# Evidence Based Global Health Manual for Preterm Birth Risk Assessment

Dilly OC Anumba Shamanthi M. Jayasooriya *Editors* 

Evidence Based Global Health Manual for Preterm Birth Risk Assessment

Dilly OC Anumba • Shamanthi M. Jayasooriya Editors

## Evidence Based Global Health Manual for Preterm Birth Risk Assessment

*Editors* Dilly OC Anumba Academic Unit of Reproductive and Developmental Medicine University of Sheffeld Sheffeld, UK

Shamanthi M. Jayasooriya Academic Unit of Primary Care University of Sheffeld Sheffeld, UK

This book is an open access publication.

University of Sheffeld. This work was supported by the National Institute for Health and Care Research (NIHR) Global Health Research Programme ([GHR 17/63/26])

ISBN 978-3-031-04461-8 ISBN 978-3-031-04462-5 (eBook) https://doi.org/10.1007/978-3-031-04462-5

© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022

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### **Preface**

I am delighted to commend this concise book to healthcare workers in Women's and Children's Health globally. The book provides evidenced practical guidance for systematic assessment of pregnancy risk for preterm birth during antenatal care, towards the provision of personalised care to prevent premature birth and other adverse pregnancy outcomes, consistent with the targets of the UN's Sustainable Development Goals (SDG, 3). It is written for maternal and newborn healthcare providers (doctors, nurses, community health workers) and provides desktop evidence-based information to facilitate antenatal risk assessment and the signposting of pregnant persons to care advice, referrals, supplements and treatments.

It is estimated that about 15 million babies are born prematurely annually, of who nearly a million die from preterm birth-related consequences. Premature birth is also the leading cause of under-5 deaths in many parts of the world, especially in low-resource settings. In the last two decades, modest improvements in child survival following preterm birth have been recorded, attributable to improved essential newborn care components.

An area where progress has lagged is the identifcation of risk factors for preterm birth for prevention by coordinated, multifactorial, intervention approaches. Whilst individually these interventions may contribute only modestly to preventing preterm birth, integrated approaches embedded into ANC can ensure synergistic reduction of the burden of preterm birth. This manual contains handy information about preterm birth screening in ANC and signposts the reader to published graded evidence, as well as relevant frameworks and guidance recommended by the World Health Organization (WHO) and other agencies. The information provided here is applicable to a global audience, but with special emphasis on low- and middleincome country (LMIC) settings where such resource is most needed.

In developing this manual, we synthesised global literature on preterm birth interventions and guidance, and conducted stakeholder-based prioritisation workshops in Bangladesh, South Africa, and Nigeria under the auspices of the National Institute for Health Research (NIHR) Global Health Research (GHR) Group for the Preterm Birth Prevention and Management of Preterm Birth in LMICs (PRIME), between 2018 and 2020. These exercises enabled us to identify context-relevant knowledge gaps which are addressed herein.

Sheffeld, UK Dilly OC Anumba

### **Acknowledgements**

We acknowledge and thank the UK's NIHR GHR programme for funding the PRIME Research Group whose researchers undertook the evidence reviews that inform this book. The views expressed in this manual are those of the authors and do not refect the position of the NIHR. We are also grateful to the multitude of stakeholders including women and their families who contributed to prioritising this piece. The evidence has global application and potential for use in multiple LMIC settings.

### **Contents**


### **List of Contributors**

**Dilly OC Anumba** Academic Unit of Reproductive and Developmental Medicine, University of Sheffeld, Sheffeld, UK

**Bronwen Gillespie** Oncology and Metabolism, University of Sheffeld, Sheffeld, UK

**Shamanthi M. Jayasooriya** Academic Unit of Primary Medical Care, University of Sheffeld, Sheffeld, UK

**Caroline Mitchell** Academic Unit of Primary Medical Care, University of Sheffeld, Sheffeld, UK

**Kerry M. Parris** Academic Unit of Reproductive and Developmental Medicine, Department of Oncology and Metabolism, University of Sheffeld, Sheffeld, UK

**Shumona Sharmin Salam** Oncology and Metabolism, University of Sheffeld, Sheffeld, UK

### **Global Antenatal Care Coverage and Content**

**Dilly OC Anumba and Shamanthi M. Jayasooriya**

### **1 Background Information**

Common global risk factors for neonatal deaths include preterm births, birth complications, and infections such as tetanus, sepsis, and pneumonia, all of which disproportionately affect low- and middle-income countries (LMICs). These risk factors can be minimised or prevented through the delivery of high-quality antenatal care (ANC) [1]. ANC encompasses health promotion, education, disease screening, diagnoses, treatments, and interventions to ensure a good pregnancy outcome. Optimum ANC requires promptly initiated sustained care between the mother and usually a health-care professional, culminating in a safe birth experience and a good outcome for both mother and her baby.

The World Health Organisation (WHO) recommendation for effective ANC services, specifc- to low-income countries, is four or more ANC visits [2], requiring each of the frst two ANC visits to take place in the frst two pregnancy trimesters and the last two visits to happen in the last trimester. Generic guidance for ANC is well documented by the WHO [3], as well as other published literature. These various guidelines seek to improve ANC globally in all settings, thereby mitigating adverse pregnancy outcomes, especially neonatal deaths from preterm birth, birth complications, and infections.

Despite the availability of guidance regarding the frequency and content of ANC, there has remained a paucity of literature addressing the gap in knowledge of

D. O. Anumba (\*)

Academic Unit of Reproductive and Developmental Medicine, University of Sheffeld, Sheffeld, UK e-mail: d.o.c.anumba@sheffeld.ac.uk

S. M. Jayasooriya Academic Unit of Primary Medical Care, University of Sheffeld, Sheffeld, UK e-mail: s.jayasooriya@sheffeld.ac.uk

prenatal risk factors for preterm birth, especially in LMICs and how to apply that knowledge to improve care aimed at prevention. Health-care professionals providing ANC should be aware of the well-evidenced risk factors as well as principles of care that mitigate against preterm birth that should form part of routine antenatal care. In view of this need, we provide in this chapter a brief summary of global ANC coverage and standards, thereby setting the scene for the subsequent chapters in this manual aimed at outlining guidance for early antenatal risk assessment of preterm birth globally, but with emphasis on practice in LMICs where the burden of preterm birth is often disproportionately high.

### **2 WHO Recommendations/Standards**

The historical, basic, four-visit-focused global ANC model was replaced by the current WHO model in 2016 [3]. The latter recommends that interventions are delivered through a minimum of eight antenatal contacts. While continuing to monitor the number of visits or contacts pregnant women have, the 2016 WHO guidance also emphasises the importance of the quality and content of care received. In order to implement the WHO antenatal care model, a monitoring framework has been developed which includes the following three aspects of ANC: the organisation of health systems, the content of care, and the women's experience of care [4].

Programmatic assessment of the effectiveness of health systems to provide good quality ANC relies on the development of suitable content of care indicators. The WHO has therefore recommended a universally relevant list of nine core global and national indicators of ANC, to be measured and monitored by all countries [1]. These nine core indicators are shown in Table 1.

### **3 Global Variation in Skill of ANC Providers**

Central to the provision of ANC is its delivery by skilled health-care professionals [3]. The benefts of ANC for the mother and child have been shown repeatedly to be higher when ANC is administered by trained health-care professionals, practice which also infuences the standard of delivery and postnatal care [5]. There are also context-specifc variations in access to, and availability of, technical equipment (such as ultrasound scans for dating and monitoring pregnancies) and biomedical engineering support for maintenance of hospital equipment.


**Table 1** Global indicators of antenatal care standards

### **4 Global Situation of Implementation of ANC Monitoring Frameworks**

Despite these published frameworks, there remains marked global variations in antenatal care coverage and standards. A full discussion of these global variations is outside the scope of this book. However, it is acknowledged that these variations are largely due to inequities regarding coverage, as well as standards and quality of ANC.

### **5 Global Inequity in Antenatal Care Coverage**

Antenatal care coverage in LMCIs is currently described by limited data sets from population-based surveys such as Demographic and Health Surveys (DHS). The lowest levels of ANC, based on data reporting a minimum of four visits, are observed in sub-Saharan Africa and South Asia [6]. The proportion of women receiving at least four antenatal care visits varies greatly, ranging from 13% in countries in sub-Saharan Africa to over 90% in other countries in Latin America, the Caribbean, and European regions (UNICEF data). Although improvement has been recorded in the global coverage of early (starting at <12 weeks' gestation) antenatal care in the last two decades, the poorest women in LMICs often still do not have access to highquality antenatal care [7].

### **6 Global Variations in the Content of Antenatal Care**

It has also been acknowledged through several studies that even among women with patterns of care that complied with global recommendations, the content of care was poor, emphasising the need for effcient and effective action to improve care quality. One report surveyed 10 LMICs as illustrative examples and reported that receipt of the six routine components of ANC (measurement of blood pressure, urine sample, blood sample, tetanus protection, iron supplementation and receipt of information on potential pregnancy complications) varied widely [8]. Furthermore, it showed that even among the subset of women starting ANC in the frst trimester and receiving over four visits, the percentage receiving all six routinely measured ANC components was low, ranging between 10% and 50%.

### **7 Antenatal Care Coverage and Preterm Birth**

Given that global attainment of ANC quality indices is highly variable, with LMICs demonstrating lower attainment than high-income countries (HICs), it is highly likely that a similar picture exists when the focus is mitigating risk of PTB. Indicators of high-quality ANC may serve as suitable proxies for assessing ANC standards to mitigate PTB. Early ANC in the frst trimester enables prompt risk assessment for preterm birth, earlier screening for infections which may be associated with PTB (such as urinary tract infections, HIV, malaria), prompt initiation of routine micronutrient supplements (including iron and folic acid), and, importantly, accurate pregnancy dating. Chapter "Pregnancy Dating Guidance" of this manual describes in-depth pregnancy dating guidance taking into account capacity limitations in LMICs. In addition, early establishment of baseline blood pressure will improve the initiation of preventative treatment where needed, the diagnosis of gestational hypertension, as well as on-going management of hypertension improving pregnancy outcomes by reducing the need for physician-indicated (iatrogenic) prematurity.

In subsequent chapters, this guidance summarizes the evidence for effective ANC screening and intervention for PTB. Many of these align with high-quality ANC, and their application has the potential to improve maternal and child health.

### **References**

1. Lincetto O, Mothebesoane-Anoh S, Gomez P, et al. Antenatal care. In: Lawn J, Kerber K, editors. Opportunities for Africa's newborns: practical data, policy, and programmatic support for newborn care in Africa. Cape Town: Partnership for Maternal, Newborn and Child Health; 2006. p. 51–62.


**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

### **Antenatal Risk Assessment for Preterm Birth: Summary Guidance for Healthcare Providers**

**Bronwen Gillespie and Caroline Mitchell**

### **1 Background Information**

About 80% of preterm births (PTB) occur in low- and middle-income countries (LMIC), and the highest rates are seen in sub-Saharan Africa and South-East Asia. This guidance aims to help identify women likely to experience PTB in LMIC settings to help reduce the risk of PTB and improve birth outcomes.

This chapter includes a summary of the following fve key areas of guidance relevant to pregnancy care for PTB:


For discussion of the in-depth evidence on each of these key areas, please see Chapters "Prenatal Risk Assessment for Preterm Birth in Low-Resource Settings: Demographics and Obstetric History" to "Evaluating Alcohol, Tobacco and Other Substance Use in Pregnant Women".

The pregnancy booking (registration) visit affords the healthcare professional an opportunity to assess a pregnant woman's risk of PTB, among other potential adverse pregnancy outcomes. Although many of the following areas may be

B. Gillespie (\*)

Oncology and Metabolism, University of Sheffeld, Sheffeld, UK e-mail: b.gillespie@sheffeld.ac.uk

C. Mitchell

Academic Unit of Primary Medical Care, University of Sheffeld, Sheffeld, UK e-mail: c.mitchell@sheffeld.ac.uk

D. O. Anumba, S. M. Jayasooriya (eds.), *Evidence Based Global Health Manual for Preterm Birth Risk Assessment*, https://doi.org/10.1007/978-3-031-04462-5\_2

routinely enquired about during antenatal booking and registration in most contexts, the information is seldom used to identify the risk of PTB.

### **2 Evidence Statements**

### *2.1 Demographics/Patient History*

There is evidence of increased risk of PTB when mothers are either very young or very old, of black ethnicity or have a low maternal body mass index (BMI) (see Sect. 2.4).

PTB is multifactorial, sometimes related to health and lifestyle factors (such as nutrition (see Sect. 2.4) and smoking (see Sect. 2.5). Social circumstances must be taken into account, not only as a PTB risk but also in terms of helping to ensure appropriate access to care.

Domestic abuse is an evidence-based risk factor of PTB. Women with a previous history of spontaneous PTB or mid-trimester miscarriage, particularly when this occurs before 32 weeks, are also at high risk of PTB.

Other PTB risk factors which identify women that should ideally receive further risk assessment and specialist care include women who have had a previous caesarean section at full cervical dilatation and women with congenital uterine abnormalities.

### *2.2 Pregnancy Dating*

Accurate pregnancy dating enables a diagnosis of preterm labour and birth to be made. This can ensure timely provision of obstetric interventions in appropriate healthcare settings for the management of complications of pregnancy and birth such as foetal growth abnormalities.

Pregnancy dating can be challenging. Women may not remember their last menstrual period, and menstrual cycle lengths may vary because of lactation following a recent previous baby (Chapter "Pregnancy Dating Guidance").

Clinical palpation may not be accurate because of excess maternal weight, foetal growth restriction, uterine fbroids or foetal malpresentation often associated with high parity. Late presentation to pregnancy booking makes estimation of pregnancy duration more diffcult.

Accuracy of pregnancy dating varies depending on the duration of the pregnancy at the time of presentation.

### *2.3 Infection Screening (See Chapter "Prenatal Risk Assessment for Preterm Birth in Low-Resource Settings: Infection")*

Some maternal infections are associated with an increased risk of PTB; infections are estimated to contribute to between 40% and 50% of all PTB. High rates of maternal bacterial and viral infections are reported in LMIC settings compared to high-income settings.

Early diagnosis and treatment of HIV has been shown to reduce mother-to-child vertical transmission and horizontal transmission to unaffected sexual partners.

### *2.4 Nutrition*

Both high and low BMI, as well as nutrient defciencies, can have implications for PTB risk, as well as for pregnancy outcomes in general. Access to a well-balanced diet can represent a challenge for pregnant women in LMICs.

Iron and folic acid (and calcium in specifc contexts) are necessary supplements for pregnancy in general, as well as having potential benefts for reducing the risk of PTB (iron and calcium).

Low-certainty evidence links some other nutrient defciencies, such as zinc, to PTB outcomes, but the value of routine supplementation over and above a healthy diet is questioned. However, specifc LMIC contexts where dietary zinc is low may beneft from supplementation.

### *2.5 Alcohol, Tobacco and Other Substance Use*

Substance use disorder during pregnancy is a critical public health concern. The most widely used substances globally in pregnancy include tobacco, alcohol, cannabis, opioids and cocaine, but other illicit substances may also be consumed.

Use of alcohol, smoking, and other psychoactive substances during pregnancy leads to an increased risk of health problems for mother and child such as spontaneous abortion, PTB (see Chapter "Evaluating Alcohol, Tobacco and Other Substance Use in Pregnant Women"), stillbirth, low birth weight and birth defects. Concurrent use of these substances (i.e. using more than one) along with other psychosocial factors further increases the risk of adverse outcomes in all settings.

Despite gaps in current knowledge, the potential benefts of the recommended actions (see Sect. 3.5) outweigh the harms (see Chapter "Evaluating Alcohol, Tobacco and Other Substance Use in Pregnant Women").

### **3 Risk Assessment and Recommended Interventions**

To enable formal evaluation and assessment of a woman's risk of PTB and to signpost the woman to appropriate care, the healthcare worker assessing the pregnant woman at booking and subsequently should systematically assess the following:

### *3.1 Risk Assessment: Demographics/Patient History*

Risk of PTB is higher for pregnant women older than 40 and for adolescents. Maternal BMI (< 19Kg/m2 is a risk factor for PTB) should be derived from maternal weight and height (see Sect. 3.4 below).

*Recommended intervention:* Document maternal age, weight and height.

Previous history of PTB or mid-trimester miscarriage is important as the earlier the pregnancy stage (gestation) of the previous PTB, the higher the risk of recurrence: women whose prior pregnancy ended between 16 and 20 weeks have a risk of having another PTB even higher than those for whom previous PTB occurred after 20 weeks of pregnancy. Short pregnancy interval (less than 6 months), previous cervical surgery, and intrapartum caesarean section at full cervical dilatation, which can damage the fbres of the cervix in the region of the cervical internal os, can increase the risk of PTB.

*Recommended intervention:* Document past obstetric history. Those deemed to be at high risk of PTB should be provided general advice as well as referred, where possible, to a specialist able to undertake further evaluation and management of risk. Specialised care, where resources permit and evidence of effectiveness exists, may include serial cervical scanning, cervical cerclage or progesterone supplementation.

### *3.2 Pregnancy Dating*

Accurate pregnancy dating should be established. In early pregnancy, a reliable last menstrual period (LMP) can be confrmed by the foetal crown-rump length (CRL) if ultrasound is readily accessible. In the case of a difference of more than 1 week between estimated dates by LMP and CRL, the expected date of delivery indicated by the ultrasound CRL is more reliable. After the frst trimester, foetal biometry using a formula (an algorithm that assesses BPD/HC/FL) may be employed if ultrasound is readily available. If ultrasound is not available and LMP is unknown, clinical assessment of the uterine fundal height (the symphysiofundal height) can be employed pending confrmation by ultrasound. Foetal biometric estimation of gestational age after 20–24 weeks is further improved if the transcerebellar distance can be employed either singly or with femur length assessment to estimate the duration of a clinically advanced pregnancy >20 weeks' gestation. When pregnancy duration has been estimated by the best and earliest possible modality, this should not be changed by foetal size estimates at later gestation.

*Recommended intervention:* Document pregnancy dating at clinic visits. See Chapter "Pregnancy Dating Guidance" for more information, including a fow diagram to guide the dating of the pregnancy process.

Enquiring about social circumstances can help ensure access to personalised care. In particular, information on domestic abuse should be sensitively and tactfully sought to offer psychosocial support and safeguarding as available per local protocols.

*Recommended interventions:* Document social history. Patients with vulnerable social circumstances and other markers (e.g. low BMI, domestic abuse) related to lack of maternal wellbeing may lead to both pregnancy risks and also signal challenges in access to care. Women should be referred to local support services available (psychosocial support, social services) as well as be highlighted for ongoing special support by an identifed caregiver.

### *3.3 Risk Assessment: Infection*

Healthcare workers should determine the context-specifc risk of infections linked to PTB, to inform testing and management as follows:

Urinary Tract Infections (UTI): UTIs and progression to pyelonephritis are risk factors for PTB.

*Recommended intervention:* A midstream urine specimen (MSU) should be collected from all women at the antenatal booking clinic. Point of care dipstick testing should be undertaken, and if there is evidence of infection from history or from the dipstick test, treatment should be instituted per clinical protocols, preferably also informed with sensitivities from MSU where laboratory culture is available.

#### **Bacterial Vaginosis (BV)**

*Recommended intervention:* Routine screening is NOT recommended for asymptomatic BV. For symptomatic BV, pregnant women should be asked about any changes to odour or consistency of vaginal discharge and/or vaginal itching.

#### **Syphilis, HIV and Hepatitis B**

*Recommended intervention:* Routine blood testing should be offered to all women at the booking clinic for syphilis, HIV and hepatitis B and treatment offered as per local protocols.

#### **Malaria**

*Recommended intervention:* In contexts where malaria infection occurs, a blood sample for malarial parasite investigation should be sent at booking and intermittent presumptive therapy offered as per local protocols.

### *3.4 Risk Assessment and Recommended Intervention: Nutrition*

Maternal BMI should be calculated at the booking and subsequent appointments.

*Recommended intervention (context-specifc):* If BMI is <19 kg/m2 or nutrition defciencies detected in undernourished populations:


Knowledge of and access to a well-balanced diet should be assessed during pregnancy.

*Recommended intervention*: Nutrition education (access to a well-balanced diet is advised above and beyond specifc micronutrient supplementation) and exercise advice is recommended for healthy pregnancy outcomes in general.

Screening for iron defciency anaemia should be done early in pregnancy and at 28 weeks.

*Recommended intervention if no defciency:* Standard care consisting of iron (daily oral iron with 30 mg to 60 mg of elemental iron) and folic acid (daily folic acid supplementation with 400 μg (0.4 mg)) to improve general pregnancy outcomes, not specifcally for PTB.

If anaemia prevalence in pregnant women is <20%, an alternative regimen of intermittent oral iron and folic acid with 120 mg of elemental iron and 2800 g (2.8 mg) of folic acid once weekly can be offered.

*Recommended intervention if defciency detected:* If a woman is diagnosed with anaemia during pregnancy, her daily elemental iron should be increased to 120 mg until her haemoglobin concentration rises to normal (110 g/L or higher).

In a context where calcium defciency may exist, patients with low dietary levels of calcium should be identifed (risk of pre-eclampsia).

*Recommended intervention:* Daily calcium supplementation (1.5–2.0 g oral elemental calcium) for populations with low dietary calcium intake (to reduce the risk of pre-eclampsia). NOTE: Iron and calcium supplements should preferably be administered several hours apart to minimise interactions that reduce their absorption.

In populations at risk of vitamin D defciency: patients with potentially low levels should be detected, due to risk for pregnancy outcomes in general. In the UK, for example, this includes women with darker skin (such as those of African, African– Caribbean or South Asian family origin) or women who have limited exposure to sunlight, who may usually be covered or housebound.

*Recommended intervention*: Vitamin D supplementation may be recommended for populations at risk of defciency to improve general pregnancy outcomes, but routine supplementation is not proven to reduce the risk of PTB.

#### 13

### *3.5 Risk Assessment: Alcohol, Tobacco and Other Substance Use*

Sensitive and non-judgemental approaches to enquiry about alcohol, smoking (and exposure to second-hand smoke) and other substance use (past and present) are recommended.

*Recommended intervention:* Document substance use disorder. The presence of family members during maternal health checks may act as a barrier to full disclosure. Effort should be made to address fears of confdentiality. Screening and referral to local services (psychosocial interventions, detoxifcation and pharmacological treatment) were available.

#### **Smoking and Second-Hand Exposure to Smoke**

*Recommended intervention:* Advice on protection from second-hand smoke in pregnancy (homes and public places). Brief intervention and more intensive psychosocial interventions per local protocols. Pharmacological interventions (Nicotine Replacement Therapy (NRT)) according to local protocols.

### **Suggested Readings (More References in Chapters 3–7).**


**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

### **Prenatal Risk Assessment for Preterm Birth in Low-Resource Settings: Demographics and Obstetric History**

**Dilly OC Anumba and Shamanthi M. Jayasooriya**

### **1 Background**

The pregnancy booking (registration) visit affords health-care professionals an opportunity to assess a pregnant woman's risk of PTB among other potential adverse pregnancy outcomes. PTB is multifactorial, with the highest rates seen in sub-Saharan Africa and Asia. This guidance facilitates early identifcation of women likely to experience PTB in LMICs. The following risk factors for PTB should ideally be explored at booking to enable pregnancy risk stratifcation and inform future care planning.

### **2 Evidence Statement**

Interventions known to mitigate PTB should be offered at pregnancy booking following a risk assessment. There is evidence of increased risk of PTB with extremes of maternal age and black ethnicity (exclusively US data). Identifed domestic abuse should trigger a referral for psychosocial support and safeguarding where services are available.

D. O. Anumba (\*)

Academic Unit of Reproductive and Developmental Medicine, University of Sheffeld, Sheffeld, UK e-mail: d.o.c.anumba@sheffeld.ac.uk

S. M. Jayasooriya Academic Unit of Primary Medical Care, University of Sheffeld, Sheffeld, UK e-mail: s.jayasooriya@sheffeld.ac.uk

Women with a previous history of spontaneous preterm birth or mid-trimester miscarriage, particularly when this occurs before 32 weeks, should be referred to specialist PTB services or a health-care professional with additional expertise in managing PTB where available. Surveillance at such specialist services should include, where resources permit, serial surveillance by cervical ultrasound and foetal fbronectin estimation. If there is capacity, individualised support that may include cervical cerclage or progesterone prophylaxis may be offered.

Other risk factors for which women should be referred for specialist preterm birth risk assessment and care include women who have had a caesarean section at full cervical dilatation and women with congenital uterine abnormalities.

### **3 Synopsis of best Evidenced Obstetric and Demographic Risk Factors for Preterm Birth**

These, together with the interventions known to mitigate the risk of PTB, are also shown in Table 1.

### *3.1 Maternal Demographics*

(i) *Maternal Age.*

Risk of preterm birth determined by maternal age follows a "U"-shaped distribution. Women over 40 yrs. (OR 1.20, 95% CI 1.06, 1.36) [2] and adolescents, 13–19 yrs., have an increased risk of very preterm (<32 w, aOR 2.12, 95% CI 1.06 to 4.25) and extremely preterm (<28 w, aOR 5.06, 95% CI 1.23 to 20.78) delivery [3], as do frst (OR = 1.21, [95% CI: 1.01–1.45]) and second (OR = 1.93, [95% CI: 1.38–2.69]) time mothers aged 14–17 yrs. when compared with 20–29 yrs. [4]. A meta-analysis of 14 cohort studies conducted exclusively in LMICs found that nulliparous women below 18 years of age had the highest risk of PTB of all age/parity (OR: 1.52, 95% CI: 1.40–1.66) [26].

(ii) *Domestic Abuse.*

Rates of PTB are higher (OR 1.91, 95% CI 1.60–2.29) as is low birth weight, LBW (OR 2.11, 95% CI 1.68–2.65) [9].

(iii) *Race.*

Black women in the USA have a fourfold increased risk of PTB (16–18%) compared to White women (5–9%) [5–8]. However, the reason for this is unclear, and its implications for risk assessment in LMICs with predominant black populations are unclear.


**Table 1** Summary of interventions for evidenced risk factors of preterm birth

*LETTZ* large loop excision of the transformation zone

### *3.2 Obstetric and Gynaecological History*

(i) *History of PTB.*

Previous PTB is a strong risk factor for repeat PTB (recurrence risk is 15–50% depending on the gestation at previous delivery and birth order [12, 13]). The earlier the gestation at previous PTB or mid-trimester miscarriage, the higher the chance of recurrence [27]. None of the studies in the main systematic review included data from an LMIC setting.

	- Previous history of cervical surgery increases the risk of PTB.
	- Previous cold knife conisation (<37 weeks; RR 2.59, 95% CI 1.80–3.72 [14%] vs [5%]).
	- Large loop excision of the transformation zone (LLETZ) (RR 1.70, 1.24–2.35, [11%] vs [7%]) [21–23].
	- Trachelectomy: preterm birth rates of 30–60% [18, 19].

Multiple pregnancy contributes to 2–3% of pregnancies but accounts for 15–20% of all PTBs [5]. Risk of PTB in twins after previous singleton PTB (56.9 versus 20.9%; OR 5.0; 95% CI 3.8–6.6) [8].

### *3.3 Factors Not Yet Shown to be Associated with Increased Risk of PTB in LMIC Settings*


### **4 Practical Clinical Risk Assessment Instructions for PTB**

• Although evaluation of the past obstetric history is routinely carried out during antenatal booking and registration in most contexts, information obtained is seldom employed to undertake a formal risk assessment for PTB. We therefore highlight below routine data collected to enable formal evaluation and categorisation of a women's risk of PTB in to low or high.

The health-care worker who conducts the booking assessment should systematically review the demographics of the woman to determine risk factors for PTB. Enquiry should address the following:


These enquiries should ultimately lead to categorisation of risk of preterm birth and the signposting of the woman to appropriate care.

### **5 Interventions for Evidenced Risk Factors for PTB**

These are outlined in Table 1.

### **6 Summary of Generic Health Systems ANC Interventions to Reduce PTB (Likely to Mitigate PTB Risk from Demographic and Obstetric Factors)**

These are shown in Table 2.

### **7 Research and Clinical Practice Recommendation**

Most of the evidence describing demographic and clinical historical risk factors for PTB is from high-income settings (HICs). Although some of these may apply to an LMIC setting, there is clear need for further research regarding the risk factors for PTB in LMIC settings where the contribution of factors such as infection and

**Moderate (clear) beneft** [1]**.**

• Screening for lower genital tract infections <37wks without signs of labour, bleeding, Or infection


**Low (possible) beneft** [1]


**Table 2** Benefts statements of generic health systems ANC interventions to reduce PTB

<sup>•</sup> Continuity of care vs other models of care for all women.

nutrient defciencies may play a more crucial role. There is also a paucity of lowcost interventions and risk mitigation interventions accessible to health-care providers in LMIC settings. However, improved antenatal risk assessment can promote advice regarding lifestyle modifcations such as smoking cessation, nutrient supplementation, and judicious use of indicated cervical cerclage, all of which could reduce the risk of spontaneous premature birth as well as of indicated preterm birth from conditions such as pre-eclampsia and placental insuffciency causing small for gestational age. Given the variable skills and competencies of providers of antenatal care (ANC) and birth in LMIC settings, further research is required to defne care models and advocate for practitioners that may reduce incidence or severity of preterm birth in LMIC settings.

### **References**


**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

### **Pregnancy Dating Guidance**

**Dilly OC Anumba**

### **1 Background**

An essential component of antenatal care is pregnancy dating, allowing for an accurate estimation of the duration of pregnancy. It is important for identifying the optimum timing of obstetric interventions such as location of birth, delivery mode, and management of foetal growth abnormalities. Accurate pregnancy dating improves the classifcation of preterm birth (PTB) and enables global PTB rates to be comparable. In low- and middle-income countries (LMICs), where the burden of PTB and intrauterine growth restriction is highest [1, 2], pregnancy dating is a challenge: women are often unable to recollect their last menstrual period, and menstrual cycle lengths vary due to short birth intervals and lactation [3, 4]. Clinical palpation to estimate uterine size is often inaccurate and infuenced by foetal growth restriction, uterine fbroids, foetal malpresentation (associated with high parity), and maternal obesity. Late presentation for pregnancy registration is common in LMICs making pregnancy dating a challenge.

This guidance details the optimum approach to pregnancy dating utilising the best resources currently available in different contexts and taking into account late presentation.

D. O. Anumba (\*)

e-mail: d.o.c.anumba@sheffeld.ac.uk

© The Author(s) 2022 D. O. Anumba, S. M. Jayasooriya (eds.), *Evidence Based Global Health Manual for Preterm Birth Risk Assessment*, https://doi.org/10.1007/978-3-031-04462-5\_4

Academic Unit of Reproductive and Developmental Medicine, University of Sheffeld, Sheffeld, UK

### **2 Evidence Statement**

Accurate pregnancy dating is important to enable accurate diagnosis of preterm labour and delivery. It varies with the duration of the pregnancy at presentation.

In early pregnancy, a reliable last menstrual period (LMP) should be employed and confrmed by the foetal crown-rump length (CRL) if ultrasound is readily accessible. A discrepancy of more than 1 week between both modalities should trigger a switch in the confrmed pregnancy duration and expected date of delivery to the ultrasound CRL as this is more reliable.

After the frst trimester, foetal biometry using a formula (algorithm that assesses BPD/HC/FL) may be employed if ultrasound is readily available. If ultrasound is not immediately accessible, clinical assessment of the uterine fundal height should be used pending confrmation by ultrasound where possible. Foetal biometric estimation of gestational age at 20–24 weeks' is further improved if the transcerebellar distance can be employed either singly or with femur length assessment to estimate the duration. Where ultrasound is unavailable, then the symphysiofundal height should be used.

### **3 Synopsis of Best-Evidenced Pregnancy Dating Methods**

### *3.1 Last Menstrual Period*

Thi**s** is the most widely used method to estimate pregnancy duration. If known with certainty, it offers a good estimation of the baby's due date and accurate pregnancy dating. However, it may overestimate pregnancy duration by more than 3 days in high-income settings (HICS) [5] and longer in LMICs [6]. It is dependent on the regularity of the menstrual cycle and subjective recall of the frst day of the last period.

(*Moderate to high certainty of evidence)*

### *3.2 First Trimester Ultrasound*

Measurement of the foetal crown-rump length (CRL) is considered to be the goldstandard method for estimating gestational age (up to 14 weeks' gestation) [5, 7]. Unfortunately, in LMICs, ultrasound early in gestation is often not universally available, and there is the tendency for pregnant women to present late for antenatal care. These issues limit the application of CRL measurement in these settings.

*(Moderate to high certainty of evidence*)

### *3.3 Ultrasound Standard Foetal Biometric Measurements at 14 to 20 Weeks' Gestation*

Standard biometric measurements (biparietal diameter, head circumference, abdominal circumference, and femur length) provide an accurate estimation of gestational age (to within ±1–2 weeks of the crown-rump length (CRL) measurement of gestational age) [8].

*(Moderate to high certainty of evidence)*

### *3.4 Ultrasound Standard Foetal Biometric Measurements after 20 Weeks' of Gestation*

Standard biometry does not perform as well as it does at less than 20 weeks' gestation, with accuracy of only ± ≥ 3 weeks of the CRL measurement [7], especially in LMICs where 19·3% of infants are born small for gestational age [2]. Measurement of the cerebellum alone or combined with femur length [9] provides more accurate estimation of gestational age compared with standard biometry measurements [10].

*(Moderate to high certainty of evidence)*

### *3.5 Symphysiofundal Height Estimation*

In late pregnancy after 20 weeks, this provides gestational age estimation comparable with the last menstrual period and may be employed against a validated normogram when women present late and menstrual dates are not reliable and access to ultrasound is limited [11].

*(Low certainty of evidence)*

Figure 1 outlines the pragmatic steps that facilitate estimating pregnancy duration as accurately as possible in low as well as high resource settings, based on careful evaluation of the last menstrual period history, the availability and utilisation of ultrasound, as well as the best ultrasound parameters that should be employed. In limited resource settings where late booking is rife, it highlights the use of clinical estimation of the symphysiofundal height to augment available information about pregnancy duration.

**Fig. 1** Flow diagram to guide pregnancy dating. *EDD* Estimated date of delivery; *CRL* Crownrump length, *HC* Head circumference, *BPD* Biparietal diameter; *FL* Femur length

### **References**


the WHO Alliance for maternal and newborn health improvement (AMANHI) study group. Lancet Glob Health. 2020;8(4):e545–e54.


**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

### **Prenatal Risk Assessment for Preterm Birth in Low-Resource Settings: Infection**

**Kerry M. Parris and Shamanthi M. Jayasooriya**

### **1 Background**

Infection is a major risk factor for PTB, accounting for 40–50% of all deliveries before 37 completed weeks of gestation. The most common route of infection is via the genital tract and subsequent microbial ascension and invasion of the amniotic cavity (25–40% of the total number of PTBs) [1–4]. Routine ANC provides an opportunity for health-care professionals to assess a pregnant woman's risk of PTB and other adverse pregnancy outcomes. High rates of maternal bacterial and viral infections are reported in LMICs, and it is in these settings where most PTBs occur (approximately 81%) [5].

### **2 Evidence Statement**

Infection in pregnancy is associated with an increased risk of PTB. Current guidelines recommend routine testing and treatment for human immunodefciency virus (HIV), hepatitis B virus, malaria (context dependent), and syphilis. The aim of this testing is to improve health outcomes of mothers and their babies and/or to prevent mother-to-child transmission.

K. M. Parris (\*)

© The Author(s) 2022

Academic Unit of Reproductive and Developmental Medicine, Department of Oncology and Metabolism, University of Sheffeld, Sheffeld, UK e-mail: mda08kmp@sheffeld.ac.uk

S. M. Jayasooriya Academic Unit of Primary Medical Care, University of Sheffeld, Sheffeld, UK e-mail: s.jayasooriya@sheffeld.ac.uk

D. O. Anumba, S. M. Jayasooriya (eds.), *Evidence Based Global Health Manual for Preterm Birth Risk Assessment*, https://doi.org/10.1007/978-3-031-04462-5\_5

The increased risk of PTB from other infections such as asymptomatic bacteriuria (ASB) should prompt testing a clean-catch midstream urine by microscopy, culture, and sensitivity, where available, and providing antibiotic treatment as appropriate. Pregnant women should be offered testing for lower genital tract infections in high-risk populations or cases of suspected disease, with or without symptoms, as evidence has shown that such treatment decreases PTB risk.

### **3 Synopsis of Best Evidenced Infectious Risk Factors for Preterm Birth**

For a summary of the evidence of infectious risk factors for preterm birth, please see Table 1, in Sect. 5.

### *3.1 Human Immunodefciency Virus*

HIV is more prevalent in LMIC than HIC settings. HIV has been shown to increase the risk of spontaneous PTB 2.1-fold when compared to HIV-negative controls (17% vs. 8%; OR 2.27; 95% CI:1.2–4.3). Furthermore, a 3.2-fold increased risk for PTB was reported in HIV-positive women, and this was strongly associated with the use of highly active antiretroviral therapy (HAART) in the second trimester, OR 6.2 (95% CI:1.4–26.2) [6].

### *3.2 Malaria*

Malaria infection is a risk factor for PTB. A systematic review and meta-analysis of 58 studies with 134,801 participants across 21 East African countries reported increased risks of PTB (aOR of 3.08 (95% CI:1.2–4.3) and also when malaria is a co-infection with HIV (aOR 2.59; 95% CI:1.84–3.66) [8]. Intermittent preventive treatment of malaria in pregnancy (IPTp) is an integral part of antenatal care in areas with moderate to high malaria transmission, alongside use of long-lasting insecticidal nets (LLINs), prompt diagnosis, and effective treatment of malaria infections.


**Table 1** Evidenced infection-associated risk factors for PTB and effectiveness of interventions

(continued)


**Table 1** (continued)

*HIV* Human immunodefciency virus, *PTB* Preterm birth, *ART* Antiretroviral therapy, *ITPp* Intermittent preventive therapy in pregnancy, *UTI* Urinary tract infection, *ASB* Asymptomatic bacteriuria, *STIs* Sexually transmitted infections, *BV* Bacterial vaginosis, *CMV* Cytomegalovirus, *HSV* Herpes simplex virus, *HIC* High-income setting, *OR* Odds ratio, *aOR* Adjusted odds ratio, *RR* Risk ratio

### *3.3 Syphilis*

Infection with syphilis-causing bacteria, *Treponeda pallidum,* is more common in LMIC than HIC settings. Syphilis is associated with an increased risk of PTB where mothers present late to antenatal care (OR 2.09; 95% CI:1.09–4.00) [9].

### *3.4 Urinary Tract Infections (UTI)*

UTIs are frequently reported as a risk factor for PTB, with studies stating odds ratios (OR) of 1.8 (95% CI: 1.4–2.1) [10], 1.8 (95% CI: 1.3–2.4) [11] and 5.05 (95% CI: 1.16–21.8) [12, 13]. Low quality evidence from a systematic review and metaanalysis conducted across 21 East African countries reported an OR of 5.27 (95% CI: 2.98–9.31) [8]. Symptomatic urinary tract infections should be treated with antibiotics, and repeated urine testing is advised in low- and high-risk women [8].

### *3.5 Asymptomatic Bacteriuria (ASB)*

Many infections during pregnancy present *subclinically or are asymptomatic*, subsequently delaying treatment and diagnosis. Untreated ASB is associated with PTB (aOR 1.6; 95% CI: 1.5–1.7) and has been shown to develop into acute pyelonephritis, itself an independent risk factor for PTB (OR: 2.6; 95% CI: 1.7–3.9) [7, 14, 26]. Increased rates of spontaneous PTB in patients with pyelonephritis have been reported (10.3% vs 7.9%; OR:1.3; 95% CI:1.2–1.5) [27]. Routine urine dipstick testing is not advised by the WHO due to high false-positive rates (118/1000) leading to unnecessary treatment and antimicrobial resistance [7].

### *3.6 Sexually Transmitted Infections (STIs)*

STIs of the lower genital tract have been linked to increased risk of PTB; the most robust evidence available reports an OR of 1.3 (95% CI:1.1–1.4) [17] in cases of trichomoniasis (caused by the *Trichomonas vaginalis* parasite). However, Gulmezoglu and Azhar (2011) reported *T. vaginalis* treatment with metronidazole to appear to increase risk of PTB (RR 1.78; 95%CI:1.19 to 2.66) [21, 28]. Odds ratios of 2.2 (95% CI:1.03–4.78) and 3.2 (95% CI:1.08–9.57) at <37 weeks delivery and < 35 weeks delivery, respectively, are reported where infection with *Chlamydia trachomatis* bacteria has been diagnosed [18, 19].

### *3.7 Bacterial Vaginosis (BV)*

A 2014 prospective cohort study found a signifcant increase in PTB risk in women with higher levels of BV-associated bacteria and a previous history of PTB, adjusted OR (aOR) 16.4 (95% CI: 4.3–62.7) [22]. Strategies to treat BV have failed to lower PTB risk [4].

### *3.8 Systemic Viral Pathogens*

Infection with some systemic viral pathogens is a risk factor for PTB; the available best evidence reports odds ratios for cytomegalovirus (CMV), 1.6 (95% CI:1.14–2.27) [24], any herpesvirus, 1.51 (95% CI:1.08–2.10) [24], and infuenza A (H1N1), 2.21 (95% CI:1.47–3.33) [25].

### *3.9 Factors Not Yet Shown to Be Associated with Increased Risk of Preterm Birth*


### **4 Practical Clinical Risk Assessment Instructions for PTB**

Health-care workers conducting the antenatal booking assessment should determine the risk of infections linked to PTB. This enquiry should determine likelihood of specifc infections known to be risk factors for PTB to inform testing and management as follows:


Enquiries and testing, where appropriate, should lead to categorisation of risk of PTB and appropriate treatment and management.

**Table 2** Beneft statements of infection interventions to reduce PTB risk

• **Moderate (clear) beneft** [7, 16]. – Testing for HIV, malaria, and syphilis. – Screening for lower genital tract infections <37wks without signs of labour, bleeding, or infection. – Antibiotics for pregnant women with UTIs. • **Low (possible) beneft** [7]. – Screening for asymptomatic bacteriuria. – Antibiotics for pregnant women with asymptomatic bacteriuria. • **No beneft** [23]. – Metronidazole for low- or high-risk women with bacterial vaginosis.

### **5 Interventions for Evidenced Risk Factors for PTB**

The evidenced effective interventions to address infections associated with preterm birth are shown in Table 1.

### **6 Summary of ANC Infection Interventions to Reduce PTB**

These are depicted in Table 2.

### **7 Research and Clinical Practice Recommendation**

Clinical practice should focus on promoting awareness of infections prior to and during pregnancy rather than routine testing of all infections linked to PTB. Further research is required to consider routine testing for chlamydia in target populations and effectiveness of dipstick testing for ASB in LMIC settings.

### **References**


**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

### **Nutritional Status and the Risk of Preterm Birth**

**Bronwen Gillespie**

### **1 Background**

The pregnancy booking visit affords the health-care professional an opportunity to assess a pregnant woman's risk of PTB, among other potential adverse pregnancy outcomes. This guidance is aimed to facilitate early identifcation of women likely to experience PTB, especially in LMICs settings, and to highlight risk factors for PTB that should signpost care pathways to try to reduce the risk and improve birth outcomes. A woman's body mass index (BMI) and nutritional status, covered in this section, affect her risk of spontaneous PTB and should be assessed.

### **2 Evidence Statement**


© The Author(s) 2022 D. O. Anumba, S. M. Jayasooriya (eds.), *Evidence Based Global Health Manual for Preterm Birth Risk Assessment*, https://doi.org/10.1007/978-3-031-04462-5\_6

B. Gillespie (\*)

Oncology and Metabolism, University of Sheffeld, Sheffeld, UK e-mail: b.gillespie@sheffeld.ac.uk

pregnant women. However, in settings where there are low dietary or maternal zinc levels, women may beneft from zinc supplementation. Nutrition is a marker of general health and until clearer evidence is available regarding the beneft of supplementing with specifc nutrients, caregivers should explore and address access to balanced diets and food security in general during the pregnancy risk assessment.

### **3 Synopsis of best Evidenced Nutrition-Related Risk Factors for Preterm Birth**

For a summary of the evidence of these nutrition-related risk factors for preterm birth, please see Table 1, in Sect. 5, below.

### *3.1 Body Mass Index (BMI)*

(i) *Low BMI.*

Low BMI is associated with an increased risk of PTB (BMI <19 kg/m2 relative risk (RR): 1.29, 95% CI: 1.15–1.46) [1, 2]. A systematic review of 78 studies involving 1,025,794 women found that the overall risk of PTB was increased in underweight women (adjusted RR 1.29, 95% CI 1.15–1.46), as were the risks of spontaneous PTB (adjusted RR 1.32, 95% CI 1.10–1.57) and induced PTB (adjusted RR 1.21, 95% CI 1.07–1.36) [2]. However, when limited to developing countries (5/52, 10% of cohort studies), no signifcant association was found (RR: 0.99, 95% CI: 0.67–1.45) [2].

Overweight (OR 1.20, 95% CI 1.04–1.38), obese (OR 1.60, 95% CI 1.32–1.94), and morbidly obese (OR 2.42, 95% CI 1.46–4.05) have been shown to increase risks of PTB [15]. Data from LMICs is absent. In one systematic review on maternal BMI which included 39 studies (1,788,633 women), fndings suggested that obese women (BMI, 35–40) have an increased risk for PTB in general (aOR = 1.33, 95% CI: 1.12–1.57), as well as for moderate (aOR = 2.43, 95% CI: 1.46–4.05) and very PTB (AOR = 1.96, 95% CI: 1.66–2.31). Very obese women (BMI > 40) have an even higher risk (AOR = 2.27, 95%CI: 1.76–2.94) [5].

<sup>(</sup>ii) *High BMI.*


**Table 1** Summary of evidenced risk factors and interventions for PTB

(continued)


**Table 1** (continued)

*PTB* Preterm birth, *BMI* Body mass index, *LMIC* Low- and middle-income countries, *SGA* Small for gestational age, *RR* Relative risk, *CI* Confdence interval

### *3.2 Dietary Patterns*

A systematic review of observational studies on maternal dietary patterns and birth outcomes found that unhealthy dietary patterns characterized by high intakes of refned grains, processed meat, and foods high in saturated fat or sugar were associated with a trend towards a higher risk of PTB (OR: 1.17; 95% CI: 0.99, 1.39; I2 = 76%). Healthy dietary patterns—characterized by high intakes of vegetables, fruits, whole grains, low-fat dairy, and lean protein foods—were associated with a lower risk of PTB (OR for top compared with bottom tercile: 0.79; 95% CI: 0.68, 0.91; I2 = 32%) [7].

### *3.3 Nutrient and Mineral Defciencies* **Defnitely** *Associated with an Increased Risk of Preterm Birth*

Observational studies suggest that pre-conceptional and periconceptional intake of some vitamin and mineral supplements are associated with a reduced risk of PTB [8]. Further evidence examines specifc supplements for nutrient defciencies:

	- A meta-analysis of 18 prospective and retrospective studies with a combined sample size of 932,090 showed a signifcant relationship between maternal anemia during pregnancy and PTB (OR 1.56 [95% CI: 1.25–1.95]) [16].
	- WHO guidelines recommend daily oral iron but suggest that weekly iron should be considered for a) cases where daily iron is not acceptable due to side effects and b) populations with anemia in pregnancy prevalence of less than 20% (as this is not considered public health risk) [3].
	- Evidence that folic acid supplementation reduces the risk of PTB is conficting [17], with one systematic review suggesting that supplementation is associated with a signifcant reduction in the risk of PTB only when being initiated after conception [12]. However, folate supplementation has established benefts for reducing birth defects.
	- The WHO recommends that in populations with low dietary calcium intake pregnant women should receive daily calcium supplementation to reduce the risk of pre-eclampsia [3].
	- One review found that high-dose calcium supplementation (at least 1 g/day) may reduce the risk of pre-eclampsia and PTB, particularly for women with low calcium diets (low-quality evidence) [13]. The average risk of PTB was reduced in the calcium supplementation group (11 trials, 15,275 women: RR 0.76, 95% CI 0.60 to 0.97; low-quality evidence); this reduction was greatest among women at higher risk of developing pre-eclampsia (four trials, 568 women: average RR 0.45, 95% CI 0.24 to 0.83). Most studies were carried out in LMIC settings [13].
	- A review examining the effect of calcium supplementation on pregnancy outcomes other than hypertension and pre-eclampsia showed no clear additional benefts on preventing PTB [14]. However, when evidence is stratifed by dose (<1000 mg vs ≥1000 mg), high-dose calcium supplementation appears to reduce PTB (12 trials, 15,479 women; RR: 0.81, 95% CI: 0.66–0.99) [3]. Current WHO guidelines recommend calcium supplementation only to reduce the risk of developing pregnancy-induced hypertension [3, 14].

### *3.4 Nutrient and Mineral Defciencies* **Possibly** *Associated with an Increased Risk of Preterm Birth in Specifc Situations*

Supplementing the following nutrient factors is not clearly established to reduce the risk of PTB. However, for some of these factors, the evidence is conficting, and for others, further research is required.

	- The WHO does not recommend vitamin D supplementation to improve maternal and perinatal outcomes, advising that sunlight is the most important source of vitamin D [3]. In some countries such as the UK, supplementation with 10 micrograms of vitamin D per day for population groups at increased risk of vitamin D defciency (those with darker skin or experiencing low sunlight exposure) and pregnant and lactating women is recommended [11].
	- Evidence (22 trials, 3725 pregnant women) suggests that supplementation with vitamin D alone during pregnancy probably reduces the risk of preeclampsia, gestational diabetes, and low birthweight but may make little or no difference to the risk of having PTB (RR 0.66, 95% CI 0.34 to 1.30; 7 trials, 1640 women) [18]. An earlier review (9 trials, 1916 pregnant women) suggests that supplementation with vitamin D combined with calcium may reduce the risk for pre-eclampsia but may actually increase the risk of PTB (RR 1.52, 95% CI 1.01 to 2.28; 5 trials, 942 women), consistent with an earlier version [19] which it updated which showed that the combination increased the risk of delivery prior to 37 weeks of gestation compared to women who received no treatment or placebo (RR 1.57; 95% CI 1.02 to 2.43; 3 studies, 798 women, moderate quality), but that supplementation of vitamin D alone reduces the risk of PTB compared to no intervention or placebo (8.9% versus 15.5%; RR 0.36; 95% CI 0.14 to 0.93; 3 trials, 477 women, moderate quality). These reviews included studies from LMIC settings (Bangladesh, India, Brazil, Iran) [18, 19].
	- Given conficting fndings between systematic reviews of observational studies and those examining the effectiveness of vitamin D from randomized control trials (RCTs) which showed no effect, it is suggested that low vitamin D levels may refect poor general maternal health status for which attention to general health rather than vitamin D supplementation is required [20].
	- Maternal zinc supplementation is contentious—while WHO guidelines recommend further research regarding zinc supplementation for pregnant women [3], low-to-moderate-certainty evidence suggests that zinc supplementation may reduce PTB (16 trials, 7637 women; RR: 0.86, 95% CI: 0.76–0.97) in women with presumed low zinc intake or poor nutrition (14 trials mostly from LMIC settings, 7099 women; RR: 0.87, 95% CI: 0.77–0.98) [21], rather than as a routine supplement for all pregnant women.
	- A systematic review found that B12 defciency (<148 pmol/L) was associated with a higher risk of low birth weight (adjusted risk ratio = 1.15, 95% confdence interval (CI): 1.01, 1.31) and PTB (adjusted risk ratio = 1.21, 95% CI: 0.99, 1.49) [22].
	- According to WHO guidelines, there is high-certainty evidence that shows that MMN supplements make little or no difference to PTB rates (14 trials; RR: 0.95, 95% CI: 0.88–1.03) [3]. However, recent evidence indicates that MMN (added to iron and folic acid) may slightly reduce the risk of PTB (average RR 0.95, 95% CI 0.90 to 1.01; 18 trials, 91,425 participants; moderate-quality evidence) and very PTB (average RR 0.81, 95% CI 0.71 to 0.93; 4 trials, 37,701 participants) when compared to iron, with or without folic acid [23].
	- Vitamin A defciency is not linked to PTB and is not generally recommended in pregnancy as it can be teratogenic [11]. However, it is appropriate to supplement pregnant women in areas where vitamin A defciency is a severe public health problem, to prevent night blindness [3].
	- One systematic review of RCTs has shown that women who received omega-3 LCPUFA experienced less PTB < 37 weeks (13.4% versus 11.9%; RR 0.89, 95% CI 0.81 to 0.97; 26 RCTs, 10,304 participants; high-quality evidence) and early PTB < 34 weeks (4.6% versus 2.7%; RR 0.58, 95% CI 0.44 to 0.77; 9 RCTs, 5204 participants; high-quality evidence) than those who did not receive omega-3 [24].
	- Low-certainty evidence from one trial suggests that restricting caffeine intake may have little or no effect on PTB (1153 neonates; RR: 0.81, 95% CI: 0.48–1.37); however, those with high intake are recommended to reduce it for better pregnancy outcomes in general [3]. Some studies indicate that high caffeine consumption is associated with low birth weight and/or prematurity [25].

### *3.5 Nutrient and Mineral Defciencies* **Not Shown to be Associated** *with an Increased Risk of Preterm Birth [3]*

Supplementation is not recommended for vitamin B6 (pyridoxine), vitamin E and C (moderate-certainty evidence shows little or no effect on PTB; 11 trials, 20,565 neonates; RR: 0.98, 95% CI: 0.88–1.09), and high protein (1 study, 505 women; RR: 1.14, 95% CI: 0.83–1.56).

### **4 Practical Clinical Risk Assessment Instructions for PTB**

As part of the general evaluation of pregnant women, some routine nutritional assessment is carried out during antenatal booking in most contexts. However, information obtained is seldom employed to undertake a formal risk assessment for PTB. Therefore, we highlight below routine data that should be collected to enable formal evaluation of a women's risk of PTB.


Nutrient and mineral defciencies: Iron defciency anemia is a risk for PTB. Pregnant women should be offered screening for anemia early in pregnancy and at 28 weeks when other blood screening tests are being performed [11]. In a context where calcium defciency may exist, or risk of pre-eclampsia is deemed substantial, or there is suspicion of low dietary calcium levels, calcium supplementation should be offered. Populations at high risk of vitamin D defciency should be offered vitamin D supplementation to improve pregnancy outcomes generally.

### **5 Evidenced Risk Factors and Interventions for PTB**

These are outlined in Table 1.

### **6 Summary of Nutrition Interventions to Reduce PTB**

These are shown in Table 2.

### **7 Research and Clinical Practice Recommendation**

To clarify outcomes for PTB, further RCTs are recommended that target populations with a high prevalence of vitamin D defciency. It would be helpful if future trials were to evaluate whether the increase of serum 25-hydroxyvitamin D concentration supplementation early in pregnancy is associated with improved maternal and infant outcomes in populations with different BMI, skin pigmentation, vitamin D status, and setting [18]. Research should also evaluate the PTB risk of combining calcium and vitamin D. Further research is also required to look at zinc and omega-3 fatty acids in relation to PTB.

#### **Table 2** Beneft statements of nutrition interventions to reduce preterm birth

#### **Very clear beneft**


#### **Moderate beneft**


#### **Possible beneft**


However, the most important focus should be on promoting a good quality diet in general, rather than a specifc supplementation regime. Studies to address ways of improving the overall nutritional status of populations in impoverished areas, rather than focusing on micronutrient and or zinc supplementation, are required [21]. The role of maternal BMI on PTB risks in LMICs warrants further study.

### **References**


**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

### **Evaluating Alcohol, Tobacco, and Other Substance Use in Pregnant Women**

**Shumona Sharmin Salam and Caroline Mitchell**

### **1 Background**

Substance use disorder in pregnancy is a critical public health concern that is linked with several adverse maternal and newborn health outcomes including preterm birth (PTB), low birth weight (LBW), and small for gestational age (SGA) babies. The most widely used substances in pregnancy in high-, low-, and middle-income countries (LMICs) include tobacco, alcohol, cannabis, opiates, cocaine, and other illicit substances. This guidance has been developed to help health-care providers in identifying and managing smoking, alcohol, and substance use disorders in pregnant women and thereby reducing the risks of PTB and other adverse maternal and child health outcomes.

This guideline summarises information from the WHO, other guidance (where available), and recently conducted systematic reviews on the risks of and interventions for antenatal exposure to smoking, alcohol, and substance use for PTB.

### **2 Evidence Statement**

Use of alcohol, tobacco, and other psychoactive substances during pregnancy leads to an increased risk of health problems for mother and child such as spontaneous abortion, stillbirth, low birth weight, birth defects, and prematurity (Table 1). Concurrent

C. Mitchell

S. S. Salam (\*)

Oncology and Metabolism, University of Sheffeld, Sheffeld, UK e-mail: shumona.salam@sheffeld.ac.uk

Academic Unit of Primary Medical Care, University of Sheffeld, Sheffeld, UK e-mail: c.mitchell@sheffeld.ac.uk

D. O. Anumba, S. M. Jayasooriya (eds.), *Evidence Based Global Health Manual for Preterm Birth Risk Assessment*, https://doi.org/10.1007/978-3-031-04462-5\_7


54


*PTB* Preterm birth, *LMIC* Low- and middle-income countries, *RR* Relative risk, *CI* Confdence interval, *NRT* Nicotine replacement therapy, *SHS* Second-hand smoke

use of these substances (i.e. poly substance use) further increases the risk of adverse outcomes in all settings.

This guideline proposes interventions (Table 1) for the identifcation and management of the following:


Despite gaps in research and knowledge, the potential benefts of the recommended actions may help improve PTB and other birth outcomes.

### **3 Synopsis of the best Evidenced Risk Factors for Preterm Birth**

For a summary of the evidence of tobacco, alcohol, and substance use-related risk factors for preterm birth, please see Table 1, in Sect. 5.

### *3.1 Smoking and Exposure to Second-Hand Smoke*


### *3.2 Alcohol Use*

A dose-response relationship between *alcohol consumption* during pregnancy and the risks of PTB was observed in a meta-analysis (2011) of 14 observational studies (*n* = 280,443 pregnant women) primarily in HICs [4]. Compared with mothers who do not drink, the overall dose-response relationships for PTB showed (i) no effect up to 18 g pure alcohol or an average of 1.5 drinks/day and (ii) 23% increase in risk at an average of three drinks or 36 g/day (RR 1.23, 95% CI 1.05–1.44) [4].

### *3.3 Substance Use*


### **4 Practical Clinical Risk Assessment Instructions for PTB**

4.1 Health-care providers should ask all pregnant women about their use of alcohol and other substances (past and present) early in pregnancy and at every antenatal visit. WHO recommends the use of validated screening instruments for this purpose [13, 14]. There may be cultural taboos which compound stigma and other diffculties in disclosure of substance use such as fear of judgement by health-care providers, breach of confdentiality, and fear of child removal after the birth.

4.2 All guidance encourages health-care practitioners to explore these issues sensitively, using a non-judgemental approach and in a confdential environment. There may, however, be child safeguarding issues which arise during this assessment which should be dealt with using in-country mechanisms, while optimising maternal physical and mental health. The presence of family members during maternal health checks may also act as a barrier to full disclosure.

4.3 Listed below are screening instruments that have been suggested to be used for prenatal assessment of pregnant women [13, 14]. There are variations in the tools regarding number of items, administration method (paper and pencil, computer), training needed, and location (prenatal clinic/outpatient/inpatient). Although some of the tools were validated, they will need to be further validated before use in an LMIC context.


### **5 Evidenced Effective Interventions for Risk Factors for Preterm Birth**

These are summarised in Table 1.


**Table 2** Benefts statements of effectiveness of smoking cessation interventions to prevent preterm birth

#### **Low (possible) beneft**


**Table 3** Benefts statements of effective interventions to promote harm reduction to prevent preterm birth


### **8 Research and Clinical Practice Recommendation**

There is strong consensus within the literature about the negative effects of alcohol, tobacco, and substance use during pregnancy, and all women should receive necessary interventions to stop (preferably) or reduce use. The evidence is of low quality, and further primary research and controlled trials are needed on effective ways to assess exposure and the use of alcohol, tobacco (including second-hand exposure), and substances; measure the effect on maternal and child health outcomes and for determining the effectiveness and cost-effectiveness of recommended interventions in pregnancy. Additionally, there is also a dearth of studies conducted in LMICs. Assessment methods should include and integrate fndings from policy, public health, behavioural and implementation science, and trials of interventions where PTB is the primary outcome measure. In addition, longitudinal cohort studies which include consideration of multi-factorial psychosocial factors are needed to assess the risks on women, children, and future generations.

### **References**


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