Optimal Strategies for Screening Common Birth Defects in Children of Low- and Middle-Income Countries: A Systematic Review

Abnormalities that are structural or functional and develop during intrauterine life are known as congenital abnormalities. These illnesses, which are also known as birth defects, congenital disorders, or congenital abnormalities, arise during pregnancy and can be detected prior to, during, or after birth. Approximately 6% of infants globally are born with a congenital defect, leading to hundreds of thousands of fatalities and morbidities related to these conditions [1]. One major contributor to the worldwide burden of disease is congenital abnormalities, with low- and middle-income countries (LMICs) bearing a disproportionate share of the burden and additionally, there is a lower likelihood of early identification and treatment facilities, which can have more severe and enduring impacts [1]. Treatment options for certain congenital defects, like clubfoot, cleft lip and palate, and hernias, can include both surgical and nonsurgical procedures and early intervention can lead to improved quality of life and some of these conditions can have long-lasting effects, such as Down syndrome, heart problems, and neural tube anomalies.

Poverty may be an indirect determinant of congenital disorders, with a higher frequency among resource-constrained families and countries. It is estimated that about 94% of severe congenital disorders occur in LMIC according to the WHO fact sheet [2]. Potential causes include not getting screened prenatally or after birth, not receiving prenatal care, pregnant women not having enough access to nutrient-dense foods, using or coming into contact with alcohol and tobacco, using natural remedies, and being more likely to contract infections like syphilis, rubella, or Zika. Other potential causes include consanguinity, self-medicating with drugs without supervision, and exposure to toxins or pollutants from the environment [3]. With timely surgery or other treatment, more than half of the disability-adjusted life years lost annually because of congenital abnormalities could be avoided.

Social stigma and discrimination are common outcomes of congenital malformations, and these can cause humiliation, isolation, and other limitations in community interactions. These conditions also come at a great financial cost; long-term disability has a big effect on people’s lives, families, healthcare systems, and communities [3]. Appropriate screening and diagnostic resources ought to be made accessible in close conjunction with prompt surgical care and exposure with referrals to specialist units. The inequities that neonates in LMICs confront must be addressed, along with the burden and difficulties associated with providing health care in resource-constrained locations and affordable ways to provide specialized care can dramatically lower neonatal mortality and enhance quality of life must be found [4].

We aim to pervade the evidence on screening methods conducted both in prenatal and postnatal period for congenital abnormalities in LMICs with the most frequently involved systems and conditions. The PRISMA guidelines were followed for this systematic review (refer to the online suppl. material at https://doi.org/10.1159/000541697).

The main objective of this systematic review was to assess the optimal strategies for screening of common birth defects both in the prenatal and postnatal period in LMICs and compare the prevalence of the common systems and conditions involved.

We used MEDLINE/PubMed, CINAHL, Cochrane Databases of Systematic Reviews, clinical Trials.gov using Medical Subject Headings and/or keywords* to conduct a systematic search for pertinent studies in these databases and trial registers. In all databases, we have used the Medical Subject Headings and keywords including “infant, newborn”, “screening”, “prenatal”, “postnatal”, “congenital malformations”, “birth defects”, “nervous system malformations”, “musculoskeletal malformations”, “orofacial malformations”, “urogenital malformations” etc. After removing duplicates on EndNote, these records were imported into the web platform Covidence. Two distinct reviewers screened all titles/abstracts and full texts, and a third reviewer resolved conflict. We conducted cross-referencing of included studies and relevant reviews to seek additional studies.

The review included the following:

• Studies published after the year 2000.

• Studies from the countries that the World Bank [5] had designated as LMICs.

• Studies with screening test(s) mentioned involving multiple or single systems and outcomes mentioned.

• Study design included cross-sectional, prospective, and retrospective cohort studies and randomized controlled trials.

The review excluded the following:

• Retrospective studies which included data from medical registries before 2000.

• Studies with trauma or iatrogenic injuries.

• Studies which were conducted solely on participants with a positive family history of congenital disorders.

• Studies mentioning specific metabolic birth abnormalities and isolated genetic syndromes.

Two review authors independently extracted data from the included study onto a standardized data extraction form in Excel that had been piloted. Two independent authors assessed the quality of the included study and disagreements were resolved by consensus or contacting a third author. The studies which met the eligibility criteria were selected for extraction on the following information: study characteristics, study setting, participants, intervention details (procedure, duration, conducted by) including dichotomous and continuous data outcomes and limitations.

After extraction of the selected full-text articles, the studies included involved screening methods and strategies being conducted during prenatal and postnatal period. We identified the most common screening tests being used for detection of congenital anomalies according to the period of birth that can be recommended for screening programs (Table 1) [6‒9]. The recommended screening tests that are missing can be compared to the screening methods that have been identified in this review. As there were a lot of variations in the screening tests and conditions reported, we were not able to carry out meta-analysis and hence conducted a descriptive analysis. The screening studies were further grouped into multisystem, cardiovascular, urogenital, eye, musculoskeletal, gastrointestinal, central nervous system, and orofacial system. Screening tests conducted in the prenatal and postpartum period were defined for each system from each study. A table-based summary of the studies was presented. A thorough system-wise comparison of the common congenital birth abnormalities and systems involved with corresponding screening methods used in the studies was conducted.

The search strategy identified 18,715 unique studies which were screened, and 1,478 articles were selected for full-text evaluation, of which 59 [10‒68] studies were finally included (Fig. 1). Of the 59 studies conducted in Asia and Africa, 17 were conducted in India, 12 in Nigeria, 10 in Ethiopia, 4 in Iran, 3 in Egypt, two each from Pakistan, Uganda, Kenya, and Cameroon, and one each from Iraq, Tanzania, Malawi, Vietnam, and Thailand. Detailed information for all the screening studies is presented in Table 2.

Majority of the studies were conducted in a tertiary care setting and the sample size ranged from 119 to 299,854 participants. It was observed that there were eight different screening methods (3 prenatal and 5 postnatal) identified in this review (Table 3). These were further discussed in detail under each system. The prenatal screening included antenatal ultrasound, fetal echocardiography, and fetal MRI, and the newborns were tested with pulse oximetry, clinical examination (with photos), postnatal ultrasound, and hip ultrasound. The review included almost 5 times as many studies on postnatal procedures than prenatal procedures.

There were 28 studies [10‒37] involving congenital anomalies from multiple systems which were from Nigeria (n = 10), Ethiopia (n = 7), India (n = 3), Cameroon (n = 2), Uganda (n = 2), Kenya (n = 2), Egypt (n = 1), and Vietnam (n = 1). This section involved two types of prenatal and a single postnatal screening method. The screening tests involved fetal ultrasound (n = 3) [13, 23, 25], fetal MRI (n = 1) [27], and postnatal clinical examination (n = 17) [10, 11, 14, 17‒19, 22, 24, 26, 28, 30‒35, 37]. In addition to this, there were two studies from Cameroon [20, 29] and one from Egypt [36] which involved both fetal ultrasound and clinical examination, while there were four studies from Nigeria [12, 15, 16, 21] which involved clinical examination with ultrasound and other investigation services where applicable for finding major congenital anomalies. The study population comprised all the reporting pregnant women/fetuses regardless of gestational age who delivered at the respective hospitals, except Mohan et al. [27] which included referrals after a suspected anomaly was found on ultrasound examination and were later tested with fetal MRI.

The prevalence of various congenital disorders with clinical examination varied from 0.28 to 8.5% [10‒12, 14‒19, 21, 22, 24, 26, 28, 30‒35, 37] and for antenatal ultrasound from 3% to 42.7% [13, 23, 25]. The three studies [20, 29, 36] which involved both fetal ultrasound and clinical examination reported prevalence ranging from 0.89% to 7.4%. There was only one study involving confirmation with fetal MRI which showed prevalence of 8.2% [27].

There were different congenital conditions identified involving central nervous system (anencephaly, hydrocephalus, spina bifida, microcephaly, meningocele), musculoskeletal (varus deformities, polydactyly, dislocation of hip), urogenital (renal agenesis, hypospadias, bladder exstrophy), cardiovascular (septal defects), gastrointestinal (gastroschisis, omphalocele, duodenal atresia, and anorectal malformation), orofacial (cleft lip and palate), and syndromes (Down and Edward) that were identified with clinical examination, while few added conditions identified through antenatal ultrasound included anencephaly, holoprosencephaly, skeletal dysplasia, conjoined twins, pericardial effusion, disposition of arteries, multicystic/polycystic kidneys, Hirschsprung disease, meconium peritonitis/ascites/calcification, esophageal atresia, diaphragmatic hernia, and cystic hygroma.

Fifteen studies [38‒52] assessed congenital disorders related to the musculoskeletal system only; 14 were conducted specifically to assess congenital talipes equinovarus (clubfoot) while one on developmental dysplasia of the hip (DDH) [52]. These studies show that the screening tests were conducted in the postnatal period only. A comprehensive physical examination conducted soon after birth led to the diagnosis of clubfoot, whose prevalence ranged from 1.01% to 3.96%. Hip ultrasound was used to screen for DDH by Kishore Kumar et al. [52]. Neonates with a favorable clinical examination (target sign) were evaluated by hip ultrasound scans, and 2.7% of the infants had DDH.

Eleven studies [53‒63] assessed congenital disorders related to the cardiovascular system and the screening tests included pulse oximetry (n = 6) [54‒57, 60, 62], fetal echocardiography (n = 3) [58, 59, 61], clinical examination [53, 62], and echocardiography (n = 2) [53, 63]. This demonstrates that the fetal echo was performed during pregnancy, while the other tests were performed during the postnatal period. Most studies included participants that were born or visited the hospital in the given period, three studies included pregnant women with and without high-risk indications (maternal or fetal) for fetal echocardiography according to the American Heart Association’s (AHA) scientific statement [58, 61] and one included only neonates with intention to treat by a cardiac intervention [59]. The prevalence of various congenital heart defects ranged from 0.57% to 32.8%. The highest prevalence was reported with fetal echocardiography (32.8%) [59], followed with pulse oximetry (22.2%) [56], echo (10.4%) [63], and clinical examination (3.1%) [53]. Few of the studies failed to define the specific conditions of congenital heart defects.

This system included studies which conducted prenatal ultrasound scan. The three studies [64‒66] assessed congenital disorders related to the urogenital system and used ultrasound to identify hydronephrosis and congenital abnormalities of kidneys such as polycystic and multicystic kidney disease, renal agenesis, and abdominal masses. The studies included all pregnant women who visited the hospital during the period of the study and underwent antenatal ultrasound scan. The result of the studies (n = 2) suggested prevalence of antenatal hydronephrosis and congenital abnormality of kidney and urinary tract to be 0.83% [66] and 0.4% [64], respectively, while the study with postnatal abdominal ultrasound (n = 1) [65] of neonates demonstrated a 5.9% prevalence of genitourinary anomalies.

There were single studies identified for orofacial [67] and central nervous system [68]. Eshete et al. [67] conducted a study to determine the prevalence of cleft lip and palate in seven health institutions in Ethiopia. The participants in the study were screened in the postnatal period with clinical examination. The number of live births included was 42,986, and sixty-four new cleft lip and palate patients were recorded with a prevalence of 0.14% (1.49/1,000 live births).

Kumar et al. [68] conducted a study in India in neonates having ventriculomegaly that was detected on antenatal ultrasound. Out of 102,216 deliveries that took place in the given study period, there were 1,875 cases of major congenital anomalies referred to the fetal medicine unit; of which 694 had central nervous system defect. Consequently, 648 cases were fully followed up out of which 263 (40.6%) were detected with fetal ventriculomegaly (FVM) on ultrasound, and further investigations led to 43.7% (115) neonates being diagnosed with isolated FVM. However, FVM was reported to be 14% (263/102,216) prevalent with antenatal ultrasound.

Birth defects represent a serious public health concern and this review reports data on the prevalence of birth defects and compares the prenatal and postnatal screening methods identified among various systems. The highest prevalence of various congenital defects was observed in the central nervous system and musculoskeletal system, followed by cardiovascular, urogenital and gastrointestinal system. Most diagnoses were made through clinical examinations which were conducted by trained health workers or physicians while few anomalies were diagnosed via prenatal tests (ultrasound or MRI) and postnatal tests. The findings suggest that women of reproductive age may be continuously exposed to risk factors for a wide range of serious exterior structural birth abnormalities, and these inevitably result in adverse health effects, psychosocial impacts, developmental challenges, and decreased economic productivity due to lifelong disabilities.

A comparative study from an upper middle-income country shows the prenatal detection rate of 50.3% from the pool of participants with at least one congenital anomaly detected in the prenatal or postnatal period (5,021/9,976). When out of the total births that were included in the study, the incidence was 0.4% (5,021/1,261,534) [69]. A study conducted across Europe showed prenatal detection rate of 0.5% (3,601/709,030) [70] which is still lower than the studies conducted in other settings of lower income country, included in this review which resulted in the detection rate of 7.4% in Egypt [36], 6.3% in Nigeria [25], and 3% in Kenya [23]. Similarly, postnatal detection rate in our review from Nigeria was 8.5% as compared to the study from the UK which reported a lower proportion of 7.4% [71] of postnatally detected cases. However, the postnatal detection rate varied from 0.85% to 8.5% in LMICs.

A similar systematic review had been conducted by Justina et al. [72] who identified studies with feasible screening methods for surgically correctable congenital anomalies in LMICs. We have run an updated search and evidence on different screening strategies conducted in LMICs with a detailed review and synthesis.

Screening of newborn infants for congenital disorders facilitates early detection, treatment, and care. Neonatal screening programs and training of primary health care providers support the diagnosis and appropriate referral for treatment of infants with congenital disorders [73]. Screening for clinically actionable diseases would be crucial to personalized medical therapy, as the postnatal period remains appropriate for screening for the great majority of monogenic disorders [74]. WHO recommends the first postnatal visit within 24 h of childbirth, and a minimum of three additional postnatal visits timed at 3 days (48–72 h), 7–14 days, and 6 weeks after birth [75]. In many LMICs, however, coverage of early postnatal care (PNC) is still at very low levels [76‒78], though it is important that all components of PNC are provided to the mother and her baby in an integrated holistic manner. Given the low coverage rates and uptake of PNC globally, the attention internationally has been largely on supporting the implementation and uptake of at least the minimum number of PNC visits that are considered effective, and, on where and who can provide PNC at the healthcare facility level as well as in the community [79].

Congenital anomalies were one of the causes of death in children, representing 8.0% of deaths in children younger than 5 years in 2021 [80]. There is an increase in morbidity and mortality as well as a decrease in quality of life when identification, diagnosis, and treatment of congenital disorders are delayed. In LMICs, different factors decrease PNC services usage like home delivery, illiteracy, low income, and cultures [81, 82], and this makes the PNC services program the weakest of all reproductive and child health programs. Because of low adherence to recommended PNC regimens, there is a significant risk to infant and maternal morbidity and mortality [83]. A study revealed that only 23.3% of women in Southern Ethiopia received PNC in a community-based cross-sectional study [84], while other studies have also reported lower coverage such as Myanmar (72.1%) [85], Zambia (63%) [86], Builsa district (62%) [87], Hadiya zone (51.4%) [88], Uganda (50%) [89], China (17%) [90], Tanzania (10.4%) [91], South Sudan (11.4%), and Ethiopia (16.2%) [92]. The importance of PNC for reducing neonatal mortality has been documented with an estimation that if PNC rates were to reach 90% in sub-Saharan Africa, then 10–27% of all neonatal deaths could be averted [93].

Additionally, the WHO has made a few recommendations to prevent congenital anomalies and genetic disorders, with particular attention to LMICs [94‒96]. These include (a) to improve the epidemiological knowledge about genetic disorders and birth defects; (b) to improve pre- and perinatal services, including family planning and maternal nutrition; (c) to select preventive programs and targets according to prevalence, severity, and the predicted outcomes of interventions, and (d) to educate health professionals and the public in genetics and birth defects. These birth disorder screening and tracking programs are either nonexistent or have just recently been started in LMICs. These areas also provide a variety of resource, training, and sustainability difficulties for monitoring the programs; hence, it has been reported that almost all birth defects (94%) [2] and deaths due to the birth defects among children (95%) occur in LMICs [29]. Therefore, low-cost screening methods for surgically curable congenital abnormalities can enhance the identification and diagnosis of various illnesses while minimizing therapy delays.

The limited evidence suggests that routine noninvasive screening tests for prenatal diagnosis which are low-cost and easily accessible can be used in LMICs to screen common congenital disorders. Across all the techniques examined, clinical evaluation was employed in over 50% of the studies, either with or without supplementary screening methods. Clinical review by physicians, with or without the photograph, received the highest ranking on the feasibility assessment [72]. A summary in the form of a table is provided to compare the screening tests based on the period of birth (Table 3). There are other screening methods that are being practiced in different settings which may have significant implications for developing any comprehensive method and instruments for this domain. These included serum AFP (maternal), cell-free fetal DNA, amniocentesis, chorionic villi sampling, otoacoustic emissions, and auditory brainstem evoked responses which, although are not included in this review (Table 1) [6‒9]. Physical examination of all newborn infants by trained primary health care practitioners is feasible in most health systems and allows the identification of many birth defects, including cardiovascular defects that are associated with a high risk of early mortality and referral [73]. The low rate of birth defect detection could be attributed to several factors, including ignorance, poverty, and a lack of resources to properly interpret findings, including training for staff members.

A practical screening method that enables early detection of congenital defects and appropriate scheduling of prenatal care and interventions is the fetal ultrasound scan. It has been demonstrated that incorporating prenatal ultrasound screening into antenatal treatment in LMICs improves prenatal detection, which in turn helps lower morbidity and mortality and enhances clinical decision-making [20]. It is important to determine if prenatal diagnosis could preserve the function of otherwise asymptomatic infants, since many infants with congenital defects do not exhibit symptoms for months or even years before being diagnosed. Similarly, the in utero development of certain forms of congenital malformations remains understudied and is currently the subject of research [97]. Additional evaluation is required on the inclusion of outflow tract visibility in the prenatal ultrasound screening protocol for abnormalities [98].

This study had some limitations. The following factors could not be evaluated: the number of ultrasounds performed per pregnancy, the type and timing of the ultrasound (e.g., first trimester ultrasound, second trimester ultrasound, detailed second trimester ultrasound, Doppler ultrasound), the experience of the operator (US). This study did not assess the various prenatal cytogenetic study techniques. Our investigation was limited to LMICs, with limited studies, so it is probable that we missed other screening methods that might have provided insight into related issues. The review reinforces the need for a population-wide congenital abnormality screening programs in all countries and in LMIC at least a prenatal ultrasound and a thorough postnatal examination should be ensured universally with a well-trained staff (physician, midwife, or skilled birth attendant) at the primary and secondary care facilities.

We thank the Aga Khan University for providing internal resources.

Ethical exemption was taken from the Aga Khan University’s Ethics Review Committees (ERCs) and from the National Bioethics Committee (NBC). A statement of consent is not applicable because this study is based exclusively on published literature.

The authors have no conflicts of interest to declare.

This study is supported by the Bill and Melinda Gates Foundation Grant (#INV-042789). The funders played no role in the design, data collection, data analysis, and reporting of this study.

U.Z., U.S., and S.F. carried out the literature review and extracted data from the reviews/studies. U.Z. conducted the analysis and interpreted the results and drafted the manuscript. J.K.D., S.H.Q., and Z.A.B. provided supervision for each step, conceptualization, and contributed to the critical revision of the manuscript.

The data that support the findings of this study are publicly available [10–68].