Background

Preterm birth is the leading cause of child death in children younger than 5 years. Large cohort studies in developed countries have shown that maternal hepatitis B virus infection is associated with preterm birth, but there is little reliable evidence from China and other developing countries, where hepatitis B virus prevalence is intermediate or high. Hence, we designed this study to investigate the association between pre-pregnancy hepatitis B virus infection and risk of preterm and early preterm birth.

Methods

Between Jan 1, 2010, and Dec 31, 2012, we did a population-based cohort study using data from 489 965 rural women aged 21–49 years who had singleton livebirths from 220 counties of China who participated in the National Free Preconception Health Examination Project. Participants were divided into three groups according to their pre-pregnancy status of hepatitis B virus infection: women uninfected with hepatitis B virus (control group), women who were HBsAg positive and HBeAg negative (exposure group 1), and women who were both HBsAg and HBeAg positive (exposure group 2). The primary outcome was preterm birth (gestation at less than 37 weeks). We used log-binomial regression to estimate adjusted risk ratios (aRR) of preterm birth for women with pre-pregnancy hepatitis B virus infection, and risk of early preterm birth (gestation less than 34 weeks).

Findings

489 965 women met inclusion criteria and were included in this study; of these, 20 827 (4·3%) were infected with hepatitis B virus. Compared with women who were not infected with hepatitis B virus, women who were HBsAg positive and HBeAg negative had a 26% higher risk of preterm birth (aRR 1·26, 95% CI 1·18–1·34) and women who were both HBsAg and HBeAg positive had a 20% higher risk of preterm birth (aRR 1·20, 1·08–1·32). Compared with women who were not infected with hepatitis B virus, women who were HBsAg positive and HBeAg negative manifested an 18% higher risk of early preterm birth (gestation less than 34 weeks; aRR 1·18, 1·04–1·34) and women who were both HBsAg and HBeAg positive had a 34% higher risk of early preterm birth (aRR 1·34, 1·10–1·61). Maternal pre-pregnancy hepatitis B virus infection was independently associated with higher risk of preterm birth and early preterm birth. These associations were similar in subgroups of participants as defined by baseline characteristics.

Interpretation

Besides mother-to-child transmission, the risk of preterm birth in women infected with hepatitis B virus should not be neglected. Comprehensive programmes that focus on early detection of hepatitis B virus infection before pregnancy and provide appropriate medical intervention for women infected with hepatitis B virus before and during pregnancy would be helpful in improving maternal and neonatal outcomes and reducing child mortality.

Funding

Chinese Association of Maternal and Child Health Studies.

Preterm birth, a birth occurring before 37 completed weeks of gestation, is the leading cause of death in children younger than 5 years. ¹ An estimated 14·9 million babies, 11·1% of all livebirths worldwide, were born preterm in 2010. ² Preterm birth complications are estimated to be responsible for roughly 35% of the world's 2·76 million annual neonatal deaths, ¹ and surviving preterm babies are at increased risk of neurodevelopmental impairments and respiratory and gastrointestinal complications. ³ In low-income and middle-income countries, babies born before 34 weeks of gestation (early preterm birth) have only a 50% chance of survival ^{4 ; 5} and the risk of maternal complications after early preterm birth is substantial. ⁶ Identifying risk factors is crucial for effective prevention, especially for early preterm birth. Several maternal factors have been associated with preterm birth, such as demographic characteristics, nutritional status, pregnancy history and current characteristics, infection, adverse behaviours, uterine contractions, and cervical length. ³ Among these factors, viral infection is an important cause of preterm birth. Previous studies have reported that maternal hepatitis B virus infection was associated with an increasing risk of preterm birth, ^{7 ; 8 ; 9 ; 10 ; 11 ; 12 ; 13 ; 14} but some studies showed inconsistent results. ^{15 ; 16 ; 17 ; 18} The association between hepatitis B virus infection and preterm birth is still controversial.

Research in context

Evidence before the study

We searched the published literature for studies on the association between hepatitis B virus infection and preterm birth through PubMed using the terms “hepatitis B virus” and “preterm birth”, including all the reports published in both English and Chinese before Sept 20, 2016. We identified two large cohort studies on the association between hepatitis B virus infection and preterm birth, but these studies were done in developed countries where the prevalence of hepatitis B virus infection was relatively low. We also identified several studies done in developing countries where the prevalence of hepatitis B virus infection was relatively high or intermediate. However, the results of these studies were controversial.

Added value of this study

In this large population-based cohort study, we examined the association between pre-pregnancy hepatitis B virus infection and risk of preterm birth in 489 965 women. To our knowledge, our study is the first explorative study of maternal pre-pregnancy hepatitis B virus infection and preterm birth in a large-scale cohort in China. Results from this study showed that maternal pre-pregnancy hepatitis B virus infection was independently associated with increased risk of preterm birth and with early preterm birth (gestation less than 34 weeks). Compared with women uninfected with hepatitis B virus, women who were infected with hepatitis B virus had a 20–26% higher risk of preterm birth. Our findings add to the improved understanding of prevention and treatment of preterm birth, which is a risk factor for mortality in children younger than 5 years.

Implications of all the available evidence

This study highlights that, besides mother-to-child transmission, the risk of preterm birth in women infected with hepatitis B virus should not be neglected. Comprehensive programmes that focus on the early detection of hepatitis B virus infection before pregnancy, monitor the risk of preterm birth, and provide appropriate medical intervention for women infected with hepatitis B virus during pregnancy would be helpful in improving maternal and neonatal outcomes and reducing child mortality. Future research should explore the underlying mechanisms of hepatitis B virus infection's effect on preterm birth and effective strategies to reduce the risk of preterm birth among infected mothers, especially in developing countries.

Hepatitis B virus infection is a major health problem, causing high mortality and societal burden worldwide. ¹⁹ China has the world's largest burden of hepatitis B virus infection, with an estimated 74·6 million people chronically infected. ^{20 ; 21} The prevalence of hepatitis B virus infection in women of reproductive age and pregnant women in China has been estimated at 3·87–9·98%. ^{18 ; 22 ; 23 ; 24 ; 25 ; 26 ; 27} Additionally, China has the second largest number of preterm births worldwide, with 1·17 million each year. However, large cohort studies depicting the association between maternal hepatitis B virus infection and preterm birth have almost always been done in developed countries with a low prevalence of hepatitis B virus infection; little reliable evidence exists from China or other developing countries where the prevalence of hepatitis B virus infection is intermediate or high. Furthermore, little has been done to investigate the association between pre-pregnancy hepatitis B virus infection and preterm birth. From a preventive point of view, identifying this association is important because it is relatively easy to intervene before pregnancy, and it might provide more effective results with respect to the gestational outcome for women with hepatitis B virus infection.

We did a large population-based cohort study in China to examine the association between maternal pre-pregnancy hepatitis B virus infection and risk of preterm and early pre-term birth.