Measurement, prevalence, causes, and health outcomes of co-existing multiple high-risk factors in pregnancy: a systematic review and meta-analysis

doi:10.21203/rs.3.rs-2336304/v1

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Measurement, prevalence, causes, and health outcomes of co-existing multiple high-risk factors in pregnancy: a systematic review and meta-analysis

https://doi.org/10.21203/rs.3.rs-2336304/v1

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Background

The co-occurrence of multiple high-risk factors during pregnancy (MHFP) is becoming increasingly common in transitioning populations, and may cause higher risk of adverse pregnancy outcomes. We performed a systematic review to better understand and summarize current evidence on MHFP.

Methods

Of 10,502 studies found, 46 original research met the inclusion criteria. Existing evidence on the measurement and definition, prevalence, causes, and health outcomes of MHFP were extracted and synthesized. The prevalence of MHFP was pooled through meta-analysis with random effects model. The linear regression model was used to estimate the trends of MHFP prevalence stratified by income levels of countries.

Results

Among 46 included studies, 76% were from high-income countries (HICs). The definition and types of high-risk factors in pregnancy are complex, multidimensional, and subjective. Four dimensions of MHFP were identified, including physical conditions, mental conditions, social-behavioural problems, and pregnancy history. Co-existing multiple physical conditions were the most common MHFP patterns, and anxiety-depression was the most studied MHFP pair. The overall pooled prevalence of MHFP was 16% according to included studies, with similar prevalence in HICs and low- and middle-income countries (LMICs). However, publications from LMICs were limited. Only three studies investigated the potential causes of MHFP. MHFP would affect women and their children’s health at multiple life stages.

Conclusion

The definition, measurement, potential clustered patterns, causes, and health outcomes of MHFP are poorly reported and highly variable. Relevant studies, including prospective cohort studies and randomized control trials, are warranted to provide more evidence on MHFP, so as better design and implement prevention and intervention programmes.

Health sciences/Health care/Public health

Health sciences/Health care/Health services

High-risk factors in pregnancy

multiple high-risk factors in pregnancy

high-risk pregnancy

pregnancy outcome

A healthy pregnancy is a foundation for healthy development of the next generation and the sustainable progress of the population and society [1]. Although deaths from complications in pregnancy have dropped by 38% globally over the past two decades [2], the overall progress on maternal and child health is insufficient and uneven. Every day, around 810 women die from preventable causes connected to pregnancy and childbirth, with 94% of these mortalities occurring in low- and middle-income countries [2]. The World Health Organization proposed a Global strategy for women’s, children’s and adolescents’ health (2016–2030) with the goal of surviving, thriving, and transforming in order to counter the remaining problems in the Millennium Development Goals as well as the new challenges of socioeconomic inequalities, financial burden for health services, unhealthy lifestyles, and mental health problems in pregnant women [3]. This strategy underscored the urgency for a holistic approach to better monitor and measure maternal health and socioeconomic status, together with their relevant risk factors [4].

Existing studies have evaluated the associations of high-risk factors in pregnancy with specific postpartum and infant outcomes [5–8]. These high-risk factors include pre-existing health conditions, pregnancy-related health conditions and complications, lifestyle factors, and maternal age (above 35 years or under 17 years), which would put women and their children at higher risks of adverse pregnancy outcomes and mortality [9]. However, previous studies have mainly focused on single risk factors. With the delayed childbearing age, a wide range of conditions or risk factors commonly occurring and co-existing during pregnancy have resulted in multiple high-risk factors in pregnancy (MHFP). Women with MHFP may have difficulties in managing their complex health conditions and are at a greater risk of adverse pregnancy outcomes than those with single risk factors or healthy pregnancies. Studies regarding MHFP have emerged but are limited. For example, the MuM-PreDiCT collaboration team from the UK focused on pregnant women living with pre-existing multimorbidity (i.e., two or more long-term health conditions) and reported a high prevalence (> 20%) of pre-existing multimorbidity among pregnant women in the UK [10, 11]. Another systematic review synthesized evidence on maternal multimorbidity during pregnancy and after childbirth in low- and middle-income countries (LMICs) and found significant associations between different types of morbidities during pregnancy [12]. These studies, however, only include a few common physical and mental conditions, failing to consider other risk factors including pregnancy history and social-behavioural problems. There is still an evidence gap on the whole spectrum of high-risk factors in pregnancy, their co-existent patterns, and MHFP-related causes and health outcomes.

Moreover, no systematic review has synthesized existing evidence on MHFP thus far, which is important to improve our knowledge and identify effective interventions and management strategies on MHFP. Therefore, the purpose of this review was to summarize the evidence on the measurement, prevalence, causes, and health outcomes of MHFP from existing original research.

Search strategy and eligibility criteria

We conducted a systematic literature review to identify all published articles on the topic of MHFP. This review was pre-registered on PROSPERO (ref: CRD42022358889). Databases including PubMed, Embase, and Web of Science were searched for relevant articles published between January 1st, 1900 to May 25th, 2022. Details of search strategies are presented in Additional file 1.

Inclusion criteria were: (1) the article type is original research; (2) the main focus of the article is on the co-existence of two or more high-risk factors during or prior to pregnancy; (3) the subtopics are the definition, epidemiology, related causes, and outcomes of MHFP; (4) study subjects are pregnant women and/or their children. (5) written in English. Studies were excluded if: (1) risk factors initiate during the postpartum period; (2) assessing the association between different types of high-risk factors prior or during pregnancy; (3) the full text was not available.

Data Extraction

Two authors (ZY, WT) screened the titles and abstracts and evaluated the full text independently to select the eligible articles with reasons for exclusion recorded. Regular group meetings were held to discuss the discrepancies with a third researcher (XX). For each included studies, basic information, including title, author, publication year, study design, country, research duration, sample size, number of participants with MHFP, objective, data collection tool, main exposure and outcome, measurements of MHFP, and main results related to MHFP were extracted (Additional file 2).

Quality Assessment

Two authors (ZY, WT) independently assessed the methodological quality of the included studies using a quality assessment tool for observational studies developed by National Heart, Lung, and Blood Institute (NHLBI) [13]. Any discrepancies were discussed with a third researcher (XX).

Evidence Synthesis

A narrative synthesis approach was used to describe: (1) the measurements and categories of high-risk factors in pregnancy and their co-existing patterns, (2) the causes of MHFP, and (3) the health outcomes associated with MHFP. Moreover, the prevalence of MHFP was extracted or calculated as the proportion of pregnant women with multiple high-risk factors among all pregnant women at the baseline. A meta-analysis was performed to pool the prevalence of MHFP using random effects model and the evidence of between-study heterogeneity, which was assessed using Cochran’s Q-statistic and I² statistics, was reported. Subgroup meta-analyses stratified by the number of high-risk factors, country origin of the participants, and the income level of countries were also conducted. The trends of prevalence of MHFP stratified by income level of countries were estimated using linear regression. The meta-analyses were conducted using STATA (version 16.0, STATA Corporation, College Station, TX, USA), and the visualization was conducted using R (version 4.1.2, R Foundation for Statistical Computing).

Overview of search results

A total of 10,502 records were identified from the three databases after duplicates removed. After title and abstract screening, 199 studies were included for full-text review. According to the inclusion criteria, 46 studies were finally included for analyses [11, 14–58]. The PRISMA diagram is shown in Additional file 3, and the characteristics of the included studies are presented in Table 1. The included studies were published from 2010 to 2022, with the majority (n = 36) published after 2016. About three-quarters (76%) of the studies were from high-income countries (HICs) [59], including the US (n = 20), the UK (n = 2), Germany (n = 2), Israel (n = 1), Canada (n = 5), Portugal (n = 1), Australia (n = 1), New Zealand (n = 1), South Korea (n = 1), and France (n = 1). The sample size varied considerably among included studies, ranging from 47 to 3,162,303 women. Most studies were of moderate (n = 36) or high quality (n = 9).

Table 1

Basic characteristics of included articles.
NO	Title	Published year	Country	Participants and sample size	Study design	Measurements of multiple high-risk factors of pregnancy (type and number)	Quality
1	Multiple Risk Factors During Pregnancy in South Africa: The Need for a Horizontal Approach to Perinatal Care [29]	2013	South Africa	1145 pregnant women	Cross-sectional study	The co-existing number of risk factors in pregnancy including depression symptoms during pregnancy, HIV positive, alcohol use prior to pregnancy, and low birth weight of previous children. (4 risk factors)	Moderate
2	The impact of chronic hypertension and pre-gestational diabetes on pregnancy outcomes [33]	2012	the US	532088 singleton, non-anomalous deliveries women	Retrospective cohort study	The co-existence of chronic hypertension and pre-gestational diabetes. (2 risk factors)	Moderate
3	Associations of anxiety disorders, depressive disorders and body weight with hypertension during pregnancy [32]	2015	Germany	283 pregnant women from gynecological outpatient settings	Prospective longitudinal study	Comorbid anxiety disorders and depressive disorders prior to pregnancy. (2 risk factors)	Moderate
4	Neonatal Outcomes and Mental Illness, Substance Abuse, and Intentional Injury During Pregnancy [31]	2010	the US	176845 pregnant women	Retrospective cohort study	The co-existence of mental illness/intentional injury or substance abuse/intentional injury or mental illness/intentional injury/substance abuse. (3 risk factors)	Moderate
5	Can We Predict Preterm Delivery Based on the Previous Pregnancy? [30]	2021	Israel	39780 women with two first singleton consecutive deliveries	Retrospective nested case-control study	Number of complications of the first pregnancy, including small for gestational age, perinatal mortality, and pre-eclampsia. (3 risk factors)	Moderate
6	Obstetric Comorbidity and Severe Maternal Morbidity Among Massachusetts Delivery Hospitalizations, 1998–2013 [28]	2019	the US	1185182 delivery hospitalizations	Longitudinal study	Obstetric comorbidity index previously published by Bateman et al., which assigns a weight of 1–5 to each of 20 conditions identified from ICD-9-CM codes at delivery and maternal age ≥ 35 years old. (20 risk factors)	Moderate
7	Association of maternal depression and anxiety with toddler social-emotional and cognitive development in South Africa: a prospective cohort study [27]	2022	South Africa	600 maternal-infant dyads	Prospective study	The co-existence of prenatal depression and anxiety. (2 risk factors)	Moderate
8	Maternal comorbidity index and severe maternal morbidity during delivery hospitalizations in Texas, 2011-2014 [26]	2019	the US	Delivery-related hospitalizations among Texan women aged 15‐49 years were identified using the 2011‐2014 Texas all‐payer inpatient hospitalization public use data files (n = 1434441)	Cross-sectional study	Maternal comorbidity index developed by Bateman et al. derived the original index using comorbidities, identified using ICD-9‐CM codes from the Medicaid Analytic extract data, to predict maternal end‐organ injury or death, which assigned a weight to each comorbid condition based on the strength of association between the condition and the outcome. The comorbidities that were included in the index were previous caesarean birth, gestational hypertension, mild or unspecified preeclampsia, pre-existing hypertension, asthma, severe preeclampsia, multiple gestation, pre-existing diabetes mellitus, drug abuse, placenta previa, chronic renal disease, HIV, cardiac valvar disease, systemic lupus erythematosus, sickle cell disease without crisis, congenital heart disease, alcohol abuse, pulmonary hypertension, chronic ischemic heart disease, and chronic congestive heart failure. (20 risk factors)	Moderate
9	Preterm birth and social support services for prenatal depression and social determinants [25]	2021	the US	47 women presenting symptoms of preterm labor or admitted for preterm birth from an urban county hospital in the San Francisco Bay Area.	Retrospective cohort study	Co-occurring depression symptom and high exposure to adverse social determinants. (2 risk factors)	Moderate
10	Comorbid Anxiety and Depression among Pregnant Pakistani Women: Higher Rates, Different Vulnerability Characteristics, and the Role of Perceived Stress [24]	2020	Pakistan	300 pregnant women	Prospective cohort study	The co-existence of anxiety and depression. (2 risk factors)	Moderate
11	Psychological distress in pregnancy and postpartum [23]	2020	the US and Canada	720 pregnant women	Prospective cohort study	Number of prenatal psychological distress, including depression, stress, and anxiety. (3 risk factors)	Moderate
12	The Influence of Preeclampsia, Advanced Maternal Age and Maternal Obesity in Neonatal Outcomes Among Women with Gestational Diabetes [22]	2020	Portugal	301 unifetal pregnancies	Retrospective cohort study	The co-existence of advanced maternal age with gestational diabetes, pre-eclampsia with gestational diabetes and maternal obesity with gestational diabetes. (4 risk factors)	Moderate
13	Depression and anxiety among pregnant women living with HIV in Kilimanjaro region, Tanzania [21]	2019	Tanzania	200 pregnant women living with HIV	Cross-sectional study	The co-existence of depression, anxiety and HIV positive. (3 risk factors)	Moderate
14	Adverse outcomes in twin pregnancies complicated by early vaginal bleeding [20]	2012	the US	2106 twin pregnancies	Retrospective cohort study	The co-existence of twin pregnancies and early vaginal bleeding. (2 risk factors)	High
15	Syndemic of Lifetime Mental Illness, Substance Use Disorders, and Trauma and Their Association with Adverse Perinatal Outcomes [19]	2020	the US	1988 women who delivered during the study period.	Retrospective cohort study	Number of psychosocial factors. (3 risk factors)	Moderate
16	Impact of comorbid polycystic ovarian syndrome and gestational diabetes mellitus on pregnancy outcomes: a retrospective cohort study [18]	2020	Australia	1545 women with gestational diabetes mellitus	Retrospective cohort study	The co-existence of polycystic ovary syndrome and gestational diabetes mellitus. (2 risk factors)	Moderate
17	Maternal psychiatric disorders and risk of preterm birth [17]	2016	the US	223394 singleton pregnancies	Observational cohort study	The co-existence of depression, anxiety, and bipolar disease. (3 risk factors)	High
18	Depression and anxiety among pregnant mothers in the initial stage of the Coronavirus Disease (COVID-19) pandemic in the southwest of Iran [16]	2021	Iran	540 pregnant mothers	Cross-sectional study	Number of comorbidities, including hypothyroidism, diabetes mellitus/gestational diabetes mellitus, other endocrine disorders, headache, hypertension, cardiovascular diseases, immune thrombocytopenic purpura. (7 risk factors)	Moderate
19	Association of maternal prenatal depression and anxiety with toddler sleep: the ChinaAnhui Birth Cohort study [15]	2022	China	2552 pregnant women in the third trimester	Prospective cohort study	Comorbid depression and anxiety. (2 risk factors)	Moderate
20	Maternal Mental Illness Is Associated with Adverse Neonate Outcomes: An Analysis of Inpatient Data [14]	2019	the US	178737 pregnant women	Longitudinal study	The Charlson comorbidity index which provides a score for comorbidities for each discharged based on ICD-9-CM. (17 items)	Moderate
21	Epidemiology of pre-existing multimorbidity in pregnant women in the UK in 2018: a population-based cross-sectional study [11]	2022	the UK	71522 pregnant women	Cross-sectional study	The presence of two or more pre-existing long-term physical or mental health conditions prior to the index pregnancy. (79 long-term chronic conditions)	Moderate
22	Risk factors for preterm birth among gravid individuals receiving buprenorphine for opioid use disorder [34]	2022	the US	507 pregnant women with opioid use disorder	Retrospective Cohort Study	The co-existence of opioid use disorder, psychiatric disorders, and hepatitis C infection. (3 risk factors)	High
23	Association of Maternal Age with Severe Maternal Morbidity and Mortality in Canada [35]	2019	Canada	3162303 pregnant women	Nationwide population-based cohort study	Maternal comorbidity index (≥ 2). (34 chronic conditions)	Moderate
24	Maternal anxiety and depressive disorders prior to, during and after pregnancy and infant interaction behaviors during the Face-to-Face Still Face Paradigm at 4months postpartum: A prospective-longitudinal study [36]	2018	Germany	533 pregnant women	A prospective-longitudinal study	Maternal anxiety and depressive disorders during pregnancy. (2 risk factors)	High
25	Adverse Birth Outcomes Among Women of Advanced Maternal Age with and Without Health Conditions in Maryland [37]	2021	the US	14933 pregnant women	Retrospective study	The co-existence of advanced maternal age with hypertensive disorders/asthma/pre-gestational or gestational diabetes. (5 risk factors)	High
26	Maternal health in pregnancy and associations with adverse birth outcomes: Evidence from Growing Up in New Zealand [38]	2017	New Zealand	6822 pregnant women	Prospective cohort study	Two or more of the following risk factors: overweight or obese, weight gain during pregnancy, smoking status, doctor-diagnosed illness (diabetes, asthma, heart disease, high blood pressure, anaemia), disability, cigarette smoking, alcohol use, lack of regular activity. (11 risk factors)	Moderate
27	Diabetes risk in women with gestational diabetes mellitus and a history of polycystic ovary syndrome: a retrospective cohort study [39]	2017	Canada	34686 women with gestational diabetes during pregnancy	Retrospective cohort study	The co-existence of polycystic ovary syndrome and gestational diabetes mellitus. (2 risk factors)	High
28	Associations Between Comorbidities and Severe Maternal Morbidity [40]	2020	the US	1480925 women with deliveries	Retrospective cohort study	The co-existence of two, or three or more comorbidities. (29 diseases items)	High
29	Perinatal Health of Women with Intellectual and Developmental Disabilities and Comorbid Mental Illness [41]	2016	Canada	3932 pregnant women	Retrospective cohort study	Intellectual and developmental disabilities and mental Illness (2 risk factors)	Moderate
30	The joint effects of obesity and pregestational diabetes on the risk of stillbirth [42]	2021	the US	3097123 pregnant women	Retrospective cohort study	The co-existence of pre-gestational diabetes with overweight, obesity or morbidly obese. (2 risk factors)	High
31	Association between the use of antidepressants and the risk of preterm birth among pregnant women with depression: a retrospective cohort study in Taiwan [43]	2021	Taiwan, China	10614 pregnant women	Retrospective cohort study	1.The co-existence of perinatal depression and antidepressants. (2 risk factors) 2.The co-existence of perinatal depression, antidepressants, anxiety disorder, multiple gestation, diabetes mellitus, hypertension, dyslipidemia, reproductive tract infection, pre-eclampsia, placenta prevail, polycystic ovaries or pregnancy with history of infertility. (12 risk factors)	Moderate
32	Risk and Risk Factors for Postpartum Type 2 Diabetes Mellitus in Women with Gestational Diabetes: A Korean Nationwide Cohort Study [44]	2022	South Korea	1647903 women	Retrospective cohort study	The co-existence of gestational diabetes with obesity, maternal age, family history of diabetes, hypertension, and insulin use. (6 risk factors)	Moderate
33	Maternal depressive symptoms, sleep, and odds of spontaneous early birth: implications for racial inequities in birth outcomes [45]	2021	the US	317 women (135 black, 182 white) in mid-pregnancy	Prospective study	Co-occurrence of depression and poor sleep quality during pregnancy. (2 risk factors)	Moderate
34	Risk of preterm delivery and hypertensive disorders of pregnancy in relation to maternal co-morbid mood and migraine disorders during pregnancy [46]	2011	the US	3432 pregnant women	Prospective cohort study	Co-morbid mood-migraine disorders. (2 risk factors)	High
35	Maternal Medical Complexity: Impact on Prenatal Health Care Spending among Women at Low Risk for Cesarean Section [47]	2017	the US	95663 commercially insured women at low risk for cesarean delivery	Prospective cohort study	Co-existence of any two or more of the ten comorbidities (hypertension, including preeclampsia and eclampsia; diabetes; gestational diabetes; thyroid disorders; obesity; asthma; infections, such as HIV and toxoplasma; mental health conditions; substance use; and amniotic fluid issues including polyhydramnios and oligohydramnios). (10 comorbidities)	Moderate
36	Collective impact of chronic medical conditions and poverty on perinatal mental illness: population-based cohort study [48]	2020	Canada	853433 women with a singleton live birth and no recent mental healthcare	Observational cohort study	The co-existence of any two or more of the 16 chronic medical conditions. (16 chronic conditions)	Moderate
37	Comorbid Depression and Anxiety Effects on Pregnancy and Neonatal Outcome [49]	2010	Not report	911 pregnant women in second trimester of pregnancy	Prospective cohort study	Comorbid depression and anxiety. (2 risk factors)	Low
38	Relationship of prenatal depression and comorbidities to infant outcomes [50]	2015	the US	419 women presenting consecutively for prenatal care at a health system serving primarily Medicaid patients	Prospective cohort study	1.The co-existence of depression with anxiety, diabetes, high blood pressure or kidney problems 2.The co-existence of anxiety with diabetes, high blood pressure or kidney problems. (5 risk factors)	Moderate
39	Migraine and the risk of post-traumatic stress disorder among a cohort of pregnant women [51]	2017	Peru	2922 pregnant women	Cross-sectional study	The co-existence of migraine and depression. (2 risk factors)	Moderate
40	Pregnancy outcomes among SARS-CoV-2-infected pregnant women with and without underlying diseases: a case-control study [52]	2021	Iran	98 pregnant women	Case-control study	The co-existence of COVID-19 and underlying diseases of heart conditions, diabetes, autoimmune diseases, chronic respiratory conditions, cancer, or asthma. (7 risk factors)	Moderate
41	Identifying Multiple Risks of Low Birth Weight Using Person-Centered Modeling [53]	2014	the US	28820 live singleton births	Cross-sectional study	The co-existence of not married, stress during pregnancy, nulliparous, young mother, smoking, drug use, no prenatal care in first trimester, Medicaid, uninsured, less than high school education. (10 risk factors)	Moderate
42	Preeclampsia and the Risk of Pancreatitis: A Nationwide, Population-Based Cohort Study [54]	2020	Taiwan, China	86315 pregnant women	Retrospective cohort study	Preeclampsia comorbid with alcohol-related diseases, biliary stone, diabetes mellitus, hyperlipidemia, hypertension, hepatitis B, hepatitis C, and the age of 36–45 years old. (9 risk factors)	Moderate
43	Number of Risk Factors in Down Syndrome Pregnancies [55]	2019	the US	125 Singleton pregnancies with delivery of live born or stillborn infant with Down syndrome	Retrospective cohort study	The co-existence of the following risk factors: maternal age ≥ 35 years at delivery, abnormal aneuploidy screening, minor ultrasound marker(s), and sonographic identification of a major anomaly. (4 risk factors)	Moderate
44	Depression and anxiety in women during pregnancy and neonatal outcome: Data from the EDEN mother–child cohort [56]	2012	France	1719 women recruited before the 20th gestational week.	Observational cohort study	Comorbid depression and anxiety. (2 risk factors)	Moderate
45	Risk of complicated birth at term in nulliparous and multiparous women using routinely collected maternity data in England: cohort study [57]	2020	England	276766 women with a singleton birth at term	Cohort study	Age, BMI, pre-existing medical conditions, important obstetric history, and complications in current pregnancy. (4 risk factors)	Moderate
46	Obstetric and perinatal outcomes of singleton pregnancies conceived via assisted reproductive technology complicated by gestational diabetes mellitus: a prospective cohort study [58]	2018	Iran	574 pregnant women	Prospective cohort study	The co-existence of assisted reproductive technology and gestational diabetes mellitus. (2 risk factors)	Moderate

Definition And Measurement Of Mhfp

There has not been an international consensus on the definition of MHFP. In the present study, we reviewed studies that focused on the co-existence of two or more high-risk factors in pregnant women. There was a different emphasis on the MHFP for each study. High-risk factors in pregnancy measured in the included studies ranged from a single risk factor (e.g., gestational diabetes) to a complex combination of risk factors (e.g., pre-existing multimorbidity). These factors were grouped into three categories [9, 12] (Table 2): pregnancy history, high-risk factors existing before pregnancy, and high-risk factors occurring during pregnancy. The factors existing before or occurring during pregnancy were further classified into three subcategories: physical conditions, mental conditions, and social-behavioural problems. The most common pair was the co-existence of anxiety and depression, which was reported by ten studies, followed by advanced maternal age and gestational diabetes (n = 3), and maternal obesity and gestational diabetes (n = 3) (Additional file 4). The pairs of chronic hypertension and pregestational diabetes, pre-eclampsia and gestational diabetes, as well as polycystic ovarian syndrome and gestational diabetes, were also reported by a couple studies (n = 2).

Table 2

Summary of measurements of multiple high-risk factors in pregnancy.
Categories	Subcategories	High-risk factors in pregnancy
Pregnancy history		λ Low birth weight of previous infants λ Small for gestational age of the first pregnancy λ Perinatal mortality of the first pregnancy λ Preeclampsia of the first pregnancy λ Previous cesarean delivery λ Important obstetric history (including caesarean birth, uterine surgery, and others) λ Pregnancy with history of infertility λ Order of index delivery ≥ 2nd
High-risk factors existing before pregnancy	Physical conditions before pregnancy	λ HIV positive λ Chronic hypertension λ Pregestational diabetes λ Polycystic ovarian syndrome λ Hypothyroidism λ Endocrine disorders λ Headache λ Cardiovascular diseases λ Immune thrombocytopenic purpura λ Heart disease λ Kidney problems λ Asthma λ Anemia λ Biliary stone λ Overweight or obesity λ Dyslipidemia/hyperlipidemia λ Family history of diabetes mellitus λ Pre-existing multimorbidity or comorbidities (Charlson comorbidity index, number of chronic diseases, or number of comorbidities) λ Hepatitis B/C infection
	Mental conditions before pregnancy	λ Anxiety disorders prior to pregnancy λ Depressive disorders prior to pregnancy λ Mental illness prior to pregnancy λ Intellectual and developmental disabilities λ Psychiatric disorders
	Social-behavioral problems before pregnancy	λ Alcohol use prior to pregnancy λ Smoking prior to pregnancy
High-risk factors existing during pregnancy	Physical conditions or complications during pregnancy	λ Advanced maternal age or maternal age ≤ 18 λ Twin pregnancy/multiple gestation λ Gestational diabetes λ Pre-eclampsia/eclampsia λ Gestational hypertension λ Multiple gestation λ Early vaginal bleeding λ Placenta previa λ Excess weight gain/weight loss/no weight gain during pregnancy λ Nausea during pregnancy λ Disability during pregnancy λ Migraine disorders during pregnancy λ COVID-19 infection during pregnancy λ Abnormal serum screening λ Abnormal ultrasonography (nuchal thickness 6 mm, echogenic intracardiac focus, echogenic bowel, renal pelvis dilatation, femur length < third percentile) λ Detection of a major fetal anomaly λ Reproductive technology of this pregnancy λ Reproductive tract infection λ Complications during pregnancy (obstetric comorbidity index, or number of gestational complications)
	Mental conditions during pregnancy	λ Depression symptoms during pregnancy λ Anxiety during pregnancy λ Mental illness during pregnancy λ Stress during pregnancy λ Bipolar disorder during pregnancy λ Schizophrenia during pregnancy λ Mood disorders during pregnancy λ Poor sleep during pregnancy
	Social-behavioral problems during pregnancy	λ Substance use disorders/abuse during pregnancy (e.g., drug abuse, alcohol abuse) λ Intentional injury during pregnancy λ Adverse employed status during pregnancy λ Poor income during pregnancy λ Food insecurity during pregnancy λ Housing instability during pregnancy λ Unacceptability of health care or prenatal care during pregnancy λ Unmarried λ Uninsured λ Low education level λ Unacceptability of social support during pregnancy λ Intimate partner violence during pregnancy λ Interpersonal trauma during pregnancy λ Lack of regular exercise during pregnancy λ Continuing to smoke during pregnancy λ Late prenatal care λ Use buprenorphine during pregnancy λ Using antidepressants during pregnancy,

Of all the patterns of MHFP, co-existing physical conditions were the most common (n = 15), while 14 studies measured co-existing mental conditions, ten studies measured co-existing mental conditions and social-behavioural problems, six studies measured co-existing physical conditions and social-behavioural problems, and three studies measured co-existing physical and mental conditions. Seven studies measured co-existence of three or more factors (Fig. 1A). A total of 11 studies reported the mean (standard deviation) or frequency distribution of maternal age among pregnant women with MHFP, allowing us to extract or calculate the mean age of pregnant women with specific MHFP patterns from each study. As shown in Fig. 1B, pregnant women with co-existing physical conditions (mean age: 29.7, 32.1, and 33.9 years, respectively) or with physical conditions and social-behavioural problems (mean age: 29.3 and 32.4 years, respectively) were generally older than those with co-existing mental conditions and social-behavioural problems (mean age: 24.0 years).

Prevalence Of Mhfp

The prevalence of MHFP among pregnant women was reported or could be calculated in 36 (78%) of studies. The heterogeneity of the 36 studies led to a wide range of prevalence from < 1–57%. The pooled prevalence of MHFP was 16% (95% CI: 15%-17%) (Fig. 2). The prevalence of two co-existing high-risk factors was 12% (95% CI: 11%-14%), and that of three or more co-existing high-risk factors was 4% (95% CI: 4%-5%) (Additional file 5–6). The 36 studies were conducted in 11 countries from the Americas, Asia, Europe, and Africa. The prevalence of MHFP for each country was extracted from a single study or pooled from several studies conducted in the same country by meta-analysis (Fig. 3). The top three countries with the highest MHFP prevalence were the UK (30%), Iran (26%), and South Korea (21%). The only country with a prevalence of < 10% was Peru (5.9%).

Among the 36 studies, 25 studies were from HICs, and ten studies were from low- and middle-income countries (LMICs) (one study did not report the country origin of the participants [49]). The pooled prevalence of MHFP was similar between HICs (prevalence: 16%, 95% CI: 14%-18%) and LMICs (prevalence: 15%, 95% CI: 12%-18%) (Additional file 7–8). Moreover, we found an overall increasing trend of MHFP from 2001 to 2020 in both HICs and LMICs (Fig. 4). However, there was a mismatch between the high prevalence of MHFP and its publications, especially in LMICs, where the total number of publications was limited.

Causes Of Mhfp

Only three of the included studies focused on the potential causes related to MHFP [11, 21, 24] (Table 3). Premji et al. [24] found that women with comorbid anxiety and depression during pregnancy had: (1) high levels of perceived stress, (2) three or more previous children, and (3) one or more adverse childhood experiences. Another study focusing on women living with HIV showed that being single, HIV shame, and lifetime experience of violence were associated with comorbid depression and anxiety [21]. Being older, multigravida, having higher body mass index, and smoking preconception were also associated with co-existence of two or more long-term physical or mental conditions among pregnant women [11]. These causes may overlap with several high-risk factors in pregnancy, suggesting potential interaction effects across different high-risk factors.

Table 3

Summary of causes and health outcomes of the co-existence of multiple high-risk factors in pregnancy.
Causes of the co-existence of multiple high-risk factors in pregnancy
λ High level of perceived stress at any time point λ Having three or more previous children λ Having one or more adverse childhood experiences λ Being single λ HIV shame λ Lifetime experience of violence λ Being older λ Multigravidity λ Having raised body mass index λ Smoking preconception
Health outcomes of the co-existence of multiple high-risk factors in pregnancy
Themes	Subthemes	Consequences
Consequences of women	Health conditions during pregnancy	λ Pre-eclampsia λ Hypertension during pregnancy λ Anxiety during pregnancy λ Severe maternal morbidity λ Caesarean λ Premature rupture of membranes
	Postpartum health conditions	λ Postpartum post-traumatic stress disorder λ Postpartum pancreatitis λ Postpartum psychological distress λ Postpartum diabetes after 6 weeks of parturition
Consequences of children	Fetal outcomes	λ Poor fetal growth/intrauterine growth restriction λ Fetal Down syndrome λ Abruption λ Complicated birth λ Preterm birth
	Neonatal health status	λ Intrauterine fetal demise/stillbirth λ Low score of 5-minute APGAR λ Small for gestational age/low birth weight λ Large for gestational age/macrosomia λ Neonatal morbidity λ Neonatal intensive care unit admission
	Infant health status	λ Toddlers’ sleep problem λ Infant interaction behaviors

Mhfp Associated Health Outcomes

A total of 39 studies investigated the MHFP-associated health outcomes (Table 3). The health outcomes of MHFP could be grouped into two categories: health outcomes for pregnant women and for children. For pregnant women, MHFP was associated with maternal conditions during pregnancy and postpartum health conditions. Again, the outcomes during pregnancy may overlap with high-risk factors in pregnancy, which were also shown in Table 2, suggesting the potential interaction effects among these health conditions. Regarding outcomes for children, MHFP could affect children’s health at multiple life stages, from the fetal to the neonatal and infant period. Preterm birth was the most reported outcome of children associated with MHFP. However, due to the heterogeneity and differences in topics across included studies, we could not pool the effect sizes of MHFP on specific health outcomes through meta-analysis.

To the best of our knowledge, this is the first comprehensive review to explore the concept of MHFP and to examine its prevalence, potential causes, and associated health outcomes. According to our findings, the definition and types of high-risk factors in pregnancy are complex, multidimensional, and subjective. The pooled prevalence of MHFP was 16% among the included studies. However, the number of studies on MHFP is still limited, and there is heterogeneity in the measurements of MHFP and in the MHFP-related topics across studies.

Previous studies have concluded that high-risk pregnancy could increase the risk of adverse outcomes for mothers and their children [9, 60]. We identified four dimensions of high-risk factors in pregnancy: physical conditions (both before and during pregnancy), mental conditions (both before and during pregnancy), social-behavioural problems (both before and during pregnancy), and pregnancy history, which are similar to previous categories of high-risk pregnancy [9]. However, there is an apparent lack of international standardisation and consensus for the definition of MHFP. Most included studies in our review focused on the co-existence of two or three specific high-risk factors, failing to propose a concept of MHFP. Also, high-risk factors measured in each of the included studies varied, making interpretation and comparison of findings across studies difficult. There is an urgent need to develop an evidence-based approach that can define MHFP among a wide range of high-risk factors in pregnancy.

The prevalence of high-risk pregnancy has been estimated in previous studies, with a range from 14.4–40.5% [61–64]. A proportion of women with a high-risk pregnancy may suffer from MHFP. Our review pooled the prevalence of MHFP among included studies and found 16% of pregnant women with MHFP. The high prevalence of MHFP calls for a broader approach to address the complex challenges resulted from the less integrated maternal healthcare systems. Furthermore, the prevalence of MHFP has been similar in HICs and LMICs and has showed an increasing trend over the past two decades. However, studies from LMICs are significantly fewer and later than those from HICs. Moreover, infectious diseases (e.g., HIV/AIDS) are still prevalent in LMICs such as Tanzania and South Africa [21, 29]. The findings suggest that MHFP is especially debilitating in LMICs, where ending maternal deaths from single risk factors and infectious diseases is already a great challenge and remains the top priority of the maternal health agenda [2]. Some of the social-behavioural problems in pregnancy, such as poor income, food insecurity, and housing instability, also showed that low socioeconomic status might endanger women’s health during pregnancy. Recognizing and understanding inequalities, especially socioeconomic status, race, gender, and health insurance status, are crucial for ensuring all women’s rights to healthy pregnancy [2].

Physical conditions and the co-existing patterns of physical conditions were the most studied, especially gestational hypertension, pre-eclampsia/eclampsia, and gestational diabetes, suggesting that physical conditions remained the primary problem affecting pregnancy health [65]. Moreover, the mean age of women with co-existing physical conditions was older, suggesting the potential association between advanced maternal age and maternal physical conditions [66–68]. Given the global trend of delayed childbearing age, the burden from physical diseases and their clusters may be challenging for maternal healthcare. It is worth noting that the number of studies focusing on the pattern of co-existing mental conditions and social-behavioural problems is also high, and that women with this pattern are relatively younger. This finding is consistent with previous studies reporting the association of pregnancy at a young age with poor mental health outcomes [69]. Considering the age-specific MHFP patterns, different strategies for maternal healthcare should be formulated targeting women in different age groups.

Our findings also showed an increasing research interest in the co-existence of mental disorders in pregnancy. Among the included studies, anxiety-depression were the most common co-existing pair. The causes and health outcomes of co-occurring anxiety and depression were multidimensional. For example, being single and having a lifetime experience of violence would increase the risk of co-existent anxiety and depression among pregnant women [21]. Regarding the outcomes, co-existence of anxiety and depression was associated with adverse pregnancy outcomes for both mothers (e.g., gestational hypertension [32]) and their children (e.g., social-emotional problems [15] and sleep problems [56]). Although these mental disorders are common in pregnant women, most women do not receive effective care services for mental health during pregnancy [70, 71]. In addition, mental disorders remain neglected in clinical practice guidelines for pregnancy care worldwide. National guidelines for pregnant women, such as those in the USA [72], the UK [73], Australia [74], Canada [75], and Germany [76], so far have only taken mental disorders into a routine screening. Structured screening, effective interventions, and treatment options for maternal mental disorders are still lacking. More importantly, the dual burden of mental disorders and their co-existence with physical conditions may bring new challenges to current maternal health care systems, calling for more research on MHFP to bridge evidence gaps in clinical practice guidelines for pregnancy care.

Strengths And Limitations

This is the first systematic review to synthesize evidence on co-existing high-risk factors in pregnancy and propose a working definition of MHFP. We used broad search strategies and inclusion criteria to identify more relevant studies. Several limitations should also be pointed out in our systematic review. First, despite the broad approach, publication bias is still a possibility. Second, we only include studies in English, which can lead to linguistic bias. Third, due to the heterogeneity in topics of included articles, we could not conduct meta-analyses to quantify the association between MHFP and its related causes and health outcomes.

Implications

Up to now, few investigators have paid attention to MHFP. There remain evidence gaps on how MHFP should be defined, which high-risk factors often co-exist, what makes a woman at risk of developing MHFP, and how MHFP influences the health status of women and their children. Relevant studies, including prospective cohort studies and randomized control trials, are warranted to propose an evidence-based definition of MHFP and provide information on MHFP-related causes and health outcomes. In addition, limited studies on this topic from LMICs call for more attention on maternal health in LMICs.

Current clinical practice and national guidelines on maternal healthcare have formulated detailed suggestions for prevention, intervention, and treatment for some specific diseases in pregnancy, such as HIV/AIDS, gestational diabetes, and gestational hypertension. There remain some neglected high-risk factors, including intentional injury, food insecurity, and housing instability, most of which are related to socioeconomic inequalities. Promoting access to healthcare services for all women, especially those in LMICs, is important for all women’s rights to healthy pregnancy. Furthermore, a call for conceptual frameworks to understand the co-occurrence of risk factors or conditions in transitioning populations, particularly in specific socioeconomic and cultural contexts [77], so as better design and implement prevention and intervention programmes to address MHFP.

Our systematic review summarized current evidence on the co-existence of high-risk factors in pregnancy and proposed a working definition of MHFP. There is still a lack of international standardisation for the definition used to measure MHFP. Relevant studies, including systematic reviews, prospective cohort studies and randomized control trials, are warranted to provide more evidence on MHFP to inform clinical practice and maternal health guidelines, particularly for LMICs.

HICs

high-income countries

LMICs

low- and middle-income countries

MHFP

multiple high-risk factors in pregnancy

NHLBI

National Heart, Lung, and Blood Institute

Ethics approval

Not applicable

Consent for publication

Not applicable.

Availability of data and materials

All data generated or analysed during this study are included in this published article.

Competing interests

The authors declare that they have no competing interests.

Fundings

This study was funded by grant to XX from China Medical Board Open Competition Program (21-416), and grant to XZ from Jiangsu Maternal and Child Health Program (F201932), Key Medical Program of Jiangsu Health Commission (ZD2021044), Huai’an Science and Technology Program (HAB202043).

Authors’ contributions

XX, XZ, and XD contributed to the design, concept, and revision of the manuscript. YZ and TW were responsible for the text screening and data extraction. YZ also contributed to the data interpretation and manuscript drafting. WD, HW, MF, and AA have revised the manuscript.

Acknowledgements

We thank the lab members who gave insightful suggestions of this study.

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There is NO Competing Interest.

Additionalfile1.docx
Additional file 1. Search strategies of the systematic review.
Additionalfile2.xlsx
Additional file 2. Basic characteristics of included studies.
Additionalfile3.docx
Additional file 3. Process of the study selection.
Additionalfile4.docx
Additional file 4. Number of studies for the co-existing patterns of high-risk factors in pregnancy.
Additionalfile5.docx
Additional file 5. Random effects meta-analysis pooled prevalence estimates and forest plots for the co-existence of two risk factors in pregnancy.
Additionalfile6.docx
Additional file 6. Random effects meta-analysis pooled prevalence estimates and forest plots for the co-existence of three or more risk factors in pregnancy.
Additionalfile7.docx
Additional file 7. Random effects meta-analysis pooled prevalence estimates and forest plots for the co-existence of two or more risk factors in pregnancy in high income countries.
Additionalfile8.docx
Additional file 8. Random effects meta-analysis pooled prevalence estimates and forest plots for the co-existence of two or more risk factors in pregnancy in low- and middle-income countries.
Graphicabstract.docx
Graphic abstract

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Measurement, prevalence, causes, and health outcomes of co-existing multiple high-risk factors in pregnancy: a systematic review and meta-analysis

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Background

Methods

Search strategy and eligibility criteria

Data Extraction

Quality Assessment

Evidence Synthesis

Results

Overview of search results

Definition And Measurement Of Mhfp

Prevalence Of Mhfp

Causes Of Mhfp

Mhfp Associated Health Outcomes

Discussion

Strengths And Limitations

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