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. 2020 Sep 29:9:e55305.
doi: 10.7554/eLife.55305.

Unexplained repeated pregnancy loss is associated with altered perceptual and brain responses to men's body-odor

Liron Rozenkrantz #  1   2 , Reut Weissgross #  1   2 , Tali Weiss #  1   2 , Inbal Ravreby  1   2 , Idan Frumin  1   2 , Sagit Shushan  1   2   3 , Lior Gorodisky  1   2 , Netta Reshef  1   2 , Yael Holzman  1   2 , Liron Pinchover  1   2 , Yaara Endevelt-Shapira  1   2 , Eva Mishor  1   2 , Timna Soroka  1   2 , Maya Finkel  1   2 , Liav Tagania  1   2 , Aharon Ravia  1   2 , Ofer Perl  1   2 , Edna Furman-Haran  2   4 , Howard Carp  5 , Noam Sobel  1   2
Affiliations

Unexplained repeated pregnancy loss is associated with altered perceptual and brain responses to men's body-odor

Liron Rozenkrantz et al. Elife. .

Abstract

Mammalian olfaction and reproduction are tightly linked, a link less explored in humans. Here, we asked whether human unexplained repeated pregnancy loss (uRPL) is associated with altered olfaction, and particularly altered olfactory responses to body-odor. We found that whereas most women with uRPL could identify the body-odor of their spouse, most control women could not. Moreover, women with uRPL rated the perceptual attributes of men's body-odor differently from controls. These pronounced differences were accompanied by an only modest albeit significant advantage in ordinary, non-body-odor-related olfaction in uRPL. Next, using structural and functional brain imaging, we found that in comparison to controls, most women with uRPL had smaller olfactory bulbs, yet increased hypothalamic response in association with men's body-odor. These findings combine to suggest altered olfactory perceptual and brain responses in women experiencing uRPL, particularly in relation to men's body-odor. Whether this link has any causal aspects to it remains to be explored.

Keywords: Bruce effect; human; miscarriage; neuroscience; olfaction; pregnancy block; repeated pregnancy loss; social chemosignaling.

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Conflict of interest statement

LR, RW, TW, IR, IF, SS, LG, NR, YH, LP, YE, EM, TS, MF, LT, AR, OP, EF, HC, NS No competing interests declared

Figures

Figure 1.
Figure 1.. Women with uRPL can identify their spouse by smell.
(a) A custom-designed Shirt Sniffing Device (SSD) to standardize body-odor sampling. The SSD consists of a glass jar containing the T-shirt, with an air intake port via soda lime filter, and air sampling port via one-way flap valve into individual-use airtight nose mask. This arrangement assured that environmental odors didn't contaminate the sample during the sampling process. The recognizable person in the figure is a co-author and not a participant. (b) Performance at 3AFC identification test (n = 66). uRPL women in purple, control women in green. Bar graphs depict group means, each dot represents a participant, dots are jittered to prevent overlay, error bars are s.e.m, **p<0.01. Black dashed line indicates chance level. (c) Bootstrap analysis. Gray lines represent the 10,000 repetitions; the purple line represents the actual uRPL-control difference value.
Figure 2.
Figure 2.. Women with uRPL have slightly better olfaction than controls.
uRPL (purple) and control (green) women were tested for various olfactory facets. (a) Percent accuracy at every-day odorant identification (n = 76). (b) Percent accuracy at monomolecule discrimination (EST, ANN, AND) (n = 76). (c) DMTS threshold (n = 36). (d) A composite score of identification, discrimination and threshold (n = 78). (e) Bootstrap test of ‘d’, 10,000 repetitions, the purple line represents the actual uRPL-control difference value. Bar graphs depict means, each dot represents a participant, dots are jittered to prevent overlay, error bars are s.e.m. *p<0.05. Black dashed line indicates chance level.
Figure 3.
Figure 3.. Women with uRPL have altered perception of men's body-odor.
(a) uRPL (purple) and control (green) women ratings of non-spouse men body-odor, score combines ratings of pleasantness, sexual attraction, intensity and fertility attributed to the odor (see separate ratings in Figure 3—figure supplement 1). n = 36. Bar graphs depict means, each dot represents a participant, dots are jittered to prevent overlay, error bars are s.e.m. *p<0.05. (b) Bootstrap test of the non-spouse result, 10,000 repetitions, the purple line represents the actual uRPL-control difference value.
Figure 3—figure supplement 1.
Figure 3—figure supplement 1.. Altered perception of men’s body-odor in uRPL.
Eighteen women with uRPL and 18 controls rated men’s body-odors of three kinds: An unworn t-shirt (Blank), a non-spouse male, and their actual spouse; on four traits: (a) Intensity; (b) Pleasantness; (c) Sexual attraction; and (d) Fertility. A multivariate RM ANOVA of Group (uRPL/Control), Odor (Blank/Non-Spouse/Spouse) and Descriptor (Intensity/Pleasantness/Sexual attraction/Fertility) revealed a main effect of Descriptor (F(3,102) = 12.4, p<0.001), reflecting that traits were applied differently, regardless of group and odor (mean Intensity: 0.49 ± 0.21, mean Pleasantness: 0.42 ± 0.14, mean Sexual attraction: 0.33 ± 0.15, mean Fertility: 0.38 ± 0.15; all pairwise comparisons t(35) > 2.12, all p<0.041, all Cohen’s d > 0.35). In addition, a significant interaction of Odor x Descriptor (F(6,204) = 8.27, p<0.001) was carried by intensity ratings alone (F(2,70) = 15.8, p<0.001; all other descriptors: all F(2,70) < 1.93, all p>0.15). This intensity difference was carried solely by differences from Blank, which was, unsurprisingly, less intense than all other otherwise (and importantly) equally-intense stimuli (mean Intensity ratings: Blank:=0.31 ± 0.26, Non-Spouse = 0.58 ± 0.23, Spouse:=0.59 ± 0.35. Blank vs. Non-Spouse and Spouse: Both t(35) > 4.7, both p<0.001, both Cohen’s d > 0.77; Non-Spouse vs Spouse: t(35) = 0.15, p=0.88, Cohen’s d = 0.03). Finally, a significant interaction of Group x Odor (F(2,68) = 3.43, p=0.038) reflected a lower rating for Non-Spouse among uRPL versus control women. This effect that materialized in the combined descriptors was mostly carried by fertility ratings, evident by independent tests between groups for Non-Spouse ratings (Pleasantness: t(34) = 1.6, p=0.12, Cohen’s d = 0.53, nonparametric Mann-Whitney = 213.5, p=0.107; Attraction: t(34) = 1.53, p=0.135, Cohen’s d = 0.51, nonparametric Mann-Whitney = 214, p=0.104; Fertility: t(34) = 2.69, p=0.011, Cohen’s d = 0.9, nonparametric Mann-Whitney = 245, p=0.009; Intensity was not statistically significant: t(34) = 1.09, p=0.28, Cohen’s d = 0.36, nonparametric Mann-Whitney = 187, p=0.44). Bar graphs depict means, each dot represents a participant, dots are jittered to prevent overlay, error bars are s.e.m.
Figure 4.
Figure 4.. Women with uRPL have smaller olfactory bulbs and shallower olfactory sulci.
(a) Olfactory bulb volume. A 3D reconstruction of uRPL (purple) and control (green) participants’ left (upper row of the two) and right (bottom row) olfactory bulbs. Bulbs sorted by size (see Figure 4—figure supplement 1 for sort by participant (uRPL to Control) match). Note that the reconstructions do not relate to the values on the Y axis, the values are reflected in the data lines alone. (b) Bootstrap test of ‘a’, 10,000 repetitions, the purple line represents the actual uRPL-control difference value. (c) Olfactory sulci depth (right, left and average) of uRPL (purple bars) and control (green bars) participants. (d) Bootstrap test of the average in ‘c’, 10,000 repetitions, the purple line represents the actual uRPL-control difference value. Bar graphs depict means, each dot represents a participant, dots are jittered to prevent overlay. Error bars are s.e.m. *p<0.05. (e) The relation between olfactory composite scores and olfactory bulb volumes for uRPL (purple) and control (green) participants. n = 46. Each square (uRPL) and triangle (control) represent a participant.
Figure 4—figure supplement 1.
Figure 4—figure supplement 1.. Smaller olfactory bulbs in uRPL.
Women with uRPL have significantly smaller olfactory bulbs (Right bulb volume: uRPL: 45.9 ± 12 mm3, control: 55.4 ± 9.7 mm3, t(44) = 2.96, p=0.005, Cohen’s d = 0.87; Left bulb volume: uRPL: 46.4 ± 8.9 mm3, control: 55.7 ± 9.4 mm3, t(44) = 3.45, p=0.001, Cohen’s d = 1.02; Average bulb volume: uRPL: 46.1 ± 9.9 mm3, control: 55.5 ± 9 mm3, t(44) = 3.37, p=0.0016, Cohen’s d = 0.99). This figure shows a 3D reconstruction of uRPL (purple) and control (green) participants’ left and right olfactory bulbs (volumes). Bulbs sorted by match of uRPL and control participants (see main text and Figure 4—source data 1 for details about the matching).
Figure 5.
Figure 5.. Women with uRPL have an altered brain response to male body-odor.
(a) Hypothalamus blood-oxygen level-dependent (BOLD) activity in uRPL (non-spouse >blank), compared to control. (b) Whole brain PPI test, reflecting greater correlation with hypothalamus (seed ROI) time series for all emotionally-weighted-movie-clips>fixation. Both scatterplots reflect the % signal change of each participant (uRPL in purple, controls in green). The diagonal is the unit slope-line (x = y). Dots above the slop line represent higher % signal change for Non-Spouse men body odor, and dots below the line represent higher % signal change for Blank. n = 46. All coordinates in MNI space.
Figure 5—figure supplement 1.
Figure 5—figure supplement 1.. Reduced gray matter volume in the right fusiform in uRPL.
For voxel-based morphometry we compared structural data from 23 uRPL and 23 control women using FSL-VBM. The threshold for significance is p<0.0001, without correction for multiple comparisons. A single locus materialized in the right fusiform.
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