring that these are economically affordable. Family income and education status are important determinants for this. It was therefore not surprising that area of residence, housing, education and family income were all significantly associated with preterm birth in our series. Similar findings were reported from other studies [35,36,37,38]. These sociodemographic factors are interlinked and whether education is the core factor or family income is difficult to decipher. What is important is that by addressing these factors it should be possible to improve not only access but appropriate utilisation of services. In fact, regularly attending antenatal care and complying with supplementation was associated with a lower risk of preterm birth in our study. Never or rarely attending antenatal care was also significantly associated with more preterm birth. In China a study showed that those who had not attended antenatal care, had an OR of 5.19 of having a preterm birth OR = 95% CI: 3.77 - 7.14) [39].

The finding of an increased risk of preterm birth with multiple pregnancy, hypertensive disorders of pregnancy diabetes mellitus and urinary tract infections was expected as this has been widely reported [37,40,41,42,43]. While some of these may be iatrogenic, we believe that a significant number may be spontaneous. The risk of preterm birth increases with a previous PTB and this increase is exponential after 2 [9].

In low- and middle-income countries where women are likely to have several babies’ inter-pregnancy interval is critical in not only ensuring that nutrients are replenished but that breastfeeding is enough to support the baby. An inter-pregnancy interval of <6 months and >2 years are considered risk factors for PTB [15,44]. In our series, IPI of <6 months was associated with PTB but not >2 years. Interestingly in the previous study from this same region [24], interpregnancy interval of <18 months was associated with an increased risk of PTB. These contrasting findings make a strong case for large cohort studies.

Preterm pre-labour (PPROM) and chorioamnionitis are well recognised precedents of PTB. These and other factors such as bleeding in pregnancy/threatened miscarriage were not investigated as these are not modifiable (at least in the context of a low-income country). Where facilities are available, microbiology of samples from those presenting in preterm labour will help isolate infective organisms and enable preventative treatment. This is an important cause of PTB that may be modified with antibiotics. While we could not do this in this study there is increasing evidence the antibiotics to women presenting in threatened preterm may reduce the risk of PTB. [21]

5. Conclusions

In our small series, the PTB rate was 7.4% which, while better that than from most low-income countries is still considerably higher that most of the rates in high-income countries. We have shown that the traditional risk factors (pre-pregnancy and pregnancy) that have been associated with PTB also apply to Sudan, however, we have in addition shown that regular attendance at antenatal clinics and compliance with folate and iron supplementation can reduce the risk of PTB. Starting pregnancy with a good/excellent nutritional status is another factor that is associated with a lower risk for PTB. Within the context of Sudan therefore, a multi-prong approach that involves, healthcare workers, epidemiologists, nutritionist public health planners and educationists is likely to tackle most of the identifiable factors that are preventable. This is more important since neonatal facilities are poor meaning those babies delivered preterm are less likely to survive.