Chapter  109:  Sexuality and Reproductive Health Following Spinal Cord Injury

Summary of Findings—Existing Evidence Base

What is the current fertility rate for men and women after SCI? We concluded that there is a sufficient body of literature to complete a comprehensive systematic review and meta-analysis on issues relating to fertility/pregnancy rates/live births in persons with SCI. Although most of these studies only report frequency data and/or percentage of “success,” they report sufficient data to provide meaningful information. Along this suggestion we believe there is sufficient usable data to permit a systematic review and possibly a meta-analysis for other topics such as pregnancy complications and prospective obstetric management.

How has the availability of Viagra® and/or other remediation affected sexual function, frequency of activity, and adjustment after SCI? We concluded that a systematic review and meta-analysis could be carried out specifically addressing treatments available for treating impotence in males with SCI. The permits of such an undertaking would need to be considered in light of the possible duplication of reports we identified. As such, and if not corrected, the estimates from such a meta-analysis could lead to biased estimates of the intervention's effectiveness.

What are the unique issues of sexuality for women after SCI? There is a new and growing body of literature addressing sexual issues in females with SCI. Many of these studies are relatively well designed qualitative interviews and surveys, often involving significant numbers of patients. The literature does address the unique issues of sexuality in women. We did not believe that a systematic review addressing this question would provide additional insights to clinicians and others.

Are there interventions shown to improve sexual responsiveness in women with SCI? There are as of yet few published trials of interventions to improve sexual responsiveness in women after SCI. We did not believe that a systematic review on this topic would provide meaningful information.

What is the optimal sequencing of effective procedures when pursuing fertility in the SCI male? This question is not well addressed in the current literature, except to say that with increasing options available the situation is improving. The literature widely accepts that fertility is not substantially altered in women after SCI. Furthermore, in males, fertility rates can only be deduced in those who choose to be fertile, and will vary according to the degree of pursuit of invasive procedures. However, there is a reasonable body of studies regarding the success rates of individual techniques and a systematic review would help guide clinicians in choosing the order of techniques to apply based on cost, success and potential side effects.

When do people become sexually active after SCI?, What is the frequency of sexual activity in the years post injury?, and When is the most effective time to present information on sexuality after SCI? We found almost no useful literature addressing these questions, although well structured interviews with rigorous attention to qualitative design could answer all three of these questions, i.e., when do patients become active, how active do they become, and when do they want information. Unfortunately, the literature regarding these questions is largely based on the expression of the clinician, rather than the opinion of the patient. Therefore, we concluded that a systematic review would not be useful.

Conclusions

In summary, we identified a reasonably large body of evidence examining different aspects of sexuality and reproductive health following SCI. In general, these studies are of a lower level of evidence and open to several sources of bias. On the basis of this report, AHRQ requested a comprehensive evidence report that incorporates and builds on findings from the Ottawa EPC Phase I Feasibility Study.

Obviously, not all sexual health questions could be addressed in a systematic review of the literature. There are many other noteworthy questions, including questions on impact of quality of life on sexual health, the differences in practice from specialized to general centers, and many questions regarding quality of life and women's sexual health. These questions are not addressed in sufficient thoroughness in the literature to warrant a systematic review. Also, systematic reviews of qualitative literature likely would not add any new insights to this field of practice. This was discussed somewhat in the feasibility study mentioned earlier. The Consortium of Spinal Cord Medicine helped focus this review by posing a series of questions for a systematic review, based on their clinical experience and on the results of the Phase 1 Feasibility Study.

Search Strategy

A search strategy was developed and tested in Medline (Search Strategy 1, Appendix A), and modified as necessary for other databases (Search Strategy 2, Appendix A). The strategy was based on a preliminary strategy proposed by UO-EPC in a feasibility task order, and was modified in consultation with three members of the review team (DD, JB and VC). The strategy was designed to be highly sensitive and was not restricted by study design, language of publication or publication status. Some of the databases searched were nominated by AHRQ in the work assignment, other databases were selected to provide more complete coverage of key journals nominated by the reviewers; for instance, both SocioFile and PsycInfo provide much more complete indexing coverage of the key journal Sexuality and Disability then does Medline, and so these databases were included.

The databases searched were Medline (1966- June Week 1 2003), Premedline (June 13 2003) and CINAHL (1975 to June Week 1 2003) using Search Strategy 1, and Cochrane Central Register of Controlled Trials, (1st Quarter, 2003), SocioFile (1974 to June 2003) and PsycInfo (1887 to June Week 1 2003) using Search Strategy 2.

Following the suggestions of the technical expert panel the proceedings of the following associations were searched for the years 1997 and 2002 (inclusive): American Urological Association, International Society of Sexual and Impotence Research, International Society for the Study of Woman's Sexual Health American Paraplegia Association, American Association of Spinal Cord Injury Nurses, American Association of Spinal Cord Injury Psychologists and Social Workers, American Association of Sex Educators, Counselors and Therapists, American Spinal Injury Association, American Academy of Physical Medicine and Rehabilitation, and American Congress of Rehabilitation Medicine.

At the suggestions of the technical expert panel and in addition to Eli Lilly Canada Inc. (producer of Cialis) and Bayer Group (producer of Levitra), the following manufacturers were also contacted: Unimed Pharmaceuticals Inc., Mentor Corporation, Vivus Inc., Timm Medical Technologies, Schering-Plough Corporation, Pfizer, Sabex 2002 Inc., and Novartis Pharmaceuticals.

The search strategy was identical to that used in the UO-EPC phase 1 feasibility study.

Eligibility Criteria

Table 2. Inclusion criteria

Table 2. Inclusion criteria

Parameter	Reproductive health	Male sexuality
Design	Does the article discuss a fertility intervention; does the article include pre and post intervention fertility rates; does the article contain an original report of a measure of fertility rates in males, females or both; and does the article report an original intervention trial after spinal cord injury?	Does the article report an original intervention trial or series with a pre and post measure for sexual dysfunction after spinal cord injury?; does the article contain an original report of a measure of sexual dysfunction?; and does the article discuss an intervention for sexual dysfunction?
Intervention	Physical: masturbation, intercourse; Device: vibration, electrode ejaculation, home insemination; Prescription medications: sympathetic agonists, physostigmine, etc.; Surgical intervention; vas aspiration, testicular biopsy, ICSI, artificial insemination, spinal cord stimulators; or Laboratory techniques.	Cognitive/behavioral: Masturbation, intercourse; Device: penile rings, vibrators, vacuum devices; Prescription medications: Intracavernous injections, oral, subcutaneous injections, intrameatal MUSE, creams; surgical intervention; penile implants, spinal cord stimulators or hormonal interventions.
Outcome	Pregnancies, live birth rates, sperm motility, successful sperm harvesting, ejaculations, sperm count, % viable sperm, hormonal, ovulation rates, cycle function, other measures of sperm morphology, volume of ejaculation.	Psychological: Validated sexual function questionnaire for males and/or females, structured interviews with qualitative analysis, educational component, global efficiency, or patient logs; or Physiologic: Penile and/or clitoral engorgement, endocrine, ultrasound testing of testicular size.

Study Selection Process

All results of searches for evidence were provided to reviewers for screening against eligibility (inclusion/exclusion) criteria. As an extension of the phase I feasibility study, two reviewers were employed at the relevance assessment phase of the evidence review. Two levels of screening for relevance were used, with the first level directed at bibliographic records during phase I, the feasibility study (i.e., title, authors, key words, abstract), and the second level focused on those “full report” articles retrieved based on the results of the first level of screening.

Screenings for relevance, assessments of study quality, and data abstraction were completed using the UO-EPC's review management Internet-based software which resides on a secure website. In the case of relevance assessment, the software simultaneously presents the bibliographic record to be screened and the eligibility questions with which to do so.

Following a calibration exercise which involved screening ten sample records using an electronic form developed and tested especially for this review (Appendix B), two reviewers independently broad screened the title, abstract, and key words from each bibliographic record for relevance by liberally applying the eligibility criteria. The record was retained if it appeared to contain pertinent study information. If the reviewers did not agree in finding at least one unequivocal reason for excluding it, it was entered into the next phase of the review. The reasons for exclusion were noted using a modified QUOROM format (Appendix C).²⁸ The screening process also identified which of the two questions the record addressed.

Reports were not masked given the equivocal evidence regarding the benefits of this practice.^{29, 30} To be considered relevant at this second level of screening, all eligibility criteria had to be met. Disagreements were resolved by forced consensus and, if necessary, third party intervention. Excluded studies were noted as to the reason for their ineligibility (see List of Excluded Studies at the end of the report).

Overview

The evidence is presented three ways. Evidence tables in the appendices offer a detailed description of the included studies (e.g., study design, population characteristics, intervention/exposure characteristics), with a study represented only once. The tables are organized by research question and design (e.g., RCTs with male sexuality interventions; observational studies examining male sexuality interventions; observational studies examining fertility rates; etc.).

Question-specific summary tables embedded in the text report each study in abbreviated fashion, highlighting some key characteristics, such as comparators and sample size. This allows readers to compare all studies addressing a given question. A study can appear in more than one summary table given that it can address more than one research question.

Study Quality

Evidence reports include studies of variable methodological quality. Differences in quality across and within study designs may indicate that the results of some studies are more biased (i.e., systematic error) then others. Systematic reviewers need to take this information into consideration to reduce or avoid bias whenever possible. There is considerable evidence that low-quality reports, compared with higher quality ones, can introduce bias into the estimates of an intervention's effectiveness.³¹ In this report, study quality was assessed through examination of each individual report. No attempt was made to contact the authors of any report. Quality was defined as the confidence that the study's design, conduct, analysis, and presentation has minimized or avoided biases in any comparisons.³² Several approaches exist to assess quality: components, checklists and scales. For this report, we have elected to use a combination of methods in an effort to ascertain a measure of reported quality across different study designs.

For RCTs the Jadad scale was used (Appendix D). This validated scale includes three items that assess the methods used to generate random assignments, double blinding, and a description of dropouts and withdrawals by intervention group.³³ The scoring ranges from one to five, with higher scoring indicating higher quality. In addition, allocation concealment [i.e., keeping the randomization blind until the point of allocating participants to an intervention group] was assessed as adequate, inadequate or unclear (Appendix D).³⁴ An a priori threshold scheme was used for sensitivity analysis: a Jadad total score of ≤ 2 indicates low quality with scores > 2 indicating higher quality; for allocation concealment, adequate = 1, inadequate = 2 and unclear = 3.

Cohort and case-control study reports were assessed using the Newcastle-Ottawa scale (NOS). The NOS is an ongoing collaboration between the Universities of Newcastle, Australia and Ottawa, Canada. It was developed to assess the quality of nonrandomised studies with its design, content and ease-of-use directed to the task of incorporating the quality assessments in the interpretation of meta-analytic results. A “star system” has been developed in which a study is judged on three broad perspectives: the selection of the study groups; the comparability of the groups; and the ascertainment of either the exposure for case-control studies, or the outcome of interest for cohort studies. The goal of this project is to develop an instrument providing an easy and convenient tool for quality assessment of nonrandomised studies to be used in a systematic review.

The inter- and intra-rater reliability of the NOS have been established. The face content validity (i.e., the extent to which the instrument appears reasonable on superficial inspection) of the NOS has been reviewed based on a critical review of the items by several experts in the field who evaluated its clarity and completeness for the specific task of assessing the quality of studies to be used in a meta-analysis. Further, its criterion validity has been established with comparisons to more comprehensive but cumbersome scales. The NOS developers continue to develop appropriate measurement properties for the instruments' development.²⁷ Quality assessments of non-comparative case series reports were assessed using a 19-item instrument adapted from Opthalmology (Appendix D).² We did not conduct any sensitivity analysis of quality assessments on the observational studies, as there is little by way of guidance to suggest what a poor quality study's score would be based on for these assessment instruments.

Qualitative Data Synthesis

A qualitative synthesis was completed for all studies included in the evidence report. A description is provided of the progress of each citation through the review process, and includes information pertaining to each report, such as their sample size. The qualitative synthesis was performed on a question-specific basis, with studies grouped according to research design (e.g., RCTs, observational studies). Each synthesis includes a narrative summary of the key defining features of the study report, if stated, (e.g., a priori description of inclusion/exclusion criteria), population (e.g., diagnosis-related), intervention/exposure (e.g., use of Viagra®), outcomes, study quality, applicability, and individual study results. A brief study-by-study overview typically precedes a qualitative synthesis.

Quantitative Data Synthesis

For several of the questions investigated in this evidence report, quantitative data synthesis was deemed appropriate. However, most of the studies were non-comparative case series and outcomes were in the form of single proportions (e.g. proportion of couples achieving at least one pregnancy). Current meta-analytic methodology generally focuses on data from studies that include a control group, such as randomized controlled trials. From a meta-analytic perspective, one of the strengths of studies that include control groups is that even if there is some degree of heterogeneity in characteristics such as population or intervention across studies, there may be little statistical heterogeneity in the contrast between outcomes in the treatment and control groups across studies. This protection against heterogeneity is not available in studies without a control group. Judicious selection of comparable studies for inclusion in a meta-analysis of single proportions therefore becomes especially crucial. Random effects techniques for pooling results attempt to adjust for the presence of statistical heterogeneity, but necessarily provide weaker inferences, and do not obviate the need for careful investigation of sources of statistical heterogeneity.

In the present work, heterogeneity of single proportions was assessed using Pearson's chi-square test. P-values less than 0.10 were taken to indicate statistically significant heterogeneity. Forest plots were constructed using Wilson score confidence intervals around individual study proportions.³⁵ Pooled estimates and their confidence intervals were obtained using the random effects estimator of Laird & Mosteller.³⁶

Fertility in Females After SCI

There were no studies found that investigated this question.

Fertility in Males After SCI

We identified 22 non-comparative case series, including 806 men, which addressed ejaculation rates in men with SCI using vibration or electroejaculation.^38–59 Three other case-series studies directly examined differences between the two techniques.^60–62 We identified two articles that described the details of electroejaculation techniques and precautions in SCI males; however, these studies did not specifically address any of the questions posed by the consortium.^{63, 64}

Several authors reported results of electroejaculation and/or vibration studies using numerical breakdowns that could not be pooled.^{24, 65, 66} Koletis et al. described his clinical results with electroejaculation in some detail, but did not define the ejaculatory outcomes well, or report the incidence of side effects.²⁴ Likewise, several abstracts either did not describe results in sufficient detail to abstract the data,^{65, 66} or more complete description of the data was found in other publications.⁶⁷

The use of physostigmine injection for ejaculation is described in two articles involving 57 SCI males.^{68, 69}

We identified 18 non-comparative case series, including 398 couples, reporting on pregnancies and/or live births.^{41, 44, 48, 50–55, 57–59, 69–74} One additional case series describing IVF after electroejaculation included SCI patients but did not adequately breakdown the success rates by diagnosis.⁷⁵

Nine studies involving 294 SCI males were designed to look at specific effects of medical and physical factors on SCI male fertility;^{56, 76–83} however, these studies did not specifically address any of the questions posed by the consortium.

Five studies reporting on 69 SCI males described other more invasive techniques used to harvest semen.^84–88

Finally, a further 12 articles reported on semen examination techniques or on various semen characteristics in SCI males, often to further delineate reasons for infertility and discuss possible treatments.^{83, 89–99} However, these studies did not address specifically any of the questions posed by the consortium. These articles are referred to again in the discussion as they highlight treatment implication.

Interventions for Female Sexual Dysfunction

We identified seven studies—six case-control studies^{6, 100–104} and one RCT¹⁰⁵—including 132 females with SCI, that addressed interventions for female sexual dysfunction.

Male Sexual Dysfunction

We identified four studies, of which three were non-comparative case-series studies^106–108 and one was a placebo-controlled clinical trial,¹⁰⁹ that evaluated the use of topical agents (n = 53 patients) for sexual dysfunction in men with SCI. Eight studies, all of which were non-comparative case-series studies, examined intracavernous injections (n = 273).^110–117 Five case-series studies evaluated penile implants (n = 363).^118–122 Nine studies, of which two were RCTs^{123, 124} and seven were case-series studies,^125–131 evaluated Viagra® (n = 627). The remaining studies examined the use of other interventions for male sexual dysfunction including: behavioural methods (one case series¹³²; n = 10); intraurethral Alprosatadil (two non-comparative case series;^{133, 134} n = 30); vacuum devices (two case series;^{135, 136} n = 50); sacral stimulators (one case series;¹³⁷ n = 33); side effects associated with Viagra® (10 studies—five RCTs^{123, 138–141} and five case-series studies^{126–128, 130, 131}) and, side effects associated with intracavernous injections of prostaglandin and/or papaverine (seven studies—six non-comparative case-series^{112, 113, 115–117, 142} and one RCT;¹⁴³ n = 287). In one methodological article, rectal probe electrical stimulation is described as a treatment for erection.⁶⁴ In 1998, Potter¹⁴⁴ describes a non-statistical trend to improvement in sexual function with fampiridine SR (4-aminopyradine) in a small group of 29 patients.

We identified two studies that described the psychosocial benefits of treating impotence in SCI males;^{145, 146} however, these studies did not specifically address any of the questions posed by the consortium. In 1992, Jaworski and colleagues used a case-control study design to describe a positive impact on marital relationships in 30 couples post-penile implant or intracavernous injection, and in 1993, Richards et al. used a noncomparative case-series design to describe similar results in 17 couples.^{145, 146} Both emphasized the need for a wider approach to treating relationship issues after SCI, rather than emphasizing erectile function alone.

Fertility in Females After SCI

There were no studies found that investigated this question.

Fertility in Males After SCI

Ejaculation rates. Different aspects of male infertility have been studied. Reports in the literature on this topic can be grouped, and some information pooled. Much of the earlier work in this area centers around interventions to aid males with SCI to ejaculate, either during sexual activities with their partners or in a clinic situation to harvest semen for implantation. Different authors and clinics have chosen different methodologies to aid ejaculation in males with SCI. They include intrathecal or subcutaneous physostigmine with masturbation, penile vibration techniques with or without pharmacologic enhancement, or electroejaculation.

In 1992, Leduc et al.⁶⁹ published the largest study to date of physostigmine in 37 patients with SCI. Side effects included ten episodes of autonomic dysreflexia, five episodes of nausea and vomiting, one episode of hallucination and one episode of dizziness. Patients required multiple medications to inhibit the side effects of physostigmine. Only antegrade ejaculation was counted and the success rate was 54%. The success rate of physostigmine was lower then that obtained with the other techniques described below, and physostigmine also demonstrated a significantly higher side-effect profile. This drug is now very difficult to obtain and this procedure should be considered for historical reference only.

Summary Table 1. Success rates of various techniques (more...)

Summary Table 1. Success rates of various techniques used to obtain semen in men with SCI

Author, Year	Study Design	Number of patients	Technique	Success rates	Quality
Bensman & Kottke, 1966	Noncomparative case series	5	Electrostimulator	Sperm obtained in 3/5 from retrograde ejaculate; no motile sperm in 2/5; in 1/3 with 410K sperm/cm4, 20–30% of the sperm had abnormal forms	4/19
Brackett et al., 2000	Case-control	12	Vas aspirated to ejaculated sperm	Vas aspirated sperm motility and viability plus or minus standard error of mean were significantly higher than mean ejaculated sperm motility and viability (54.4% +/- 5.0% and 74.1% +/- 5.3% versus 14.1% +/- 2.6% and 26.1% +/- 4.9%, respectively)	7* (NOS)
Brindley et al., 1986	Noncomparative case series	12	Implanted sperm reservoir	8 pts (67%) motile spermatozoa were recovered	6/19
				2 pregnancies (17%) achieved with subsequent live births (by AIH).
Hirsch et al., 1994	Case-control	10	Testicular biopsy	Spermatogenesis similar between SCI men and controls	4* (NOS)
Perkash et al., 1985	Noncomparative case series	30	Electrical stimulator	Sperm count in n=18 men >40 million	7/19
				Total sperm count in 22 pts >20 million
				Normal Sperm morphology: mean 55%, range 40–75%
				Sperm progressive motility <20% in 27 of 35 specimens
				No motile in 10 specimens & less than 10% motile in 13; 10%–20% motile in 4 pts; >30% motile in 5 pts

NOS = Newcastle Ottawa Scale

Figure 1. Meta-Analysis—Ejaculation

   Figure 1. Meta-Analysis—Ejaculation

Forest plot of the success rate of vibration and/or electrode stimulation in noncomparative case-series studies that reported ejaculation as an outcome. The data was pooled and the overall estimate and its confidence interval was calculated using the random effects estimator of Laird & Mosteller.³⁶ Quality scores are out of a possible 19. Estimates from studies prior to 1993 are denoted by open circles. Only results from the past 10 years (1993-2003) were pooled to account for changes in techniques and technology.

Figure 1

Pregnancies and live births. Not all authors chose to present both pregnancy and live birth data. However, there is no suggestion in the literature that the spontaneous abortion rate of a pregnancy conceived from an SCI male exceeds that of the general population; therefore, we chose to combine both sets of data. These results represent the number of couples who have achieved at least one pregnancy or live birth over the number of couples who tried to conceive. It is very important to note that some authors reported their fertility rates after very simple procedures such as vibration or electrode ejaculation, whereas some studies were performed in clinics that greatly increased the odds of achieving pregnancy by adding a variety of advanced fertility techniques.

Seventeen studies published between 1987 to 2001, involving a total of 400 patients from the US, UK and Australia, have documented pregnancy rates.^{41, 44, 44, 48, 48, 50, 51, 51, 52, 52–54, 54, 55, 55, 57–59, 59, 69, 69–71, 71, 72, 72–74, 147} Thirteen studies published between 1991 to 2001, involving a total of 341 patients from Canada, US, UK and Australia, have documented live-birth rates.⁷⁰ Eleven of these studies overlap and report both pregnancy and live-birth rates.^{44, 48, 51, 52, 54, 55, 59, 69–72}

Figure 2. Meta-Analysis—Pregnancy

   Figure 2. Meta-Analysis—Pregnancy

Forest plot of the success rate for pregnancy in the noncomparative case-series studies that reported pregnancy as an outcome. The data was pooled and the overall estimate and its confidence interval was calculated using the random effects estimator of Laird & Mosteller.³⁶ Quality scores are out of a possible 19. Estimates from studies prior to 1993 are denoted by open circles. Only results from the past 10 years (1993-2003) were pooled to account for changes in techniques and technology.

Summary Table 3. Success rates and complications observed (more...)

Summary Table 3. Success rates and complications observed with electroejaculation and/or vibration

Author/Year	Procedure	Success Ratio*	Complications
Sarkarati et al. (1987)	Vibration	29/34	Pain in 4/34 pts.(electroejaculation)
	Electroejaculation		Minor headache and/or 20 to 40 mm.Hg increase in systolic BP occurred in a few patients (autonomic dysreflexia)
Pryor et al. (1995)	Vibration	6/6	Case 1: headaches and spasticity due to ephedrine, switched to imipramine
	Case 1: ephedrine, imipramine, sodium bicarb.		Case 2: NR (not recorded)
	Case 2: ephedrine and sodium bicarb, imipramine and sodium bicarb		Case 3: NR
	Case 3:		Case 4: NR
	Case 4: ephedrine and sodium bicarb		Case 5: NR
	Case 5:		Case 6: NR
	Case 6: intra-uterine insemination
Lim et al. (1994)	Electroejaculation	12/12	“No incidence of severe hypertension due to autonomic dysreflexia”
	Vibration		“Post-electroejaculation proctoscopy showed no damage to the rectal mucosa of any patient”
			“1 patient had significant problems with recurrent urinary tract infections”
			“1 pt complained of severe stomach cramps during electroejaculation”
VerVoort et al. (1988)	Electroejaculation	7/7	“All patients complained of headache/blurred vision/sweating/flushing and increased BP with no nifedipine”
			“Autonomic hyperreflexia effects reduced during electroejaculation with nifedipine”
Sonksen et al. (1994)	Vibration	58/66	“Population I: 4 pts had light headache/no increase in BP;1 pt had glycerine nitrate sublingual”
	Population I - 25 pts.(Vibrator A, no nifedipine)		“Population II - no discomfort”
	Population II - 41pts.(Vibrator B, nifedipine sublingual prophylactically)
Heruti et al. (2001)	Electroejaculation	14/14	Abdominal pain or spasm in 17 stimulations
			raised BP in 15 stimulations
			3 cases of increased spasm
			1 case of syncope
			occurred in total of 16 patients, no tx needed, no further complications
Brindley (1981)	Electroejaculation	50/84	7 pts experienced intolerable pain - procedure stopped
Halstead et al. (1987)	Electroejaculation	10/12	Mild dysreflexia (3pts) disruption of normal bowel program (1 pt)
Rawicki & Hill (1991)	Electroejaculation	24/38	Electroejaculation: autonomic hyperreflexia in pts with high lesions; pain in pts with low lesions
	Vibration		Vibration: autonomic hyperreflexia in pts with high lesions; 1pt with superficial ulcer; 2 pts with superficial trauma to the glans resulting in bruising
	Subcutaneous physostigmine		Subcutaneous physostigmine: blurring vision (4/5); nausea and vomiting (2/5); marijuana-like highs (2/5)
	24 pt total
	(3 pt had electroejaculation under general anaesthetic due to pain)
	pts with lesions above C7 treated with labetolol 100mg or nifedipine 10mg

*

success of ejaculation

Figure 3. Meta-Analysis—Live Birth

   Figure 3. Meta-Analysis—Live Birth

Forest plot of the success rate of live birth in noncomparative case-series studies that reported live birth as an outcome. The data was pooled and the overall estimate and its confidence interval was calculated using the random effects estimator of Laird & Mosteller.³⁶ Quality scores are out of a possible 19. Estimates from studies prior to 1993 are denoted by open circles. Only results from the past 10 years (1993-2003) were pooled to account for changes in techniques and technology.

Summary Table 4. Pregnancy and live birth rates for (more...)

Summary Table 4. Pregnancy and live birth rates for studies that used AF techniques compared with those that did not

Study	N	AF vs non-AF	Pregnancies	Live births
Brackett 1995	23	AF	11/23 (48%)	8/23
Brinsden, 1997	35	AF	18/35 (51%)	14/35
Dahlberg, 1995	35	AF	18/35 (51%)	14/35
Elliot, 2002	73	AF	NR	45/73
Heruti, 2001	33	AF	18/33 (55%)	18/33
Hultling, 1997	25	AF	16/25 (64%)	11/25
Nehra, 1996	33	AF	17/33 (52%)	17/33
Pryor, 1995	6	AF	5/6 (83%)	NR
Pryor, 2001	11	AF	8/11 (73%)	NR
Taylor, 1999	19	AF	14/19 (74%)	NR
Beretta, 1996	6	non-AF	3/6 (50%)	NR
Buch, 1993	6	non-AF	NR	2/6
Chung, 1997	27	non-AF	7/27 (26%)	4/27
Halstead, 1987	10	non-AF	0/11 (0%)	NR
Hultling, 1994	12	non-AF	6/12 (50%)	2/10
Leduc, 1992	6	non-AF	3/6 (50%)	3/6
Lucas, 1991	10	non-AF	1/10 (10%)	1/7
Sonksen, 1997	28	non-AF	10/28 (36%)	9/28

NR=not reported

Figure 2

Figure 3

Are Fertility Rates Changed After Freezing a New Patient's Sperm?

Summary Table 2. Study examining the impact of freezing (more...)

Summary Table 2. Study examining the impact of freezing sperm

Author, Year	Study Design	Number of patients	Fertility Rate	Quality
Padron et al., 1994	Controlled clinical trial	9	Frozen sperm from SCI men retain motility similar to that of normal men	Not applicable (non-RCT)

Are There Better Fertility Rates Using Electroejaculation or Vibration? Does Order of Method Influence Outcome?

We identified four trials that directly compared vibration and electroejaculation for inducing ejaculation in SCI males.^{60–62, 149} In a controlled clinical trial published in 1997, Brackett et al.⁶¹ collected semen using vibration and/or electroejaculation from 77 males with SCI. Although total semen volume and sperm counts were similar, the percent motile sperm and percent sperm with rapid linear motion were significantly higher in the vibration-induced samples. This was observed for the vibration compared to electroejaculation groups, as well as within the ten patients who had both procedures performed. This study was a non-RCT and therefore could not be quality assessed using the Jadad scale.

In the same year, Ohl et al.⁶⁰ published results from an RCT that used both vibration and electroejaculation in a random fashion to obtain ejaculate from 11 males with SCI. They found that the antegrade specimen of the vibration-induced ejaculate had a higher quality (i.e., more motility) than the electroejaculate-induced antegrade specimens, however, the electroejaculated group had a higher retrograde volume, evening out the total motile sperm count (greater total volume in electroejaculated samples, better quality in vibration induced samples). The authors reported that the electroejaculate group experienced more pain, and all patients preferred the vibration procedure. This study received a quality score of 2/5 on the Jadad scale.

In 1998, Le Chapelain¹⁵⁰ analysed semen samples from 39 male SCI subjects and described improved semen quality with vibration-induced ejaculation compared with either electroejaculation or physostigmine.

Finally, Park et al.⁶² reported an abstract in 1999 that used a case-control design to examine both electroejaculation and vibration in 17 males with SCI. Although sperm quality was superior using vibration, this technique was unsuccessfull for those with lesions at and below T10, requiring electroejaculation to be used with the lower lesions.

Figure 1

To Improve Fertility Rates, When Should Invasive Techniques Such as Testicular Biopsy or Intracytoplasmic Sperm Injection be Used?

Figures 2

3

Are There Pregnancy Complications and Prospective Obstetric Management Issues for SCI Females?

We did not find any reports that provided the necessary data for us to project the number and frequency of complications and other obstetric issues in females with SCI. There are numerous case reports, however, without the larger sample size obtained with a case-series study, it is difficult to conduct further research or inform practice or policy regarding this important health issue.

Interventions for Female Sexual Dysfunction

Summary Table 5. Studies examining various interventions (more...)

Summary Table 5. Studies examining various interventions for female sexual dysfunction

Author, Year	Study Design	Number of Patients	Quality Score
Whipple, 1996	Case-control	21 (16 SCI/5 controls)	6* (NOS)
Komisaruk et al., 1997	Case-control	21 (16 SCI/5 controls)	6* (NOS)
Sipski et al., 1995a	Case-control	21 (13 SCI/8 controls)	6* (NOS)
Sipski et al., 1995b	Case-control	35 (25 SCI/10 controls)	5* (NOS)
Sipski et al., 1996	Case-control	20 (10 SCI/10 controls)	7* (NOS)
Sipski et al., 2001	Case-control	89 (68 SCI/21 controls)	5* (NOS)
Sipski et al., 2000	RCT	19	2/5 (Jadad)

The studies by Komisaruk et al.¹⁰³ and Whipple et al.,¹⁰⁴ appear to be separate reports on the same cohort of 16 women with SCI (n = 6 with upper SCI, n = 10 with lower SCI). In a case-control study published in 1997, Komisaruk and colleagues¹⁰³ measured altered pain thresholds with genital stimulation in 16 SCI and five non-SCI females. The authors found that similar to their able-bodied counterparts, pain thresholds were increased with genital self-stimulation even in women with complete SCI. This finding led the authors to postulate that in the women with upper SCI, genitospinal visceral afferent pathways function (although unrecognized by the American Spinal Injury Association criteria) and/or there exists a functional genital afferent pathway that bypasses the spinal cord and projects directly to the brain. Whipple and colleagues¹⁰⁴ studied the 16 SCI females in the laboratory during self-stimulation and reported that only those with lesions below T-10 experienced increases in blood pressure; no SCI subjects had alterations in heart rate. Three females with complete SCI experienced orgasm with genital self-stimulation.

Sipski has published four case-control studies examining this topic in the most detail.^{6, 100–102} It is unknown, however, whether all of these patients represent new or restudied patients, although the outcome measures are different between the studies as the author is examining different phenomena. In 1996, Sipski et al.¹⁰² demonstrated that even in females with supposedly complete SCI (n = 10), manual genital stimulation increased their sexual arousal, although requiring a higher level of concentration than able-bodied controls (n = 10). In a later study, Sipski et al.⁶ demonstrated that with manual and audiovisual stimulation combined, greater than 50% of SCI women (n = 68) experienced orgasms that could not be differentiated from able-bodied controls (n = 21). Those with complete lower motor neuron dysfunction affecting S2–S5 had the lowest orgasm rate, and those with preservation of sensory function in dermatomes T11-L2 had greatest preservation of psychogenic-mediated sexual function. In another study, Sipski et al.¹⁰¹ found similar orgasm rates among SCI women, with higher orgasm rates observed among women stimulated with a vibrator and among women who reportedly had higher sexual drive and greater awareness of their anatomic sexual function. Finally, Sipski et al.¹⁰⁰ demonstrated that women with complete SCI could respond with audiovisual stimulation in those physiologic functions that are controlled above the level of their injuries, whereas genital physiologic response could only be achieved by stimulation below the level of the injury. Overall, Sipski advocates using these data for behavioral counselling in SCI women, to help them achieve a higher level of sexual satisfaction by learning how their body works sexually after SCI.

The six case-control studies that addressed interventions for female sexual dysfunction all scored equal to, or above five on the NOS, with the highest score of seven obtained by Sipski et al.¹⁰²

Summary Table 8. Case-series evidence for the use of (more...)

Summary Table 8. Case-series evidence for the use of penile implants for erectile dysfunction in men with SCI

Author, Year	N Implants	Complications	Quality Score
Golji, 1979	30	2 cases infection causing extrusion	7/19
		2 cases wound infections treated conservatively
Green & Sloan, 1986	40	3 cases extruded rods	7/19
		1 case penile erosion
Gross et al., 1996	209	14 cases requiring removal of implant	5/19
		21 cases rod perforation
Iwatsubo et al., 1986	37	2 cases infection causing extrusion	5/19
		1 case severe pain
		1 case mechanical failure
Montague, 1994	47	2 cases infection requiring removal	6/19
		1 case penile erosion requiring removal
		2 cases mechanical failure

Male Sexual Dysfunction

Aside from a number of RCTs evaluating Viagra®, all of the studies that we identified which addressed this topic were case-series studies. The most common problems faced when trying to analyze this literature is that many authors chose different outcome measures. For example, some authors use a validated erectile grading system such as Schramek's, whereas others used their own grading system; some authors used all or parts of the IEFF sexual satisfaction rating scale, whereas others designed their own scales. When authors use either an on/off grading system or a common question on the IEFF, we have pooled the data when appropriate.

Behavioral interventions. We found only one study, a case-series study, that examined behavioral interventions.¹³² Courtois et al.¹³² demonstrated improvement in penile rigidity in ten SCI males before and after biofeedback followed by home perineal muscle training exercises. No measurements of sexual satisfaction were incorporated into the study. The quality score was 11/19.

Summary Table 6. Evidence for the use of vasoactive (more...)

Summary Table 6. Evidence for the use of vasoactive agents to stimulate erection in men with SCI

Author, Year	Topical Substance	Response	Quality Assessment
Beretta, 1993	Transcutaneous Minoxidil	4/15 had full erections	8/19
Kim & McVary, 1995	Topical prostaglandin	2/9 had clinical erections	10/19
Kim et al, 1995	Topical papaverine gel	3/12 had full erections	Not applicable (non-RCT)
Sonsken, 1992	Nitroglycerine patch	5/17 had full erections	7/19

Summary Table 7. Evidence for the use of intraurethral (more...)

Summary Table 7. Evidence for the use of intraurethral Alprostadil to stimulate erection in men with SCI

Author, Year	N	Results	Quality Assessment
Bodner, 1999	15	3/15 achieved erections sufficient for intercourse	8/19
Waldbaum, 1998	15	4/15 achieved erections sufficient for intercourse	Not applicable (abstract)

Intracavernous injections. Intracavernous (penile) injections of vasoactive substances have reported to treat SCI male impotence in the literature for several decades. Injected substances include papaverine, phentolamine, prostaglandin E1, or combinations of two or three of the above. Many clinics use combination therapy (papaverine, phentolamine, prostaglandin E1) for economic reasons, and there is no clear difference in efficacy between these substances.

Figure 4. Meta-Analysis—Intracavernous Injections (more...)

   Figure 4. Meta-Analysis—Intracavernous Injections

Forest plot of the success rate of intracavernous injections in noncomparative case-series studies that reported satisfactory erections as an outcome. The data was pooled and the overall estimate and its confidence interval was calculated using the random effects estimator of Laird & Mosteller.³⁶ Quality scores are out of a possible 19.

Figure 4

The studies by Zaslau et al.¹¹⁵ and by Sidi et al.¹¹⁶ were performed in individuals with SCI and either hypertension or diabetes. These studies found that the combination of SCI and another comorbidity decreases the efficacy of the injections.

The quality of these studies ranged from 6/19 to 13/19. Thirty-eight percent of the intracavernous injection studies met 11 of 19 (58%) quality criteria, with the highest score obtained by Sidi et al.¹¹⁶

Vacuum tumescence devices. We found only two case-series studies that examined external vacuum pump devices for erectile dysfunction in males with SCI.^{135, 136}

In 1989, Zasler et al.¹³⁵ studied a novel vacuum pump system (Synergist) that uses a silicon sheath in 20 males with SCI, and reported that patient and partner assessments of the device efficacy and sex-life satisfaction with the device were very good to excellent. Although the device was required to stay on during intercourse, all patients in the study had complete SCI and therefore diminished sensation was not an issue. However, the silicon sheath did provide some protection for the partner. No side effects were reported. This report received a 13/19 quality assessment score. It is not known whether this device is still marketed.

In 1992, Heller et al.¹³⁶ studied two similar commercially available vacuum-pump systems in 30 males with SCI. All 30 subjects were trained on how to use the device in the clinic, and then 17 opted to purchase the device and use it at home. All 17 couples were satisfied with using the device during sexual activity. Some patients experienced transient testicle swelling (n = 3) and some experienced transient petechial hemorrhages (n = 5), although all of these side effects were resolved within 1 hour of use. This report received a quality assessment score of 8/19.

Sacral stimulators. Sacral stimulators have been championed by Brindley and others as a method of achieving continence with low voiding pressures in patients with complete SCI In general, the procedure is reserved for complete injuries since it necessitates a sacral rhizotomy with loss of a reflex erection, reflex voiding, or defecation; Brindley describes the stimulator as a way of voluntarily controlling these functions. We identified a single case-series study¹³⁷ that reported erection rates in SCI males treated with sacral stimulators for bladder control. van der Aa et al.^137–152 reported that 29 of 33 subjects with implants could achieve a full sustainable erection by stimulating the S2 or S3 anterior routes. The report of this case-series study did not, however, state how the stimulator-induced erection impacted sexual function, or if there were side effects such as bladder or bowel incontinence during sexual activity. The study by van der Aa et al.¹³⁷ received a 5/19 quality assessment score.

Summary Table 9. RCT evidence for the use of Viagra® (more...)

Summary Table 9. RCT evidence for the use of Viagra® for sexual dysfunction in men with SCI

Author, Year, Location	Number of subjects (N);	Results	Adverse Events	Quality Score
	Number of dropouts (D)
Giuliano et al., 1999 France, U.K., Australia	N=178	76% improved erections and a preference for Viagra® vs 4% for placebo	Headache: Viagra®=30, placebo=8	3/5 (Jadad)
	D=7		Flushing: Viagra®=12, placebo=2
			Dyspepsia: Viagra®=5, placebo=0
			Visual effects: Viagra®=4, placebo=0
			Rhinitis: Viagra®=3, placebo=0
Maytom et al., 1999, UK	N=27	Erections in clinic >60% at base: Viagra®=65%; placebo=8%	Headache: Viagra®=4, placebo=1	3/5 (Jadad)
	D= 0	Global Efficacy Question (did treatment improve erections?): Viagra®=75%; placebo=7%	Dyspepsia: Viagra®=1, placebo=0
			Vomiting: Viagra®=1, placebo=0
			Dizziness: Viagra®=1, placebo=0
			Rash: Viagra®=2, placebo=3

Figure 5. Meta-Analysis—Viagra®

   Figure 5. Meta-Analysis—Viagra®

Forest plot of the use of Viagra® in noncomparative case-series studies that reported improved erectile function as an outcome. The data was pooled and the overall estimate and its confidence interval was calculated using the random effects estimator of Laird & Mosteller.³⁶

Figure 4

Is Viagra Really More Benign Than Intracavernous Injections?

Summary Table 10. Side effects associated with the (more...)

Summary Table 10. Side effects associated with the use of intracavernous injection or Viagra® for sexual dysfunction in men with SCI

Author, Year	Intervention (number of pts)	Side Effects (number of pts)
Anonymous, (1999)	Viagra® (26)	2 pts with dyspepsia and respiratory disorder
Clontz et al., 1999 (abstract)	Viagra® (12)	visual changes (1) and headache (3)
Derry FA et al., (1998)	Viagra® (27), vibration	headache (4)
		dyspepsia (1)
		dizziness (1)
		anxiety (1)
Giuliano et al., (1999)	Viagra® (178)	headache (30)
		flushing(12)
		dyspepsia(5)
		rhinitis (3)
		abnormal vision (4)
		discontinued treatment (6)
Kier et al., 1999	Viagra® (29)	visual change (3%)
		headache (17%)
		dizziness (3%)
		flushing (3%)
Laschke et al., (abstract, 2002)	Viagra® (69)	headaches and flushing (25%)
Sanchez et al., 2001	Viagra® (170)	headache (10)
		flushing (15)
		GI discomfort (7)
		nasal congestion (8)
		visual disturbances (7)
		restlessness, palpitations, hiccup, dry mouth (9)
		unbearable abdominal pain (1)
Schmid et al., 2000	Viagra® (41)	headache(3) or dizziness(2)
		flushing (2)
		dyspepsia (1)
		blurred vision (1)
		2 withdrew because of adverse events
Shenot et al., 1999 (abstract)	Viagra® (29)	headache (7%)
		flushing (7%)
Takeda et al., 2000 (abstract)	Viagra® (36)	headache, facial flush, chest strangled feeling
Beretta et al., 1986	Papaverine (22)	7 pts with prolonged erections
Earle et al., 1992	Papaverine, papaverine & phentolamine, prostaglandin E1 (22)	pain with 2 pts, one using papaverine one using papaverine and phentolamine
Hirsch et al., 1994	Prostaglandin E1 (14)	2 pts with subclinical corporal fibrosis
Kapoor et al., 1993	Papaverine: 101 volunteers, 65 papaplegics, 36 tetraplegics	3 subcutaneous haematoma, 2 cavernosal fibrosis, 3 prolonged erection, 1 systemic effects
Renganathan et al., 1997	Transdermal nitroglycerin vs papaverine (28)	9 pts complications with papaverine: 8 had mild edema, 1 pt with prolonged erection
Sidi et al., 1987	Papaverine HCl, or combo papaverine/phentolamine mesylate (66)	4 pts with sustained erections that required irrigation
Tang et al., 1995	Prostaglandin E1 (15)	2 pts pain at injection site
Zaslau et al., 1999	Fixed combo of prostaglandin E1 and papaverine (37)	2 pts stopped due to pain/ecchymosis at injection site

How Does the Morbidity of Prostaglandin Injections Compare With the Older, Less Expensive Papaverine or Phentolamine

Summary Table 11. Side effects associated with intracavernous (more...)

Summary Table 11. Side effects associated with intracavernous injections

Author, Year	N treated	Substance	Side Effects	Quality Score
Beretta et al. 1986	22	Papaverine	7 had priapism	5/19
Earle et al. 1992	22	Papaverine, papaverine & phentolamine, prostaglandin E1	pain with 2 pts, one using papaverine one using papaverine and phentolamine	7/19
Hirsch et al. 1994	27	Prostaglandin E1	2 had penile scarring detectable only on ultrasound after repeated use	6/19
Kapoor et al. 1993	101	Papaverine	3 had subcutaneous haematoma	10/19
			2 had cavernosa fibrosis after 3 years use
			1 had priapism
			1 had a vasovagal reaction requiring dosage reduction
Renganathan et al. 1997	28	Papaverine	1 had priapism	0/5 (Jadad)
			8 had local swelling requiring no intervention
Sidi et al. 1987	66	Papaverine or papaverine/phentolamine mixture	4 had priapism	13/19
			3 had minor hematomas
			1 had localized site induration requiring discontinuation
Tang et al. 1995	15	Prostaglandin E1	2 complained of pain at injection site	12/19
Zaslau et al. 1999	28	Papaverine and prostaglandin E1 mixture	2 complained of pain at injection site	10/19

What is the Morbidity of Vacuum Tumescence Devices?

As described above in the two identified reports of studies of vacuum tumescence devices,^{135, 136} when used with proper clinic instruction and according to the specifications of the manufacturers, these devices have a very low morbidity rate with no irreversible morbidity's noted. Although there are case reports of penile ischemia in the literature, these case reports serve only as a warning not to leave the device on too long and cannot help us with ascertaining a complication rate.

In a comparative cases series, Chancellor et al.¹⁵⁶ compared vacuum-pump devices with papaverine injections in 18 males with SCI. The injections and pumps were equally effective and neither group suffered any complications during the study. After trying both treatments, seven patients chose to remain with the pump and another seven chose the injections. A third arm of this study used topical minoxidil, but unfortunately no patients achieved satisfactory results with this treatment.

What Indications, if Any, Remain for Implantable Penile Prosthetic Devices?

Sperm Quality in Males with SCI

There has been much discussion regarding the abnormal sperm found in the ejaculate of males with SCI including: decreased sperm counts,⁸⁷ decreased sperm motility,^{82, 87, 94}increased reactive oxygen species formation,⁹⁴ sperm autoimmunity,⁸³ necrospermia,⁹¹ the inhibitive effect of seminal plasma in SCI males,⁹⁰ and the presence of antisperm antibodies.⁹⁵ Methods used to counteract these negative effects include retrieving the semen more proximally through testicular biopsy or aspiration.^{85, 88} Medical factors can also be optimized in order to try to improve sperm quality. Chapelle et al.¹⁵⁷ studied 135 SCI males at various neurological levels using physostigmine and testicular volume, and found that damage to the T12-L2 region of the cord (T12 metamer) correlated with testicular atrophy and poor ability to ejaculate. Three studies examining the effects of bladder management on sperm quality found that those men managing their bladders with high-pressure reflex voiding had reduced sperm quality, whereas those men using intermittent catheterization had the best sperm parameters.^76–78 Two studies documented the effect of repeated ejaculation on sperm quality and demonstrated that repeated ejaculation improved sperm quality to a plateau, but that too frequent ejaculation (once per week) decreased sperm quality.^{79, 80} They also indicated that these procedures should be timed monthly with the female partner's cycle. Chen et al. compared the sperm counts in antegrade versus retrograde sperm samples, and found that although there was a non-statistical trend towards better sperm counts in antegrade specimens, retrograde ejaculation occurred more frequently.^{56, 89} Bracket et al. studied the effect of temperature on the semen of SCI males and found that although the semen of SCI males lose motility faster than the sperm of normal males, especially at higher (body as opposed to room) temperatures,⁸² scrotal temperature and gonadotropin levels did not contribute to poor semen quality in SCI males.⁸¹

Although sperm motility and other aspects of fertility are seldom reported after acute SCI, studies show that in the chronically spinal cord injured individual (>1 year), there is no relationship between duration of injury and sperm quality.^{77–79, 87} However, Mallidus et al.⁴⁶ demonstrated that the sperm motility and viability first improve after the acute patient comes out of spinal shock then rapidly starts to deteriorate, reaching the levels observed in males with chronic SCI by Day 16 after injury.⁴⁶ Padron,¹⁴⁸ in a case-series study, and Green³⁷ in a case report, demonstrated that although sperm from SCI males freezes reliably, there is still a great reduction in sperm motility.

When these data are considered together, one can conclude that there is little to support the practice of freezing the sperm of SCI males after 16 days post-injury, and that even the advantages of early freezing (within the first 2 weeks) is outweighed by the loss of sperm motility during the procedure, since with modern techniques one is virtually certain of obtaining fresh sperm from the SCI male when he is ready to conceive a child in later years.

Sexual Dysfunction Eligibility Criteria

Measures of sexual dysfunction under consideration:

1. Psychologic: Validated sexual function questionnaire for males and/or females, structured interviews with qualitative analysis, educational component, global efficiency, or patient logs.

2. Physiologic: Penile and/or clitoral engorgement, endocrine, ultrasound testing of testicular size.

1. Does the article contain an original report of a measure of sexual dysfunction? (see list above)

   Yes

   No

   Can't Tell

   Interventions under consideration for sexual dysfunction:

   1. Cognitive/behavioral: Masturbation, intercourse

   2. Device: Penile rings, vibrators, vacuum devices

   3. Prescription medications: Intracavernous injections, oral, subcutaneous injections, intrameatal MUSE, creams

   4. Surgical intervention; Penile implants, spinal cord stimulators or E. Hormonal interventions.

2. Does the article discuss an intervention for sexual dysfunction? (see list above)

   Yes

   No

   Can't Tell

3. Does the article report an original intervention trial or series with a pre and post measure for sexual dysfunction after spinal cord injury?

   Yes

   No

   Can't Tell

Fertility Eligibility Criteria

Measures of fertility rates under consideration:

Pregnancies, live birth rates, sperm motility, successful sperm harvesting, ejaculations, sperm count, % viable sperm, hormonal, ovulation rates, cycle function, other measures of sperm morphology, volume of ejaculation.

1. Does the article contain an original report of a measure of fertility rates in males, females or both?

   Yes

   No

   Can't Tell

   Fertility interventions under consideration:

   1. Physical: masturbation, intercourse, or

   2. Device: vibration, electrode ejaculation, home insemination or

   3. Prescription medications: sympathetic agonists, physostigmine, etc.,

   4. Surgical intervention; vas aspiration, testicular biopsy, ICSI, artificial insemination, spinal cord stimulators, or

   5. Laboratory techniques.

2. Does the article discuss a fertility intervention?

   Yes

   No

   Can't Tell

3. Does the article report an original intervention trial after spinal cord injury?

   Yes

   No

   Can't Tell

4. Does the article include pre and post intervention fertility rates?

   Yes

   No

   Can't Tell

5. Were results for SCI reported separately?

   Yes

   No

6. Is this a non-English language article?

   Yes

   No

Sexual Dysfunction

1. Initials of reviewer:

2. Reference identification # (Refid):

3. Author, Year:

4. Number of review-relevant studies that this report describes

5. Publication status (select one):

6. If you answered ‘Other’ to the preceding question, specify:

7. If other included reports refer to this same study, provide the Refid(s)

8. Country in which the study was conducted (select all that apply):)

9. If you answered ‘Other’ to the preceding question, specify: Number of sites: (text)

10. Funding source type (select all that apply):

11. Specify the funding source(s):

12. Study design (select one): Other (Please specify)

13. If you answered ‘Other’ to the preceding question, specify:

14. Total # of individuals screened:

15. Full sample size (enrolled in study):

16. Full sample size (completing study):

17. Full sample's percentage of male participants:

18. Comments, including notable differences between study arms / cohorts re ‘% male participants’:

19. Mean age (SD/SE; range) of all study participants:

20. Comments, including notable differences between study arms/cohorts re age:

21. Sample's percentage of married participants:

22. Comments, including notable differences between study arms/ cohorts re % of married participants:

23. From which racial groups were participant's drawn (select all that apply)?)

24. Specify each racial group's percentage/proportion of full sample:

25. Comments, including notable differences between study arms/cohorts re racial composition:

26. Specify each socioeconomic status group's percentage/proportion of full sample: Comments, including notable differences between study arms/cohorts re socioeconomic status:

27. Specify number of previous pregnancies:

28. Specify patient prescription drug history specific to SCI versus other:

29. Specify partner prescription drug history specific to SCI versus other:

30. Specify previous sexual dysfunction of patient:

31. Specify previous sexual dysfunction of partner:

32. Specify previous sexual dysfunction treatment of patient (Note: treatment type, duration, dose etc.):

33. Specify previous sexual dysfunction treatment of partner (Note: treatment type, duration, dose etc.):

34. Specify patient history of STD:

35. Specify partner history of STD:

36. Specify patient psychiatric/psychological history (e.g., depression):

37. Specify partner psychiatric/psychological history (e.g., depression):

38. Specify pre-existing cognitive impairments:

39. Specify previous patient drug and/or alcohol abuse:

40. Specify previous partner drug and/or alcohol abuse:

41. Specify patient general medical history including prior diseases, and/or conditions Specify partner general medical history including prior diseases, and/or conditions: Specify other causes of sexual dysfunction:

42. Concurrent conditions (list all that apply): (text)

43. Specify the type and severity (mean; SD/SE; range: with units) of each concurrent condition, as well as how it was defined and diagnosed:

44. Specify the percentage/proportion of the whole sample re each type of each concurrent condition:

45. Comments, including notable differences between study arms/cohorts re concurrent conditions:

46. Specify pre-study medications or treatments for each concurrent condition, with dose/frequency:

47. Comments, including notable differences between study arms / cohorts re pre-study medication(s) or treatments, including dose/frequency:

48. Specify cause of spinal cord injury:

49. Specify the level of spinal cord injury:

50. Specify ASIA Level:

51. Specify duration since spinal cord injury:

52. Please list general comments, including notable differences between arms/cohorts re participants' baseline control of condition? (e.g., do any red flags stand out between the groups?):

53. List of study's inclusion criteria:

54. List of study's exclusion criteria:

55. Intention of study (select all that apply)

56. Type of study (select one):

57. Data were analyzed according to which criterion (select one)?

58. Study duration, including units (includes run-in period protocol/duration, washout protocol/duration, etc.):

59. Specify product name used for pharmacologic, device and/or other intervention(s): Specify name of manufacturer of pharmacologic, device or other intervention product: Medications allowed or mandated during the study (dose/ frequency):

60. Comments, including notable differences between study arms/ cohorts re participants' medication:

61. Concurrent therapies (e.g., physiotherapy; occupational therapy; chiropractic; counseling etc.) allowed or mandated during the study (intensity; frequency; duration):

62. Comments, including notable differences between study arms/ cohorts re participants' concurrent therapies:

63. Permitted or required medications or treatments for concurrent conditions (specify dose/ frequency, and for which concurrent condition):

64. Outcomes assessed (e.g. efficacy, incidence, prevalence, etc):

65. Number of study arm/ cohorts (note: in a cross-over trial, each different phase is considered an exposure / intervention arm):

66. Define the study arms or cohorts of interest to the present review: (text Study arm number:

67. Sample size at study entry: (text)

68. Sample size of those who completed the study:

69. Intervention length (weeks, months):

70. Arm Type/Group Type (placebo, active, control):

71. Intervention/ exposure type (e.g. drug or placebo):

72. Dose / frequency:

73. Timing (AM, PM):

74. Study arm number (Click here if there is no more arm/cohort):

75. Sample size at study entry:

76. Sample size of those who completed the study:

77. Intervention length (weeks, months):

78. Arm type (placebo, active, control):

79. Intervention/ exposure type (e.g. drug or placebo):

80. Dose / frequency:

81. Timing (AM, PM):

82. Study arm number (Click here if there is no more arm/cohort):

83. Sample size at study entry:

84. Sample size of those who completed the study:

85. Intervention length (weeks, months):

86. Arm type (placebo, active, control):

87. Intervention/ exposure type (e.g. drug or placebo):

88. Dose / frequency:

89. Timing (AM, PM):

90. Study arm number:

91. Sample size at study entry:

92. Sample size of those who completed the study:

93. Intervention length (weeks, months):

94. Arm type (placebo, active, control):

95. Intervention/ exposure type (e.g. drug or placebo): Sexual Dysfunction: Quality Assessment

96. Dose / frequency:

97. Timing (AM, PM):

98. Anatomic/Physiologic (e.g., clitoral engorgement; errection; penile tumes. girth; EMG; vaginal lubrication):

99. Sexual satisfaction:

100. Psychological (e.g., sexual functioning questionnaires; depression scale & scores): Infection rates:

101. Divorce:

102. Additional Outcomes Not Covered Above - Other(s):

103. Specify Follow-up(s) (length; duration & results):

104. Adverse events/ side effects reported in the present study (including local (e.g., infection); systemic (e.g., hypotension, death, etc.);

105. Other (e.g., psychological etc.) per study arm/cohort:

106. General Study Comments (Identify any problems with the research design (e.g., definition of placebo/control(s); inappropriateness of run-in and washout periods), or its implementation):

Fertility

1. Initials of reviewer:

2. Reference identification # (Refid):

3. Author, Year:

4. Number of review-relevant studies that this report describes:

5. Publication status (select one):

6. If you answered ‘Other’ to the preceding question, specify:

7. If other included reports refer to this same study, provide the Refid(s):

8. Country in which the study was conducted (select all that apply): (check)

9. If you answered ‘Other’ to the preceding question, specify: (text)

10. Number of sites: (text)

11. Funding source type (select all that apply): (check

12. Specify the funding source(s): (text)

13. Study design (select one):

14. Other (Please specify)

15. If you answered ‘Other’ to the preceding question, specify: (text)

16. Total # of individuals screened: (text)

17. Full sample size (enrolled in study): (text)

18. Full sample size (completing study): (text)

19. Full sample's percentage of male participants: (text)

20. Comments, including notable differences between study arms / cohorts re ‘% male participants’: (text)

21. Mean age (SD/SE; range) of all study participants: (text)

22. Comments, including notable differences between study arms/cohorts re age: (text)

23. Sample's percentage of married participants: (text)

24. Comments, including notable differences between study arms/ cohorts re % of married participants: (text)

25. From which racial groups were participants drawn (select all that apply)? (check) Specify each racial group's percentage/proportion of full sample: (text)

26. Comments, including notable differences between study arms/cohorts re racial composition:

27. Specify each socioeconomic status group's percentage/proportion of full sample: (text)

28. Comments, including notable differences between study arms/cohorts re socioeconomic status: (text)

29. Specify previous gynaecological/obstetric history of patient: (text)

30. Specify previous gynaecological/obstetric history of partner: (text)

31. Specify previous birth control use: (text)

32. Specify number of previous pregnancies: (text)

33. Specify complications of previous pregnancies: (text)

34. Specify previous abortions and list reasons if provided: (text)

35. Specify patient prescription drug history specific to SCI versus other: (text)

36. Specify partner prescription drug history specific to SCI versus other: (text)

37. Specify previous fertility treatment of patient (Note: note treatment type, duration, dose etc.): (text)

38. Specify previous fertility treatment of partner (Note: note treatment type, duration, dose etc.): (text)

39. Specify patient history of STD: (text)

40. Specify partner history of STD: (text)

41. Specify patient psychiatric/psychological history (e.g., depression): (text)

42. Specify partner psychiatric/psychological history (e.g., depression): (text)

43. Specify pre-existing cognitive impairments: (text)

44. Specify previous patient drug and/or alcohol abuse: (text)

45. Specify previous partner drug and/or alcohol abuse: (text)

46. Specify patient general medical history including prior diseases, and/or conditions: (text)

47. Specify partner general medical history including prior diseases, and/or conditions: (text)

48. Specify other causes of infertility: (text)

49. Concurrent conditions (list all that apply): (text)

50. Specify the type and severity (mean; SD/SE; range: with units) of each concurrent condition, as well as how it was defined and diagnosed: (text)

51. Specify the percentage/proportion of the whole sample re each type of each concurrent condition: (text)

52. Comments, including notable differences between study arms/cohorts re concurrent conditions: (text)

53. Specify pre-study medications or treatments for each concurrent condition, with dose/frequency: (text)

54. Comments, including notable differences between study arms / cohorts re pre-study medication(s) or treatments, including dose/frequency: (text)

55. Specify cause of spinal cord injury: (text)

56. Specify the level of spinal cord injury: (text)

57. Specify ASIA Level: (text)

58. Specify duration since spinal cord injury: (text)

59. Please list general comments, including notable differences between arms/cohorts re participants' baseline control of condition? (e.g., do any red flags stand out between the groups?): (text)

60. List of study's inclusion criteria: (text)

61. List of study's exclusion criteria: (text)

62. Intention of study (select all that apply) (check)

63. Type of study (select one): (mult)

64. Data were analyzed according to which criterion (select one)? (mult)

65. If you answered ‘Other’ to the preceding question, specify:

66. Study duration, including units (includes run-in period protocol/duration, washout protocol/duration, etc.): (text)

67. Specify product name used for pharmacologic, device and/or other intervention(s): (text) Specify name of manufacturer of pharmacologic, device or other intervention product: (text)

68. Medications allowed or mandated during the study (dose/ frequency): (text)

69. Comments, including notable differences between study arms/ cohorts re participants' medication: (text)

70. Concurrent therapies (e.g., physiotherapy; occupational therapy; chiropractic; counseling etc.) allowed or mandated during the study (intensity; frequency; duration): (text)

71. Comments, including notable differences between study arms/ cohorts re participants' concurrent therapies: (text)

72. Permitted or required medications or treatments for concurrent conditions (specify dose/ frequency, and for which concurrent condition): (text)

73. Outcomes assessed (e.g. efficacy, incidence, prevalence, etc): (text)

74. Timing of outcome assessments and when, relative to start of intervention (e.g. at week 4): (text)

75. Number of study arm/ cohorts (note: in a cross-over trial, each different phase is considered an exposure / intervention arm): (text)

76. Define the study arms or cohorts of interest to the present review: (text)

77. Study arm number: (text)

78. Sample size at study entry: (text)

79. Sample size of those who completed the study: (text)

80. Intervention length (weeks, months): (text)

81. Arm type (placebo, active, control): (text)

82. Intervention/ exposure type (e.g. drug or placebo): (text)

83. Dose / frequency: (text)

84. Timing (AM, PM): (text)

85. Study arm number (Click here if there is no more arm/cohort): (text)

86. Sample size at study entry: (text)

87. Sample size of those who completed the study: (text)

88. Intervention length (weeks, months): (text)

89. Arm type (placebo, active, control): (text)

90. Intervention/ exposure type (e.g. drug or placebo): (text)

91. Dose / frequency: (text

92. Timing (AM, PM): (text)

93. Study arm number (Click here if there is no more arm/cohort): (text)

94. Sample size at study entry: (text)

95. Sample size of those who completed the study: (text)

96. Intervention length (weeks, months): (text)

97. Arm type (placebo, active, control): (text)

98. Intervention/ exposure type (e.g. drug or placebo): (text)

99. Dose / frequency: (text)

100. Timing (AM, PM): (text)

101. Study arm number (Click here if there is no more arm/cohort): (text)

102. Sample size at study entry: (text)

103. Sample size of those who completed the study: (text)

104. Intervention length (weeks, months): (text)

105. Arm type (placebo, active, control): (text)

106. Intervention/ exposure type (e.g. drug or placebo): (text)

107. Dose / frequency: (text)

108. Timing (AM, PM): (text)

109. Seminal parameters (e.g., specify ejaculation volume; sperm concentration; sperm motility; morphology): (text)

110. Ejaculation rates (frequency): (text)

111. Cycle function: (text)

112. Ovulation rates (e.g., specify total # of ovulatory cycles of the female partner; state the # of cycles with fertilization; state the # of pregnancy rates per treatment cycle): (text)

113. Pregnancy rates (specify # reported): (

114. Miscarriage/ectopic pregnancy rates (genetic or other): (text)

115. Induced Abortion(s) (genetic or other): (text)

116. Live births (e.g., # of births and if singletons, twins or higher order): (text)

117. Psychological (e.g., sexual functioning questionnaires; depression scale & scores): (text)

118. Genetic abnormalities: (text)

119. Infection rates: (text)

120. Divorce: (text)

121. Additional Outcomes Not Covered Above:

122. Other(s): (text)

123. Specify Follow-up(s) (length; duration & results): (text)

124. Adverse events/ side effects reported in the present study (including local (e.g., infection); systemic (e.g., hypotension, death, etc.);

125. Other (e.g., psychological etc.) per study arm/cohort: (text)

126. General Study Comments (Identify any problems with the research design (e.g., definition of placebo/control(s); inappropriateness of run-in and washout periods), or its implementation): (text)

Jadad Scale

Allocation Concealment

Refers to the technique used to implement the randomization sequence, not to generate it.

Adequate

• Sequentially numbered, opaque, sealed envelopes (SNOSE)

• Pharmacy controlled

• Numbered or ordered containers

• Central randomization - for example by telephone to a trials office or other method whose description contained elements convincing of concealment - for example a secure computer assisted method.

Inadequate

• Alternation

• Reference to case record numbers or to dates of birth

Unclear

• No mention of an allocation concealment approach at all

• An approach that does not fall into either adequate or inadequate allocation concealment

Newcastle-Ottawa Scale (NOS)

Fertility

Sexual Dysfunction