New Results

Quantification of miscarriage sex bias in England and Wales, 1993-2017

John F Mulley
doi: https://doi.org/10.1101/418186

Abstract

Study question How extensive is miscarriage sex bias?

Summary answer Girls are more susceptible to miscarriage, with 941-986 males miscarried per 1,000 females in England and Wales between 1993-2017.

What is known already The human sex ratio at birth is skewed towards males, with on average 1,053 boys born for every 1,000 girls in England and Wales between 1993 and 2017. Stillbirth also shows a male bias, averaging 1,112 boys lost per 1,000 girls over the same period. If the sex ratio at conception is equal, and more boys are lost to stillbirth, then more girls must be lost during pregnancy.

Study design, size, duration Here I use data on live births, stillbirths and legal therapeutic and elective abortions in England and Wales from 1993-2017 to determine relevant annual numbers of conceptions if 10%, 20%, 25% or 33% of conceptions result in miscarriage.

Participants/materials, setting, methods Subtracting known numbers of boys and girls in live births and stillbirths from the predicted conceptions, and predicting sex ratios of aborted fetuses, allows calculation of the sex ratio of miscarried products of conception.

Main results and the role of chance There were 23,616,601 to 31,723,793 conceptions in England and Wales between 1993-2017, resulting in 16,656,203 live births (8,114,739 female and 8,541,464 male); 86,714 stillbirths (41,059 female and 45,655 male); and 4,512,024 legal abortions. There were 2,361,660 to 10,468,852 miscarriages, averaging between 94,466 per year (941 males per 1,000 females) if 10% of all conceptions result in miscarriage to 418,754 per year (986 males per 1,000 females) for a miscarriage risk of 33%. more girls were aborted than boys, more boys were born live and stillborn, and significantly more girls were miscarried (P < 0.00001, Pearson’s χ2 test)

Limitations, reasons for caution The abortus sex ratio was determined on the assumption that early (≤12 weeks) abortions are biased towards females (55:45) and later abortions (≥13 weeks) are biased towards males (45:55). If the abortus sex ratio is balanced, the miscarriage sex bias is exacerbated, with between 691-921 males lost per 1,000 females. The miscarriage rate is also currently unclear, but my predictions of the number of missing conceptions suggests that the values used here are not unreasonable.

Wider implications of the findings Girls are more susceptible to miscarriage than boys, and there is a greater loss of girls throughout pregnancy. This study quantifies the extent of this miscarriage sex bias, and provides a starting point for understanding why this bias exists, how and when it varies, and when it is established during pregnancy. In the absence of evidence to support a male-biased primary sex ratio, it seems likely that the greater loss of girls is the result of parental conflict and imprinting, perhaps because of a trade-off between an elevated risk of early loss of female embryos versus a greater robustness of survivors, as evidenced by the greater number of boys that are stillborn, and the higher infant mortality rate of boys.

Study funding/competing interest(s) None to declare.

Trial registration number Not applicable.

Background

Males and females differ from the very point of conception, with females having two X chromosomes, and males one X and one Y. Only males can express genes on the Y chromosome, and, prior to the completion of X chromosome inactivation, females can produce up to twice the amount of gene product for any gene encoded by the X chromosome. These differences are evident not only in the metabolism of early male and female embryos1–4, but also in differential survival throughout gestation. The human sex ratio at birth is consistently biased towards boys, and remarkably stable (Figure 1), with on average 1,053 boys born for every 1,000 girls in England and Wales between 1927 and 2017. Indeed, the slight bias towards boys at birth is so stable that deviations are indicative of sex-specific abortions5. This bias at birth is consistent, even though boys are more susceptible to stillbirth6, with on average 1,127 boys lost per 1,000 girls between 1927 and 2017, and only three years between 1927 and 2017 where more girls were stillborn (1974, 1975 and 2016 (Figure 1)). More generally, the human sex ratio fluctuates from conception to birth, with a greater loss of males in the first few weeks, followed by a greater loss of females in the first trimester, and a general male bias from around week 20 onwards7, although these fluctuations are generally minor, and the overall sex ratio never deviates by more than a few percent. Historically, the male bias at birth was taken to result from the production of a greater proportion of males at conception (the primary sex ratio), although more recent data from in vitro fertilisation supports a balanced PSR in humans (see Orzack et al.7 for discussion), as does the simple mechanics of equal segregation of X and Y chromosomes during spermatogenesis. If the sex ratio at fertilisation is equal, then there must be an overall greater loss of girls during gestation8, but how many? And is the spontaneous abortion (hereafter referred to as ‘miscarriage’) sex ratio stable, or does it fluctuate? It is well established that adverse events such as terrorist attacks impact the sex ratio at birth, with a decrease in the number of boys9,10, and so we should expect that this will be reflected in the miscarriage sex ratio. Whilst 10% of clinically-recognised pregnancies end in miscarriage, the true number is estimated to be much higher as many pregnancies are lost before they are identified, and up to one third of all pregnancies may end in miscarriage11–15. Determining the sex of miscarried products of conception has typically been complicated by the necessity to collect foetal tissue and identify sex chromosomes, where contamination by maternal tissues could lead to an overestimation of the number of miscarried girls16.

Figure 1.
Figure 1.

Live birth and stillbirth sex ratio in England and Wales, 1927-2017. On average 1,055 males were born per 1,000 females, and there are no years where more females are born than boys. The definition of stillbirth changed from 28 weeks of gestation to 24 weeks of gestation in 1992, and on average 1,133 boys were stillborn per 1,000 girls between 1927 and 1992, and 1,112 per 1,000 between 1993 and 2017. In the entire dataset, there are only three years where more girls were stillborn than boys (1974, 1975, 2016).

In England and Wales, all births and stillbirths must be registered, and there is extensive historical data available on numbers of live births and stillbirths, including sex ratios (it should be noted however that in October 1992, the Stillbirth (Definition) Act 1992 changed the gestation cut-off for stillbirths from 28 or more weeks of gestation to 24 or more weeks, and so data from 1993 onwards is not comparable to previous years – this study therefore focuses on data from 1993 to the most recent relevant releases (2017)). In addition to extensive live birth and stillbirth data, the requirement that all practitioners in England and Wales who perform therapeutic or elective abortions must notify the Chief Medical Officer means that abortion statistics (including number of abortions by gestation week) are available going back to the late 1960’s. The stability of the overall sex ratio at birth (Figure 1) suggests that, in England and Wales at least, there is no sex-selective abortion, and the general increase in the number of legal abortions, and the lack of maternal deaths due to complications of illegal abortions17 also suggests that there are few if any unrecorded abortions in England and Wales. If the human sex ratio is female-biased until around week 12, and male-biased subsequently7, then we can calculate the proportion of males and females that are legally aborted each year and so determine the total number of pregnancies (here defined as a conception resulting in a live birth, stillbirth, or abortion). Using predicted values for the number of conceptions that resulted in miscarriage, it is then possible to calculate the total number of conceptions, and, from that, the miscarriage sex ratio.

Here, I use a 25 year dataset from 1993 to 2017, comprising 16,656,203 live births, 86,714 stillbirths, and 4,512,654 legal abortions to calculate the miscarriage sex ratio for 23,616,601 to 31,723,793 predicted conceptions and so demonstrate the extent and variability of any miscarriage sex bias.

Methods

Data for numbers of maternities, live births and stillbirths, including numbers of males and females, were collected from the Office for National Statistics (https://www.ons.gov.uk/) ‘Review of the Registrar General on births and patterns of family building in England and Wales’, Series FM1 (numbers 22-37, covering 1993-2008), the ‘Characteristics of Birth 2, England and Wales’ dataset (2009-2013), the ‘Birth characteristics dataset’ (2014-2016), and the ‘Summary of key birth statistics, 1838 to 2017’. Data on numbers of legal abortions from 2011-2017 were obtained from the Department of Health and Social Care (DHSC) ‘Abortion statistics, England and Wales’ collection (https://www.gov.uk/government/collections/abortion-statistics-for-england-and-wales), and for 1993-2010 from the UK Government Web Archive (http://www.nationalarchives.gov.uk/webarchive/). Numbers of stillbirths by age of mother for 2012 were obtained from the from the ‘Child Mortality Statistics 2012’ dataset (https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/datasets/childmortalitystatisticschildhoodinfantandperinatalchildhoodinfantandperinatalmortalityinenglandandwales), and England and Wales population data were obtained from the ‘MYE2: Population Estimates by single year of age and sex for local authorities in the UK, mid-2012’ (https://www.ons.gov.uk/peoplepopulationandcommunity/populationandmigration/populationestimates/datasets/populationestimatesforukenglandandwalesscotlandandnorthernireland).

Gestation week data is variable across the abortion dataset, and so statistics were pooled into abortions occurring either ≤12 weeks or ≥13 weeks. A comprehensive study of the human sex ratio from conception to birth7 supports a female-biased cohort sex ratio during early pregnancy based on chorionic villus sampling, amniocentesis and induced abortions, and I have therefore chosen a conservative estimate of a 55:45 female:male sex ratio ≤12 weeks and 45:55 female:male ≥13 weeks. Using these values, I calculated the number of male and female abortuses each year. For comparison, abortus sex was also calculated on the assumption that the abortus sex ratio is equal (50:50).

Adding together the total number of live births, stillbirths and legal abortions provided the number of pregnancies, and accepting that these represent 90%, 80%, 75% or 67% of actual conceptions (i.e. the probability that a conception resulted in miscarriage was 10%, 20%, 25% or 33%) determined the relevant number of conceptions. If the primary sex ratio is equal, then equal numbers of males and females are conceived, and subtraction of the known numbers of live and stillborn males and females, and the predicted male and female abortuses left the number of products of conception lost to miscarriage.

Statistical significance of deviation of calculated numbers of miscarried males and females from expected numbers (males and females are equally susceptible to miscarriage) was assessed using Pearson’s χ2 test. All calculations were rounded to the nearest whole number to reflect the impossibility of conceiving a fraction of a person, and so in some cases annual totals are not the sum of their constituent parts. It also goes without saying that the ratios presented here address only a narrow range of biological sex, not gender, and are predicated on the simplistic assumption that XX = female and XY = male.

Results

In England and Wales between 1993 and 2017 there were 16,489,289 maternities (a pregnancy resulting in the birth of one or more children including stillbirths, of which around 1.5% resulted in multiple births); 16,656,203 live births (8,114,739 female and 8,541,464 male, with on average 1,053 males born per 1,000 females); 86,714 stillbirths (41,059 female and 45,655 male, with on average 1,112 males stillborn per 1,000 females); 4,512,024 legal abortions, and between 23,616,601 to 31,723,793 conceptions (Supplemental table S1). Of the 4,512,024 abortions, 4,044,380 occurred ≤12 weeks of gestation and 467,644 occurred ≥13 weeks, with 2,435,740 girls aborted to 2,076,284 boys, for an average of 853 boys aborted per 1,000 girls (Figure 2, Table 1). There were 2,361,660 – 10,468,852 miscarriages in the years 1993-2017, averaging between 94,466 per year (941 males per 1,000 females) if 10% of all conceptions result in miscarriage to 418,754 per year (986 males per 1,000 females) for a miscarriage risk of 33% (Table 2). From this 25 year dataset for England and Wales, more girls were aborted than boys, more boys were born live and stillborn, and significantly more girls were miscarried (P < 0.00001, Pearson’s χ2 test, Figure 3).

View this table:
Table 1.

Live births, stillbirths and abortions in England and Wales, 1993-2017. Numbers of males and females for live births and stillbirths reflect classifications as recorded on the relevant birth registers. Abortus sex is calculated from the total number of abortions on the assumption that the sex ratio ≤12 weeks of gestation is 55:45 in favour of females, and 45:55 in favour of males from ≥13 weeks of gestation. Total or average values are provided in the bottom rows.

View this table:
Table 2.

Predicted miscarriages in England and Wales, 1993-2017. Values are determined based on the number of calculated number of conceptions, as determined by the number of live births, stillbirths and abortions, accounting for the relevant miscarriage risk factor (where 10%, 20%, 25% or 33% of all conceptions result in miscarriage). Total or average values are provided in the bottom rows.

Figure 2.
Figure 2.

Sex ratio of legal abortions in England and Wales, 1993-2017, determined on the assumption that early (≤12 weeks) abortions are biased towards females (55:45) and later abortions (≥13 weeks) are biased towards males (45:55).

Figure 3.
Figure 3.

Relative miscarriage sex bias in England and Wales, 1993-2017, calculated as 1-(females miscarried/males miscarried), calculated if 10%, 20%, 25% or 33% of all conceptions result in miscarriage. A value of 0 would indicate no bias, a positive value would show male bias, and a negative value a female bias. Average values are −0.071 for the 10% dataset, −0.035 for 20%, −0.028 for 25% and −0.021 for 33%). Miscarriages are biased towards females in every year of this 25 year dataset, with a marked decrease in the miscarriage sex ratio around 2005-2006, following the 7th July 2005 terrorist bombings in London.

Discussion

Miscarriage affects around 10% of clinically-recognised pregnancies, and a far higher number of unrecognised ones. If we are to reduce or remove the prevalence of this emotionally-damaging pregnancy outcome, we must understand the factors that influence pregnancy retention or loss. The bias towards males in the human sex ratio at birth has long hinted at a greater loss of females during pregnancy, but the problems inherent in obtaining and interpreting tissue samples from miscarried products of conception has made estimation of the role played by fetal sex in pregnancy outcome almost impossible. Using population-level data on births and abortions, I show that the male bias in the human sex ratio at birth is the result of a greater loss of females to miscarriage during pregnancy and quantify the number of males and females lost over a 25 year period in England and Wales. More females than males are also aborted, largely as a result of a greater number of abortions occurring ≤12 weeks of gestation when the sex ratio is skewed towards females. There is no evidence that the greater proportion of aborted females is the result of sex-specific abortion. If the female abortion bias is removed (i.e. the abortus sex ratio is equal, irrespective of when the abortion occurred) then the female bias in miscarriage is exacerbated, with between 691-921 males lost per 1,000 females (Supplemental tables S2, and S3, Supplemental Figure S1). Why might females be more susceptible to loss than males?

It is typically suggested that early loss of female embryos (particularly in recurrent miscarriage) is the result of problems related to X chromosome inactivation, and especially skewed or highly skewed inactivation, where either the maternal or paternal copy is preferentially inactivated18–24. However, results in this area are contradictory25–28, and it is unclear how applicable this phenomenon is to miscarriage more generally. An alternative explanation might lie in imprinting and parental conflict. If pregnancy is viewed as a conflict between mother and offspring, rather than a cooperative process, then the selective pressure on maternal genes will be to limit the supply of resources to the developing offspring so as to maximise (or at least stabilise) maternal fitness, whereas fetal genes will be selected to maximise growth29,30. Imprinting therefore serves to limit the growth and/or function of the placenta. There is also conflict between maternal and paternal alleles, as fathers have an interest in improved survival of current offspring, even at the expense of future offspring, which may have a different father. Imprinted paternal alleles may therefore have a stronger effect, as fathers have fewer opportunities to influence maternal investment31,32. X-linked alleles can only be imprinted in females, as males never inherent a paternal X chromosome, and inheritance of paternally imprinted X chromosomes retards fetal growth in mice33. Iwasa et al.34 proposed a “reverse imprinting” model, where expression of maternal alleles might be favoured if elevated expression of a gene increases the possibility of spontaneous abortion, but leads to an increase in robustness (increased growth and pre- and post-natal survival) of embryos that pass this stage. If losses occur early in pregnancy, minimal resources have been invested and so the cost to the mother is limited. Boys exhibit greater infant mortality than girls35 (and higher stillbirth rates, see above) and so it may be that the greater loss of girls earlier in pregnancy actually explains their later robustness.

Interestingly, only a relatively minor change in primary sex ratio to produce between 49.85% and 49.89% females rather than 50% is sufficient to remove the miscarriage sex bias, even with the greater number of females aborted (Supplemental table S4). If the abortus sex ratio is equal, the primary sex ratio must produce between 49.09% to 49.32% females to remove the miscarriage sex bias (Supplemental table S5). It is worth briefly considering how such a biased primary sex ratio might be produced. Right and left ovaries are not symmetrical, and differ with respect to anatomical relations and venous drainage, with the left ovary drained by the left renal vein, and the right drained by the inferior vena cava. The higher venous pressure in the left renal vein results in slower drainage, and so hormones produced by the left ovary during ovulation will remain in this side for longer than in the right. This asymmetry may impact frequency and pattern of ovulation, and reproductive potential of ooctyes from left and right ovaries, where the right ovary may be more productive36–40. Ovarian asymmetry is known from a number of other species, such as birds, which develop only one ovary41,42, mice, where the right ovary is more productive than the left43, certain species of bat44, as well as shrews45, hamsters, and waterbuck46,47. Perhaps the best evidence for a role for ovarian asymmetry in manipulation of sex ratios comes from the Mongolian gerbil (Meriones unguiculatus), where male embryos are more common in the right uterine horn, and females more common in the left48. When the left and right, ovaries are switched, the sex ratio follows the ovary, and when the right ovary is cut in half and placed in both positions more males are produced from both uterine horns49. A similar situation has been identified in cows50, although that may be complicated by movement of embryos between uterine horns. Parental hormones influence offspring sex ratios51–55, and levels of testosterone in follicular fluid during oocyte maturation may determine whether an egg is fertilised by X or Y chromosome-bearing sperm56,57. This influence of parental hormones on offspring sex ratios in humans is perhaps most clearly indicated by the alteration to the secondary (birth) sex ratio following violent events such as terrorist attacks9,10, evident here as a decline in the miscarriage sex bias around 2005 and 2006, following the 7th July 2005 terrorist attacks in London (Figure 3). Whilst glucose can influence embryo survival, and seems to adversely impact females2,4,58, it seems most likely that hormonal variations, resulting from an inherent ovarian asymmetry (established during embryonic development of the adrenogonadal primordia from the genital ridges under the influence of an earlier PITX2-derived asymmetry41), would control either sperm chemoattraction59–62 (or repulsion63), or preferential fertilisation by X and Y chromosome-bearing sperm. However, in the absence of evidence in support of the above, and given unbiased segregation of sex chromosomes during sperm formation, a primary sex ratio of 50:50 can safely be assumed, and miscarriage sex bias is real.

My analysis represents the first attempt to theoretically determine both the sex ratio of abortuses, and the sex ratio of miscarried products of conception. Obviously, there is a disconnect between year of birth, stillbirth or abortion and year of conception, and certain assumptions had to be made, such as the number of aborted males and females (55:45 in favour of females ≤12 weeks and 45:55 in favour of males ≥13 weeks)7.

Similarly, the number of conceptions that result in miscarriage is unknown, but the values used here (10%, 20%, 25%, 33%) are in accordance with accepted ranges11–14. However, far higher values have been proposed. In 1975, Roberts and Lowe attempted to predict the annual number of conceptions in England and Wales in 197164, and suggested that up to 78% of conceptions were lost. Their analysis was based only on married women, hypothesised a mean frequency of coitus twice a week (one in four of which was unprotected), and did not include data for pregnancies ending in abortion. Using data from the National Surveys of Sexual Attitudes and Lifestyles (Natsal) it is possible to refine these calculations, and Natsal-365 suggests that women aged 16-44 in the survey period (6th September 2010 – 31st August 2012) had on average 4.9 occasions of sexual intercourse (defined as vaginal, oral or anal intercourse) in the preceding 4 weeks, of which 69% included vaginal sex (defined as a man’s penis in a woman’s vagina). The frequency of sexual intercourse for this age group is likely nearer 1.2 occasions per week, with 0.85 instances of vaginal sex per week. The annual frequency (i.e. for 52 weeks) of vaginal sex for women aged 16-44 in the survey period was therefore 44.2, not the 104 previously used by Roberts and Lowe64. The proportion of unprotected acts of coitus during the survey period is also now lower than the 25% estimate of Roberts and Lowe, and is likely nearer 5-7% for women aged 16-4466, increasing to around 10% if less effective methods of contraception are included, or to 1/6 if some consideration is given to those trying to conceive or who were already pregnant. The number of unprotected instances of vaginal sex per woman per year is therefore around 7, and, of these, 1/14 will occur within 48 hours of ovulation. Given a fertilisation rate of around 60% in in vitro fertilisation67, where sperm quality is likely higher than that of a “normal” ejaculate, an in vivo fertilisation rate of one in three seems reasonable. The Office for National Statistics mid-year population estimate for mid-2012 predicted that there were 8,884,341 women between the ages of 16-39 in England and Wales, and using these values I have estimated the number of “missing” conceptions (i.e. those not accounted for in the relevant live birth, stillbirth and abortion statistics, which can be considered to represent miscarried products of conception) (Table 3). For women aged 16-39 in 2012, the overall miscarriage rate was 43%, and for women aged 20-39 (responsible for 91% of all live births, 88% of stillbirths and 78% of abortions), the average rate of loss was 38%. Given the inherent uncertainty in these calculations, the miscarriage ranges used in my analysis (10%, 20%, 25%, 33%) therefore seem in accordance with this theoretical prediction, and the identification of an inherent female bias seems robust.

View this table:
Table 3.

Theoretical prediction of the number of miscarried products of conception in England and Wales in 2012. Sexual habits are based on Natsal-365 for women aged 16-44, and the remaining data are from ONS statistical datasets as described in the text. The predicted miscarriage rate is 43% overall, or 38% for women aged 20-39 (responsible for the majority of live births, stillbirths and abortions).

Finally, it should be noted that I cannot (and do not) make any distinction between sporadic and recurrent miscarriages. This may prove to be significant in future, as a study of fetal sex in recurrent miscarriages16 found a much higher females-biased sex ratio than found here (64:36, based on 313 products of conception), although this study may have had issues with maternal contamination, and is based on a much smaller sample size. Luckily, we are now in a position where investigation of miscarriage sex bias may not be so heavily influenced by maternal contamination, as cell-free fetal DNA68 offers an alternative method of determining fetal sex based on presence or absence of a Y chromosome (or a specific region of the Y chromosome)69,70, even as early as 5-7 weeks of gestation. With an appropriate program of blood sampling and tracking of pregnancy outcomes, it will be possible to assess miscarriage sex ratio, and definitively show to what extent fetal sex influences adverse pregnancy outcomes.

Funding statement

No relevant funding to declare.

Author contributions

JFM did everything.

Acknowledgements

I would like to thank Tom Brekke, Daniel Brison and David Steinsaltz for comments and advice on the manuscript, and Gudrun Rieck for general discussion.

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Posted November 29, 2018.
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Quantification of miscarriage sex bias in England and Wales, 1993-2017
John F Mulley
bioRxiv 418186; doi: https://doi.org/10.1101/418186
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