Outbreaks of a Presumed Infectious Agent Associated with Changes in Fertility, Stillbirth, Congenital Abnormalities and the Gender Ratio at Birth

Aims: To investigate changes in the gender ratio (M/F) at birth, fertility and stillbirth rates in England and Wales.

Study Design: Analysis of average GR (1974-2010) for 570 UK local government areas. Re-analysis of average GR for births in the UK (2007-2014), by place of birth of the mother. Trend analysis of monthly births and stillbirths. Analysis of annual births (2001-2014) with small area data aggregated to 74 social groups.

Place and Duration of Study: England and Wales, 1974 to 2015.

Methodology: Average GR ±95% CI over a 35-year period in local government areas, role of population density and deprivation. Analysis of year-to-year volatility in the GR. GR by place of birth of the mother re-analyzed by proportion of countries outside an assumed Poisson distribution. A running 12-month total of monthly births or year-to-year differences in annual male and female births in 181,408 small areas.

Results: No evidence for an overall change in the GR between 1974 and 2010. Average GR ranges from 1.004 ± 0.021 in Bridgnorth (Shropshire) to 1.108±0.032 in Maldon (Essex). High population density and levels of deprivation, act to reduce the GR. Country of birth of the mother leads to instances of higher or lower than average GR. Low levels of nuclear radiation are associated with higher GR. Year-to-year volatility in the GR is independent of the average GR and is not influenced by population density or deprivation. After adjusting for size the average volatility ranges from ± 2.28% in Brighton to ± 10.06% in Nottingham, i.e. both average GR and the volatility are independently influenced by the local environment. The running 12-month total (moving total) of births reveals a series of events where the fertility rate suddenly jumps stays high for around 12 months, and then suddenly reverts to the baseline. The GR also jumps to a higher level, as does the stillbirth rate. Mini-outbreaks of a presumed infectious agent can occur at any time, but appear to cluster at certain times to create larger national events. Different social groups show higher levels of penetration and magnitude of the increase in births or change in the gender ratio. Preliminary analysis of increased hospital admissions associated with these outbreaks reveal increases in a range of conditions affecting reproduction, pregnancy, neonates and specific types of congenital malformation.

Conclusion: The GR is sensitive to place of birth of the mother, population density, deprivation, location and social group. Year-to-year volatility in the GR is location and social group specific. Fertility rate, gender ratio and stillbirth rate respond to outbreaks of a presumed infectious agent. Fertility, GR and stillbirths all stay high for around 12-months before reverting to baseline. Social behaviors play a role in the magnitude of the effect. The increased fertility rate associated with these outbreaks has capacity implications for maternity units. It is likely that the proposed agent exerts its effect in the period 2 to 15 weeks after conception when female fetal mortality is highest. The primary effect of the proposed agent is likely to be via immune manipulation. A potential role for the immune modifying virus, cytomegalovirus, is discussed.