8. Reproduction

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The panel evaluated a number of measures of reproductive health and performance. Parameters that either affect or reflect the breeding performance will be presented first. These include:

• incidence of cystic ovaries,
• number of services required per conception,
• average duration from calving to conception (days open),
• incidence of twinning (multiple births) and,
• overall risk of a cow not becoming pregnant.

Subsequently three parameters that reflect the state of the cow during her gestation period and at the subsequent calving were evaluated and these included:

• the risk of abortion/fetal loss,
• effect of rbST on gestation length, and
• incidence of retained placenta.

8.1 Incidence of Cystic Ovaries

Most studies reported the incidence of cystic ovaries in terms of the risk of this condition (i.e.the number of cows affected divided by the number of cows at risk).

8.1.1 Meta-analysis

Two meta-analyses were carried out.

• Effects of rbST on the risk of cystic ovaries based on studies using all companies' products.
• Effects of rbST on the risk of cystic ovaries based on studies using Monsanto's product.

. meta val cilow cihigh , ci eform pr gr(f) id(std_lbl) cl xline(1)ltrunc(.33) rtrunc(6) xlabel(.33, .5, .75, 1, 1.5, 2, 3,6 ) b2("Cystic Ovaries Risk - All Companies")

Meta-analysis (exponential form)

Effect of rbST on 3.5% FCM

Method	Pooled Est	95% CI Lower	95% CI Upper	Asymptotic z_value	Asymptotic p_value	No. of studies
Fixed	1.224	0.953	1.572	1.583	0.113	8
Random	1.269	0.946	1.703	1.590	0.112

Test for heterogeneity: Q= 8.330 on 7 degrees of freedom (p= 0.304)
Moment-based estimate of between studies variance = 0.028

Effect of rbST on 3.5% FCM

Study	Weights Fixed	Weights Random	Study Est	95% CI Lower	95% CI Upper
1 Mm1	3.64	3.30	1.09	0.39	3.04
1 Mp1	2.66	2.47	1.20	0.36	3.99
7 Mm1	13.76	9.89	1.80	1.06	3.05
7 Mp1	2.50	2.33	2.56	0.74	8.85
291 Ua1	1.29	1.24	1.68	0.30	9.44
1218 Ca1	1.91	1.81	3.46	0.84	14.27
5407 Mm1	22.03	13.56	0.88	0.58	1.33
5407 Mp1	13.63	9.83	1.08	0.64	1.84

Cystic Ovaries Risk - All Companies

. meta val cilow cihigh , ci eform pr gr(f) id(std_lbl) cl xline(1)ltrunc(.33) rtrunc(6) xlabel(.33, .5, .75, 1, 1.5, 2, 3,6 ) b2("Cystic Ovaries Risk - Monsanto")

Meta-analysis (exponential form)

Effect of rbST on 3.5% FCM

Method	Pooled Est	95% CI Lower	95% CI Upper	Asymptotic z_value	Asymptotic p_value	No. of studies
Fixed	1.174	0.908	1.518	1.227	0.220	6
Random	1.201	0.891	1.619	1.204	0.228

Test for heterogeneity: Q= 6.036 on 5 degrees of freedom (p= 0.303)
Moment-based estimate of between studies variance = 0.024

Effect of rbST on 3.5% FCM

Study	Weights Fixed	Weights Random	Study Est	95% CI Lower	95% CI Upper
1 Mm1	3.64	3.35	1.09	0.39	3.04
1 Mp1	2.66	2.50	1.20	0.36	3.99
7 Mm1	13.76	10.33	1.80	1.06	3.05
7 Mp1	2.50	2.36	2.56	0.74	8.85
5407 Mm1	22.03	14.39	0.88	0.58	1.33
5407 Mp1	13.63	10.26	1.08	0.64	1.84

Cystic Ovaries Risk - Monsanto

8.1.2 Comments and Conclusions

With the exception of the multiparous cows in the PAMP study (12), all studies reported an increased risk of cystic ovaries associated with rbST treatment, although only one of the individual relative risk estimates was statistically significant. This one significant result was derived from a study in which rbST had been administered intramuscularly (5). Overall, it appeared that treatment increased the risk by approximately 20% although this apparent increase was not statistically significance (P = 0.11).

Two of the papers reviewed, evaluated the mechanism by which rbST may affect ovarian performance and it was found to have an affect on the development and size of ovarian follicles (27,28). This would be consistent with a possible increase in the frequency of cystic ovaries.

The Panel concluded that although there appeared to be an increased risk of cystic ovaries in treated cows, most of the evidence for this effect came from a study in which rbST was administered intramuscularly. The Panel concluded that there were insufficient data to draw a firm conclusion about the effect of rbST on cystic ovaries.

8.2 Services per Conception (SPC)

Services per conception reflects the number of times that cows which ultimately conceived had to be bred in order to conceive. The parameter does not take into account cows which were bred but which did not conceive.

8.2.1 Meta-analysis

Two meta-analyses were carried out to evaluate the effects of rbST on the number of services per conception.

• Effects of rbST on the number of services per conception based on studies using all companies' products.
• Effects of rbST on the number of services per conception based on studies using Monsanto's product.

. meta val se , pr gr(f) id(std_lbl) cl xline(0) ltrunc(-3) rtrunc(3) xlabel(-3, -2, -1, 0, 1, 2, 3) b2("Services Per Conception - All Companies")

Meta-analysis

Effect of rbST on 3.5% FCM

Method	Pooled Est	95% CI Lower	95% CI Upper	Asymptotic z_value	Asymptotic p_value	No. of studies
Fixed	0.001	-0.218	0.220	0.009	0.993	12
Random	-0.002	-0.258	0.254	-0.014	0.989

Test for heterogeneity: Q= 13.371 on 11 degrees of freedom (p= 0.270)
Moment-based estimate of between studies variance = 0.035

Effect of rbST on 3.5% FCM

Study	Weights Fixed	Weights Random	Study Est	95% CI Lower	95% CI Upper
1 Mm1	4.96	4.23	-0.80	-1.68	0.08
1 Mp1	5.72	4.78	-0.70	-1.52	0.12
168 Cm1	12.66	8.80	0.28	-0.27	0.83
168 Cp1	12.66	8.80	0.10	-0.45	0.65
168 Cm2	5.59	4.68	0.04	-0.79	0.87
168 Cp2	3.12	2.82	0.88	-0.23	1.99
261 Ma1	5.59	4.68	0.30	-0.53	1.13
644 Ma1	0.27	0.27	0.46	-3.32	4.24
644 Ma2	0.45	0.44	0.26	-2.67	3.19
5298 Ea2	5.67	4.74	0.45	-0.37	1.27
5418 Ma1	2.35	2.17	-0.90	-2.18	0.38
5422 Mm1	20.85	12.10	-0.10	-0.53	0.33

Services Per Conception - All Companies

. meta val se , pr gr(f) id(std_lbl) cl xline(0) ltrunc(-3) rtrunc(3) xlabel(-3, -2, -1, 0, 1, 2, 3) b2("Services Per Conception - Monsanto")

Meta-analysis

Effect of rbST on 3.5% FCM

Method	Pooled Est	95% CI Lower	95% CI Upper	Asymptotic z_value	Asymptotic p_value	No. of studies
Fixed	-0.255	-0.564	0.054	-1.618	0.106	7
Random	-0.258	-0.572	0.056	-1.613	0.107

Test for heterogeneity: Q= 6.061 on 6 degrees of freedom (p= 0.416)
Moment-based estimate of between studies variance = 0.002

Effect of rbST on 3.5% FCM

Study	Weights Fixed	Weights Random	Study Est	95% CI Lower	95% CI Upper
1 Mm1	4.96	4.91	-0.80	-1.68	0.08
1 Mp1	5.72	5.65	-0.70	-1.52	0.12
261 Ma1	5.59	5.52	0.30	-0.53	1.13
644 Ma1	0.27	0.27	0.46	-3.32	4.24
644 Ma2	0.45	0.45	0.26	-2.67	3.19
5418 Ma1	2.35	2.33	-0.90	-2.18	0.38
5422 Mm1	20.85	19.92	-0.10	-0.53	0.33

Services Per Conception - Monsanto

8.2.2 Comments and Conclusions

The Panel concluded that there was no effect of rbST on the number of services per conception required in cows which did conceive.

8.3 Days Open (DO)

Days open is the number of days from calving until a cow is rebred and conceives. It can only be computed for cows which have a confirmed pregnancy.

8.3.1 Meta - Analysis

Two meta-analyses were carried out to evaluate the effects of rbST on the number of days open.

• Effects of rbST on the number of days open based on studies using all companies' products.
• Effects of rbST on the number of days open based on studies using Monsanto's product.

. meta val se , pr gr(f) id(std_lbl) cl xline(0) ltrunc(-50) rtrunc(100) xlabel(-50, -25, 0, 25, 50, 75, 100) b2("Days Open - All Companies")

Meta-analysis

Effect of rbST on 3.5% FCM

Method	Pooled Est	95% CI Lower	95% CI Upper	Asymptotic z_value	Asymptotic p_value	No. of studies
Fixed	5.120	1.230	9.010	2.579	0.010	18
Random	7.151	1.115	13.188	2.322	0.020

Test for heterogeneity: Q= 23.212 on 17 degrees of freedom (p= 0.142)
Moment-based estimate of between studies variance = 34.096

Effect of rbST on 3.5% FCM

Study	Weights Fixed	Weights Random	Study Est	95% CI Lower	95% CI Upper
1 Mm1	0.00	0.00	-7.00	-36.35	22.35
1 Mp1	0.00	0.00	-24.00	-63.78	15.78
7 Mm1	0.03	0.02	2.00	-8.71	12.71
7 Mp1	0.02	0.01	16.00	2.14	29.86
124 Um1	0.00	0.00	76.00	19.46	132.54
124 Up1	0.00	0.00	18.00	-43.04	79.04
124 Ua2	0.00	0.00	56.00	-2.77	114.77
168 Cm1	0.01	0.01	17.50	-3.29	38.29
168 Cp1	0.01	0.00	-5.40	-32.84	22.04
168 Cm2	0.13	0.02	2.20	-3.34	7.74
168 Cp2	0.00	0.00	29.80	-11.50	71.10
403 Cp1	0.00	0.00	66.00	-55.96	187.96
644 Ma1	0.00	0.00	21.00	-99.49	141.49
644 Ma2	0.00	0.00	7.00	-96.56	110.56
5298 Ea2	0.00	0.00	18.00	-23.58	59.58
5407 Mm1	0.03	0.01	7.00	-5.32	19.32
5407 Mp1	0.01	0.01	16.00	-2.16	34.16
5418 Ma1	0.01	0.01	-8.00	-29.07	13.07

Days Open - All Companies

. meta val se , pr gr(f) id(std_lbl) cl xline(0) ltrunc(-50) rtrunc(100)
xlabel(-50, -25, 0, 25, 50, 75, 100) b2("Days Open - Monsanto")

Meta-analysis

Effect of rbST on 3.5% FCM

Method	Pooled Est	95% CI Lower	95% CI Upper	Asymptotic z_value	Asymptotic p_value	No. of studies
Fixed	5.627	-0.376	11.629	1.837	0.066	9
Random	5.577	-0.738	11.891	1.731	0.083

Test for heterogeneity: Q= 8.406 on 8 degrees of freedom (p= 0.395)
Moment-based estimate of between studies variance = 4.825

Effect of rbST on 3.5% FCM

Study	Weights Fixed	Weights Random	Study Est	95% CI Lower	95% CI Upper
1 Mm1	0.00	0.00	-7.00	-36.35	22.35
1 Mp1	0.00	0.00	-24.00	-63.78	15.78
7 Mm1	0.03	0.03	2.00	-8.71	12.71
7 Mp1	0.02	0.02	16.00	2.14	29.86
644 Ma1	0.00	0.00	21.00	-99.49	141.49
644 Ma2	0.00	0.00	7.00	-96.56	110.56
5407 Mm1	0.03	0.02	7.00	-5.32	19.32
5407 Mp1	0.01	0.01	16.00	-2.16	34.16
5418 Ma1	0.01	0.01	-8.00	-29.07	13.07

Days Open - Monsanto

8.3.2 Comments and Conclusions

When the data from 18 groups studied (involving all companies products) were evaluated there was a small but statistically significant (P=0.01) increase (approximately 5 days) in average days open. When only studies based on Monsanto's data were evaluated, a similar effect was observed although it was not quite statistically significant (P=0.066).

The Panel concluded that there was evidence that the average days open would be slightly increased by the use of rbST. This effect was small and amounted only to approximately 5 extra days. However, as with services per conception, days open was only computed for cows which conceived.

8.4 Twinning (Multiple Births)

Twinning is the birth of two calves. In the context of this review, it signifies the birth of two calves at the parturition following the lactation with rbST administration. In general, twin births are considered undesirable because they are much more likely than single births to be followed by complications.

8.4.1 Meta-Analysis

Two meta-analyses were carried out to evaluate the effects of rbST on the risk of twinning

• Effects of rbST on risk of twinning based on studies using all companies' products.
• Effects of rbST on risk of twinning based on studies using Monsanto's product.

. meta val cilow cihigh , ci eform pr gr(r) id(std_lbl) cl xline(1)
ltrunc(.33)rtrunc(12) xlabel(.33, .5, .75, 1, 1.5, 2, 3,6,12 ) b2("Twinning Risk - All Companies") t2("random effects")

Meta-analysis (exponential form)

Effect of rbST on 3.5% FCM

Method	Pooled Est	95% CI Lower	95% CI Upper	Asymptotic z_value	Asymptotic p_value	No. of studies
Fixed	1.314	0.819	2.110	1.132	0.258	5
Random	1.767	0.716	4.362	1.235	0.217

Test for heterogeneity: Q= 12.062 on 4 degrees of freedom (p= 0.017)
Moment-based estimate of between studies variance = 0.647

Effect of rbST on 3.5% FCM

Study	Weights Fixed	Weights Random	Study Est	95% CI Lower	95% CI Upper
7 Mm1	0.94	0.58	11.68	1.54	88.51
7 Mp1	0.88	0.56	7.08	0.88	56.90
168 Ca2	5.55	1.21	1.57	0.68	3.61
5407 Mm1	4.68	1.16	1.45	0.59	3.59
5407 Mp1	5.10	1.19	0.50	0.21	1.18

Twinning Risk - All Companies

. meta val cilow cihigh , ci eform pr gr(r) id(std_lbl) cl xline(1)
ltrunc(.33)rtrunc(12) xlabel(.33, .5, .75, 1, 1.5, 2, 3,6,12 ) b2("Twinning
Risk - Monsanto") t2("random effects")

Meta-analysis (exponential form)

Effect of rbST on 3.5% FCM

Method	Pooled Est	95% CI Lower	95% CI Upper	Asymptotic z_value	Asymptotic p_value	No. of studies
Fixed	1.207	0.679	2.146	0.642	0.521	4
Random	2.083	0.571	7.602	1.111	0.267

Test for heterogeneity: Q= 11.803 on 3 degrees of freedom (p= 0.008)
Moment-based estimate of between studies variance = 1.201

Effect of rbST on 3.5% FCM

Study	Weights Fixed	Weights Random	Study Est	95% CI Lower	95% CI Upper
7 Mm1	0.94	0.44	11.68	1.54	88.51
7 Mp1	0.88	0.43	7.08	0.88	56.90
5407 Mm1	4.68	0.71	1.45	0.59	3.59
5407 Mp1	5.10	0.72	0.50	0.21	1.18

Twinning Risk - Monsanto

8.4.2 Comments and Conclusions

Most of the evidence for, or against, an increased risk of twinning came from the PAMP study (12). The results from that study are split. There appeared to be a decreased risk in primiparous cows and an increased risk of twinning in multiparous cows (although neither were statistically significant). One other study (5) reported a large increases in risk of twinning associated with rbST (relative risks of 7.1 and 11.7 in primiparous and multiparous cows respectively although only the latter was statistically significant). However, cows in this latter study were injected intramuscularly and Monsanto suggests that IM injections resulted in a higher incidence of reproductive problems.

The Panel concluded that there may be an increased risk of twinning but no firm conclusions could be drawn.

8.4.3 Additional Information Required

The problem with assessing the impact of rbST on twinning was the limited number of studies which followed cows through to calving following treatment with the drug. Although the two main studies providing data on the risk of twinning (5,12) had data from a total of 791 cows, one would require data from 2000 cows (1000 cows in each treatment group) to be relatively certain of detecting a doubling of the risk (from 2.5% to 5%).

A recent study published in the Journal of Dairy Science (29) has reported a general increased risk of twinning in Holstein Friesian cows with a rise in the incidence from 1.4% of lactations in1983 to 2.4% in 1993. This paper also identified increased milk production and increased frequency of cystic ovarian diseases as risk factors for increasing the number of twins born. Since rbST increases milk production and appears to increase the risk of cystic ovarian disease (P= 0.11) these may both have contributed to the apparent increased risk of twinning which was observed in most of the studies reported.

8.5 Non-Pregnancy Risk

Many studies reported the proportion of cows which ultimately conceived during the treatment period (reported as a pregnancy rate). In order to be consistent with other health outcomes, the overall effect of rbST on pregnancy has been evaluated in this report as the risk of the cow failing to conceive (i.e. non-pregnancy).

One difficulty in analyzing these data was the problem of identifying which pregnancies occurred before the onset of treatment and which ones occurred afterwards. Whenever possible, data from the two time periods were separated and only those from the treatment period were used in the analysis.

8.5.1 Meta-analysis

Two meta-analyses were carried out to evaluate the effects of rbST on the non-pregnancy risk .

• Effects of rbST on the non-pregnancy risk based on studies using all companies' products.
• Effects of rbST on the non-pregnancy risk based on studies using Monsanto's product.

. meta val cilow cihigh , ci eform pr gr(f) id(std_lbl) cl xline(1)
ltrunc(.33)rtrunc(6) xlabel(.33, .5, .75, 1, 1.5, 2, 3,6 ) b2("Non-Pregnancy Risk - All Companies")

Meta-analysis (exponential form)

Effect of rbST on 3.5% FCM

Method	Pooled Est	95% CI Lower	95% CI Upper	Asymptotic z_value	Asymptotic p_value	No. of studies
Fixed	1.434	1.229	1.674	4.579	0.000	20
Random	1.434	1.229	1.674	4.579	0.000

Test for heterogeneity: Q= 18.968 on 19 degrees of freedom (p= 0.459)
Moment-based estimate of between studies variance = 0.000

Effect of rbST on 3.5% FCM

Study	Weights Fixed	Weights Random	Study Est	95% CI Lower	95% CI Upper
1 Mm1	1.56	1.56	2.73	0.57	13.10
1 Mp1	0.79	0.79	2.89	0.32	26.06
7 Mm1	20.92	20.92	1.34	0.87	2.06
7 Mp1	3.83	3.83	3.84	1.41	10.45
157 Um1	1.85	1.85	3.00	0.71	12.68
157 Up1	2.40	2.40	1.67	0.47	5.92
157 Ua2	5.89	5.89	2.40	1.07	5.38
168 Cm1	5.06	5.06	0.91	0.38	2.17
168 Cp1	3.30	3.30	1.24	0.42	3.65
168 Cm2	3.09	3.09	2.01	0.66	6.13
168 Cp2	1.40	1.40	0.83	0.16	4.35
291 Ua1	10.09	10.09	1.22	0.66	2.26
403 Cp1	13.76	13.76	1.10	0.65	1.87
644 Ma1	2.03	2.03	1.67	0.42	6.60
644 Ma2	2.15	2.15	1.67	0.44	6.35
5403 Ca1	6.34	6.34	3.33	1.53	7.25
5407 Mm1	37.72	37.72	1.42	1.03	1.95
5407 Mp1	12.19	12.19	0.97	0.55	1.70
5418 Ma1	25.06	25.06	1.26	0.85	1.86
5425 M	1.62	1.62	3.75	0.80	17.53

Non-Pregnancy Risk - All Companies

. meta val cilow cihigh , ci eform pr gr(f) id(std_lbl) cl xline(1)
ltrunc(.33)rtrunc(6) xlabel(.33, .5, .75, 1, 1.5, 2, 3,6 ) b2("Non-Pregnancy Risk- Monsanto")

Meta-analysis (exponential form)

Effect of rbST on 3.5% FCM

Method	Pooled Est	95% CI Lower	95% CI Upper	Asymptotic z_value	Asymptotic p_value	No. of studies
Fixed	1.404	1.163	1.696	3.525	0.000	10
Random	1.404	1.163	1.696	3.525	0.000

Test for heterogeneity: Q= 8.678 on 9 degrees of freedom (p= 0.467)
Moment-based estimate of between studies variance = 0.000

Effect of rbST on 3.5% FCM

Study	Weights Fixed	Weights Random	Study Est	95% CI Lower	95% CI Upper
1 Mm1	1.56	1.56	2.73	0.57	13.10
1 Mp1	0.79	0.79	2.89	0.32	26.06
7 Mm1	20.92	20.92	1.34	0.87	2.06
7 Mp1	3.83	3.83	3.84	1.41	10.45
644 Ma1	2.03	2.03	1.67	0.42	6.60
644 Ma2	2.15	2.15	1.67	0.44	6.35
5407 Mm1	37.72	37.72	1.42	1.03	1.95
5407 Mp1	12.19	12.19	0.97	0.55	1.70
5418 Ma1	25.06	25.06	1.26	0.85	1.86
5425 M .	1.62	1.62	3.75	0.80	17.53

Non-Pregnancy Risk - Monsanto

8.5.2 Comments and Conclusions

Although the point estimates of the relative risk of non-pregnancy varied widely across studies, they were quite consistently greater than 1. Overall, the relative risk of non-pregnancy was approximately 1.4 (equivalent to a 40% increase in the risk of non-pregnancy).

One study (30) reported conception data in terms of the hazard ratio for pregnancy (which estimates the risk of a treated cow getting pregnant at a given point in time compared to the risk of a control cow). That study reported a significantly reduced hazard ratios (0.38) which indicates that treated cows were less likely to conceive.

The Panel concluded that the use of rbST in non-pregnant cows increased the risk of the cow not becoming pregnant by approximately 40%. In commercial dairy operations, failure to conceive would normally result in the cow being culled. (See Section 8.9 - Overall Assessment of Reproductive Effects)

8.6 Risk of Abortion

8.6.1 Meta-analysis

Two meta-analysis were carried out to evaluate the effect of rbST on the risk of abortion.

• Effects of rbST on the risk of abortion based on studies using all companies' products.
• Effects of rbST on the risk of abortion based on studies using Monsanto's product.

. meta val cilow cihigh , ci eform pr gr(f) id(std_lbl) cl xline(1)
ltrunc(.33)rtrunc(6) xlabel(.33, .5, .75, 1, 1.5, 2, 3,6 ) b2("Abortion Risk - All Companies")

Meta-analysis (exponential form)

Effect of rbST on 3.5% FCM

Method	Pooled Est	95% CI Lower	95% CI Upper	Asymptotic z_value	Asymptotic p_value	No. of studies
Fixed	1.177	0.751	1.845	0.710	0.478	6
Random	1.165	0.712	1.905	0.608	0.543

Test for heterogeneity: Q= 5.679 on 5 degrees of freedom (p= 0.339)
Moment-based estimate of between studies variance = 0.047

Effect of rbST on 3.5% FCM

Study	Weights Fixed	Weights Random	Study Est	95% CI Lower	95% CI Upper
1 Ma1	1.58	1.47	3.10	0.65	14.77
127 Um1	2.66	2.36	0.47	0.14	1.56
127 Up1	2.63	2.34	1.00	0.30	3.35
127 Um2	1.78	1.64	0.57	0.13	2.48
5407 Mm1	7.59	5.60	1.37	0.67	2.79
5407 Mp1	2.78	2.46	2.00	0.62	6.48

Abortion Risk - All Companies

. meta val cilow cihigh , ci eform pr gr(f) id(std_lbl) cl xline(1)
ltrunc(.33)rtrunc(6) xlabel(.33, .5, .75, 1, 1.5, 2, 3,6 ) b2("Abortion Risk - Monsanto")

Meta-analysis (exponential form)

Effect of rbST on 3.5% FCM

Method	Pooled Est	95% CI Lower	95% CI Upper	Asymptotic z_value	Asymptotic p_value	No. of studies
Fixed	1.666	0.945	2.938	1.765	0.078	3
Random	1.666	0.945	2.938	1.765	0.078

Test for heterogeneity: Q= 0.991 on 2 degrees of freedom (p= 0.609)
Moment-based estimate of between studies variance = 0.000

Effect of rbST on 3.5% FCM

Study	Weights Fixed	Weights Random	Study Est	95% CI Lower	95% CI Upper
1 Ma1	1.58	1.58	3.10	0.65	14.77
5407 Mm1	7.59	7.59	1.37	0.67	2.79
5407 Mp1	2.78	2.78	2.00	0.62	6.48

Abortion Risk - Monsanto

8.6.2 Comments and Conclusions

The definition of abortion and how it was determined varied considerably across studies. However, most of the evidence about the effect of rbST on the risk of abortion was derived from the PAMP study (12) in which abortion was simply defined as "abortion indicated by dairyman".

When all studies were evaluated, there appeared to be no evidence of an increased risk of abortion. However, when only studies based on Monsanto's product were examined, the estimate of the relative risk was 1.67 (P=0.078).

"Fetal loss"was also reported in two Monsanto studies: PAMP and "Multi-location IM study"(4,12). Although not clearly defined, this was presumably based on the loss of rectally confirmed pregnancies. Relative risk of 1.2, 1.11 and 1.78 were reported for PAMP - primiparous, PAMP - multiparous and "Multi-location IM"respectively, but none of the individual estimates were significantly greater than 1.

The overall conclusion of the Panel was that there was some evidence of an increased risk of abortion / fetal loss associated with use of the product but there were inadequate data to draw a firm conclusion.

8.6.3 Additional Information Required

As noted above, there were inadequate data to allow the Panel to come to a firm conclusion about the effect of rbST on the risk of abortion/fetal loss. Studies to provide those data would have to have a consistent process for defining and recording abortions and fetal losses.

8.7 Gestational Length

Gestation length is the time (number of days) from the breeding of conception to the subsequent calving.

8.7.1 Meta-analysis

Two meta-analyses were carried out to evaluate the effects of rbST on gestation length.

• Effects of rbST on gestation length based on studies using all companies' products.
• Effects of rbST on gestation length based on studies using Monsanto's product.

. meta val se , pr gr(r) id(std_lbl) cl xline(0) ltrunc(-10) rtrunc(10)
xlabel(-10, -5, 0 , 5, 10) b2("Gestation length - All Companies") t2("random effects")

Meta-analysis

Effect of rbST on 3.5% FCM

Method	Pooled Est	95% CI Lower	95% CI Upper	Asymptotic z_value	Asymptotic p_value	No. of studies
Fixed	0.021	-0.968	1.011	0.042	0.966	10
Random	-0.402	-2.459	1.655	-0.383	0.702

Test for heterogeneity: Q= 26.632 on 9 degrees of freedom (p= 0.002)
Moment-based estimate of between studies variance = 6.341

Effect of rbST on 3.5% FCM

Study	Weights Fixed	Weights Random	Study Est	95% CI Lower	95% CI Upper
1 Mm1	0.24	0.10	-6.00	-9.97	-2.03
1 Mp1	0.26	0.10	0.00	-3.88	3.88
168 Cm1	0.41	0.11	-1.00	-4.05	2.05
168 Cp1	0.26	0.10	-1.00	-4.88	2.88
168 Cm2	0.15	0.08	1.00	-3.99	5.99
168 Cp2	0.13	0.07	1.00	-4.54	6.54
5298 Ea2	0.03	0.03	-3.00	-13.53	7.53
5407 Mm1	1.99	0.15	1.00	-0.39	2.39
5407 Mp1	0.30	0.10	-4.00	-7.60	-0.40
5422 Mm1	0.15	0.08	8.00	3.01	12.99

Gestation length - All Companies

. meta val se , pr gr(r) id(std_lbl) cl xline(0) ltrunc(-10) rtrunc(10)
xlabel(-10, -5, 0 , 5, 10) b2("Gestation length - Monsanto") t2("random effects")

Meta-analysis

Effect of rbST on 3.5% FCM

Method	Pooled Est	95% CI Lower	95% CI Upper	Asymptotic z_value	Asymptotic p_value	No. of studies
Fixed	0.196	-0.947	1.339	0.336	0.737	5
Random	-0.356	-4.026	3.313	-0.190	0.849

Test for heterogeneity: Q= 25.261 on 4 degrees of freedom (p= 0.000)
Moment-based estimate of between studies variance = 14.065

Effect of rbST on 3.5% FCM

Study	Weights Fixed	Weights Random	Study Est	95% CI Lower	95% CI Upper
1 Mm1	0.24	0.06	-6.00	-9.97	-2.03
1 Mp1	0.26	0.06	0.00	-3.88	3.88
5407 Mm1	1.99	0.07	1.00	-0.39	2.39
5407 Mp1	0.30	0.06	-4.00	-7.60	-0.40
5422 Mm1	0.15	0.05	8.00	3.01	12.99

Gestation length - Monsanto

8.7.2 Comments and Conclusions

The Panel concluded that there was no consistent evidence of an effect of rbST on gestation length.

8.8 Retained Placenta

The proposed label for the product also refers to a possible increased risk of retained placenta in the carry-over period in treated cows. One study (4) which recorded the frequency of retained placenta following treatment with rbST reported a relative risk of 1.6 (P=0.1). The Panel concluded that while there appeared to be some evidence of increased risk of retained placenta, there were insufficient data on which to base a firm conclusion.

8.9 Overall Assessment of Reproductive Effects

The Panel concluded that the use of rbST has some negative effects on reproduction in dairy cows. Treatment was associated with a substantially increased risk of non pregnancy and a small increase in days open in cows which did conceive. The Panel concluded that although there was some evidence of increased risks of cystic ovaries, twinning, retained placenta and abortion/fetal loss, a lack of data precluded firm conclusions being drawn about these four outcomes. Studies which employed a consistent approach to defining and recording these reproductive events would be required to provide such data. There did not appear to be any effect of rbST on the number of services required for cows which did conceive or the length of the subsequent gestation.

8.10 Ability to Control/Eliminate Detrimental Effects

Given that most of the cows in the studies reported were on well managed reproductive programs, the Panel did not feel that current dairy health management practices would be able to control or eliminate the apparent detrimental effects of rbST on reproductive performance if treatment started at approximately day 60 post-calving when most cows are not pregnant. However, since the detrimental effects were primarily related to the breeding of cows, an obvious solution to avoid these problems would be to delay use of the product until cows were confirmed pregnant. Delaying use of the product until after pregnancy has been confirmed would not deal with the potential increased risk of retained placenta or abortion/fetal loss, if those increased risks are confirmed.

8.11 Additional Information Required

In general the panel felt that there was good information available for the two most important measures of reproductive performance: days open and non-pregnancy rate. Unfortunately, there were insufficient data to confirm or rule out possible increased risks of cystic ovaries, twinning, retained placenta, and abortion/fetal loss. Delaying use of rbST until after cows conceive would remove any concern about the possible effects of the drug on cystic ovaries and twinning rates. Additional data from studies with a consistent approach to detecting abortion/fetal loss will be required before firm conclusions about the possible effects of rbST on the loss of pregnancy can be drawn.