The fertile window is 3 days wide, not 6, which 6-day belief originated in a flawed 1995 study

About a quarter of a century ago, a US medical statisticians’ study caused a media sensation, when it declared that the fertile period (the days of menstrual cycle during which conception can occur from unprotected sex) is much shorter than the 10 +/- 2 days that had been declared in a 1985 publication [1] by the World Health Organization. Ten years after the W.H.O.  publication, the fertile window of only 6 days was enthusiastically celebrated by the popular media.

That was when in 1995 a New England Journal of Medicine paper [2] reported on work carried out at the N.I.H. (National Institutes of Health) between 1982 and 1985. The Wilcox et al. team performed statistical analysis of data on sex steroid hormone measurements in frozen samples of urine and the data from the studied women’s journals of sexual activity “from the time they stopped using birth control until the eighth week of clinical pregnancy or up to six months if no pregnancy was clinically evident”.

There was no other effort to determine ovulation besides the quantification of estrogen and progesterone metabolites in the studied women’s urine. The authors assumed that the estrogen/progesterone ratio (E2/P) corresponds to the LH surge, which was in turn believed to “correspond approximately with the day of ovulation”. The approximation is a significant drawback feature because the estimate had an important caveat already before the 1995 study. The caveat was the recognition that “there is a minimum error of +/- 12 hours in this estimate of ovulation, which in practice may be +/- 24 hours” [1], because the LH is an imperfect reference. Data from our pilot studies show that a delay of ovulation after the LH surge is one aspect of the imperfection.

We note a meaningful qualitative agreement between the data in the 1995 paper by Wilcox et al. and a 1992 publication by France et al. [3], keeping in mind that the 1992 data are from 55 pregnancies (and births) while the 1995 data are based on 34 pregnancies. These 34 pregnancies in the Wilcox et al. study resulted from 129 menstrual cycles in which intercourse was recorded to have occurred on a single day during the fertile period, as in the other study. This single coitus during fertile window is an important feature of study design.

Remarkably, when the sums of male and female births from the France et al. data are plotted against cycle day with respect to ovulation (as estimated by Peak mucus), a pattern similar to that found by Wilcox et al. is revealed. This will be shown in the following. First, let’s summarize.

Both referenced studies [2] and [3] show three days of comparatively high conception rates: Wilcox from day -2 to day 0 while France from day -3 to day -1. Day 0 is the estimated day of ovulation, estimated in different ways in the two studies.

The image below shows the distribution of the Wilcox et al. conception probabilities on days near the estimated day of ovulation (screen shot of their Fig. 2; click on the image to enlarge it).

In view of the one-day uncertainty in the underlying estimate of ovulation (from urinary E2/P data), this sharp cutoff may not be real, and even more suspect is this peculiarity in the Wilcox data: Regardless of the fact that the E2/P ratio drops rapidly upon ovulation (as a result of luteinization of the dominant follicle), it is not clear why, in the 1995 Wilcox et al. study, “intercourse that was recorded on a given morning was assumed to have occurred the previous day”. That assumption could clearly put any day +1 scores into the count of day 0 scores, and thus lead to the unprecedented outcome of the surprisingly sharp cutoff at ovulation.

Wilcox et al. Fig. 2 Conception probabilities cropped

A criticism applies also to the data of France et al., based on the uncertainty of +/- 3 days in the Peak mucus method. The image below shows the results on one of their three time scales, namely the Peak mucus method of estimating ovulation. The graph on the left is the distribution of all births while on the right is the distribution by gender of the born babies.

3-day fertile window based on France et al. data
Click on the image to enlarge it.

Comparing the birth distribution plots in the two studies brings out clearly the importance of the quality of the ovulation marker for the outcome of such studies. Estimating (rather than actually detecting) ovulation is not good enough.

In the context of what is known about the fertilizable lifetimes of the gametes, it is the contention of this writer that the real fertile window is in fact less than 6 days wide. The data of the discussed studies are consistent with the contention. This is because the low birth counts on the extremes of the birth distribution curves in the discussed studies are more than likely experimental artifacts resulting from their inaccurate determination of ovulation. In the discussed studies, ovulation was merely estimated and assumed, not detected as ultrasound-visualized follicle rupture, with further confirmation (e.g., by cul-de-sac fluid culdocentesis evidence).

As a result of the deficient design of their studies, we see such data as three births on day -6 in the France et al. publication, which is difficult (if not impossible) to reconcile with the most commonly accepted 2 to 3 days of fertilizable lifetime of the sperm [4], [5]. If these three births were data point outliers that in fact belong to one or another day count within 3 days of day -6 (the uncertainty in the Peak mucus method), this and other such adjustments would considerably alter the reported birth distribution pattern.

In the data of both studies, an overwhelming majority of pregnancy or birth counts is concentrated within three days, and only a small number of the counts occur within the skewed (slanted) boundaries of the respective distributions. (The boundaries are skewed – or slanted – as the counts fall from the respective high pregnancy/birth count or high probability of conception to zero count or zero probability.)

Also, the boundaries of both patterns are skewed in the same manner: Both distribution curves fall off slowly in the pre-ovulatory phase (both decline over 4 days), and they fall off rapidly after ovulation, although only the 1995 Wilcox et al. data fall off to zero immediately after the estimated day of ovulation.

The most significant quantitative difference between the overall birth distributions in the two studies is in their widths. The 1992 birth distribution by France et al. is 9, 9, and 10 days wide, depending on the method of estimating ovulation, and with the largest value of 10 resulting on the start-of-the-LH-peak time scale. In 1992, this width of the fertile window was in agreement with the then recently WHO-generated fertile widow figure of 10 +/- 2 days. The 1995 birth distribution by Wilcox et al. is only 6 days wide, and this was enthusiastically celebrated by the popular media, and the Wilcox et al. 6-day fertile window is referenced to this day – basically as an industry standard.

Yet, the NIH now says [6] that: 1) 90% of women don’t know that 2 days before through the day of ovulation is the best time to get pregnant; 2) 25% of women don’t know a normal menstrual cycle can vary between 21 and 35 days; and 3) Like blood pressure and heart rate, a woman’s menstrual cycle is a sign of her overall health.

The reliance on the flawed 1995 study is detrimental to those who want to practice fertility awareness. That’s because the study teaches in effect that there are 3 days when a woman is “a little fertile” in addition to the 3 days when she is “most fertile” – only because of the deficient method of determining daily fertility status (by relying on hormone metabolites in circulation).

Tracking ovarian steroid hormones in body fluids is inaccurate because it does not monitor the complex mechanism of folliculogenesis, i.e. the mechanism of the menstrual cycle, which underlies daily fertility status.

In contrast, bioZhena’s ovulographicTM technique of tracking folliculogenesis-in-vivoTM (via the cervix) does monitor the interplay (feedback) between the ovarian and the brain hormone signals, which is essential for fertility awareness.

The image below is an illustration of how bioZhena’s monitoring the brain-ovary interplay provides the essential information for the practice of fertility awareness, utilizing the wealth of information contained in the recorded menstrual cyclic profile (raw data translated into plain language indications of fertile status – not shown – and shareable to the users’ healthcare providers for better diagnosis and treatment by enabling correlation of symptoms with the menstrual cyclic profile).

The contents of the image can be viewed with better legibility in the set of three animated slides hyperlinked below and in reference [8]. The third slide additionally indicates how the menstrual cyclic profile (or signature) relates to the stages of folliculogenesis including the elucidation of the dominant follicle maturation peak (i.e. the long-term predictive peak anticipating ovulation and controlling the length of the menstrual cycle).

Three day window and Wealth of Info composite image

https://biozhena.files.wordpress.com/2018/03/wealth-of-info-elucidation-silent-3-slides-animated-ed.pps
Click on the last slide to exit, or navigate the slides using the buttons found in left bottom corner, or the arrow keys on your keyboard.

For more about bioZhena’s menstrual cycle monitoring via the ectocervix, visit the OvulonaTM blog article [7].

See the post script in the article [7] for a detailed description and elucidation of the cyclic profile features including the details of the ascending and descending branches of the dominant follicle maturation peak (the long-term predictive peak in the follicular phase of the cycle).

The ascending and descending peak branches are labeled “GC+TC E2up” and “GC P4up”, respectively – shorthand for granulosa cells and theca cells secreting estrogen and progesterone, i.e. the sex steroids known from separate in vivo experiments to drive the Ovulona cervical tissue sensor’s response in the respective directions: estrogen up and progesterone down. The sensitivity of the cervix to the steroids gives rise to the multitude of features in the cyclic profile, and the ensuing accurate determination of the fertile window.

 

References

[1] World Health Organization, “A prospective multi-centre trial of the ovulation method of natural family planning. V.”, International Journal of Fertility 30 (3), 18 – 30, 1985.

[2] A.J. Wilcox, C.R. Weinberg and D.D. Berg, “Timing of sexual intercourse in relation to ovulation. Effects on the probability of conception, survival of the pregnancy, and sex of the baby”, New England Journal of Medicine 333, 1517 – 1521, 1995.

[3] J.T. France, F.M. Graham, L. Gosling, P. Hair and B.S. Knox, “Characteristics of natural conception cycles occurring in a prospective study of sex preselection: fertility awareness symptoms, hormone levels, sperm survival, and pregnancy outcome”, International Journal of Fertility 37 (4), 224 – 255, 1992.

[4] Leon Speroff, Robert H. Glass and Nathan G. Kase, “Clinical Gynecologic Endocrinology and Infertility”, Williams & Wilkins, 5th edition, 1994.

[5] Eli Y. Adashi, John A. Rock, and Zev Rosenwaks, editors, “Reproductive Endocrinology, Surgery, and Technology”, Lippincott – Raven, 1996.

[6]https://www.nichd.nih.gov/newsroom/digital-media/infographics/ovulation

[7]https://biozhena.wordpress.com/2007/12/11/the-ovulona/

[8]https://biozhena.files.wordpress.com/2018/03/wealth-of-info-elucidation-silent-3-slides-animated-ed.pps

Advertisements

%d bloggers like this: