The birth rate model including long-term time trends and seasonal effects explained 93%–95% of the variation in the monthly data outside the pandemic period in all study populations (Supplementary Table 1
). The difference between the observed and expected monthly birth rates (residuals) was plotted for each population, together with the morbidity or mortality rate indicators of pandemic influenza activity (). The monthly indicators of influenza activity peaked in October–November 1918 in all populations studied except for rural Denmark, where it peaked during late November to early December 1918 ().
Figure 1. Timing of influenza pandemic and birth rate reduction in Denmark, Norway, Sweden, and the United States. A, Time series of monthly natality rates in Denmark during several decades surrounding the 1918 pandemic. It can be seen that an unusual and unseasonal (more ...)
Temporal Coincidence in the Mean Peak Influenza Month and Birth Depression Peak Month in Each Country Under Study, Using Center of Gravity Statistics
A statistically significant period of birth rate depression was identified in all study populations, reaching a remarkably consistent trough 6.1–6.8 months after the peak of the influenza pandemic, based on the center of gravity analysis (; ). Birth rates declined by 2.2 births per 1000 persons, on average, in each of the study populations (range, 1.3–4.0 births per 1000 persons), which amounts to a 5%–15% reduction in births relative to annual baseline expectations. This annual reduction corresponds to an excess of ~1 in 10 pregnant women infected with influenza during their first trimester having miscarried in autumn 1918.
In Scandinavia, the natality decline began in January–February 1919, with the “missing” births concentrated in April and May 1919, 6–7 months after peak pandemic activity. Following this temporal natality depression, a compensatory surge of births was noted 7.5–10 months later in these countries, beginning in October 1919 and peaking in winter 1920. This surge represents an excess of 0.8–5.8 births per 1000 persons—a 4%–20% increase in births relative to annual baseline expectations (). These patterns were the only sustained deviations from the expected number of births throughout the 30-year study period in these populations. The United States experienced a decrease in births culminating 6.6 months after peak pandemic activity, remarkably consistent with the Scandinavian experience. The compensatory increase in birth rates was not as pronounced in the United States as in the other locations at 0.3 births per 1000 persons (1.3% in excess of annual expectation). No other period of sustained deviations from the expected number of births was observed in the United States throughout the 10 years studied.
To explore the association between influenza and birth rates at a finer geographical scale, we compared the timing of the 1918 influenza pandemic and trends in birth rates in Copenhagen and rural Denmark (). Although the timing of the influenza pandemic and natality depression in Copenhagen was consistent with the nationwide patterns described above, the pattern for rural Denmark was shifted by 1–2 months. Influenza morbidity peaked in October 1918 in Copenhagen and November–December 1918 in rural Denmark. Accordingly, the decline in birth rates began in Copenhagen in January 1919, with the most births missing in mid-April 1919; in rural Denmark, the natality dip began in March 1919, with the most births missing in June 1919 (). The time elapsed between the peak of the influenza pandemic and center of gravity of missing births was consistent for the 2 regions (6.5 months in Copenhagen; 6.6 months in rural Denmark), suggesting that the same phenomenon occurred in the capital city and rural areas, with a 1–2 month lag between locations.
Figure 2. Asynchrony in timing of influenza (flu) activity and birth patterns across Denmark. The influenza epidemic struck Copenhagen (Cph) 1–2 months before it hit the rural areas in Denmark. The delayed effect is mirrored by the birth depression, with (more ...)
We considered the potential impact of influenza-related deaths in women of childbearing age as a potential explanation for the postpandemic decline in birth rates. In Copenhagen, detailed annual sex-, age-, and cause-specific mortality data were available; a total of 743 women aged 20–49 years were reported to have died from influenza from July 1918 through June 1919, in a population of ~135
000 women 20–49 years of age [26
]. Yet there were ~1200 births missing in spring 1919 in Copenhagen. Even in the extremely unlikely scenario that all women 20–49 years of age who died in Copenhagen were pregnant when they died, it would explain only 62% of the missing births. Finally, we examined evidence of a third trimester effect on the fetus. If a fetus had been near term at the time of the 1918 pandemic, a miscarriage event would likely have been recorded as a stillbirth at the time of the mother’s pandemic illness in autumn 1918. There were 2 nonconsecutive months of excess stillbirths in Denmark during the pandemic period, in November 1918 and January 1919, representing a total of 11.4 excess stillbirths per 1000 live births for the 2 months, or 64 excess stillbirths. We also observed similar deviations in 4 other months, which were spread out over the study period 1911–1929 ().
Figure 3. Lack of trends in monthly stillbirths in Denmark. Stillbirths are shown as excess numbers per 1000 live births, after normalization by long-term mean. Although there is a significant excess of stillbirths in November 1918 and January 1919, it is not a (more ...)
Taken together, these findings, of (1) the consistency of the time elapsed between the peak pandemic activity in autumn 1918 and the drop in birth rates 6.1–6.8 months later across 4 study populations in Scandinavia and the Unites States, (2) the lack of a similar drop in birth rates in any other period during 1911–1930, (3) the minor contemporaneous increase in stillbirths, (4) the relatively low number of influenza-related deaths in young adult women associated with the autumn 1918 pandemic, and (5) the compensatory increase in birth rates occurring within 1 year of the pandemic, strongly suggest that the 1918 pandemic was associated with miscarriages in the first trimester of pregnancy.