Birth intervals are a crucial component of fertility behaviour and family planning. Short birth intervals are associated—although not necessarily causally—with negative health-related outcomes, but less is known about their associations with family functioning. Here, the associations between birth intervals and marital stability were investigated by Cox regression using a nationally representative, register-based sample of individuals with two  or three  children from contemporary Finland (observation period 1972–2009). Shorter interbirth intervals were associated with an increased risk of parental divorce over a ten-year follow-up. Individuals with birth intervals of up to 1.5 years had 24–49 per cent higher divorce risk compared to individuals whose children were born more than 4 years apart. The pattern was similar in all socioeconomic groups and among individuals with earlier and later entry to parenthood. Our results add to the growing body of research showing associations between short birth intervals and negative outcomes in health and family functioning. Is the manuscript technically sound, and do the data support the conclusions?The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: PartlyReviewer #2: Yes**********2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: YesReviewer #2: Yes**********3. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.The Reviewer #1: NoReviewer #2: No**********4. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: YesReviewer #2: Yes**********5. Review Comments to the AuthorPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: PLOS One reviewSummary: The current manuscript uses Finnish population data to examine the relation between interbirth intervals and divorce rates over a 37 year span of time with an average follow-up of 10 years. They find that shorter intervals are associated with increased divorce rates. The paper would be improved by a reorganization of the introduction and a greater consideration of alternative explanations.Abstract:1. Adjust language that it is established that short interbirth intervals are associated with adverse perinatal outcomes, as this is still somewhat debated.Introduction:1. The first paragraph of the introduction briefly provides some history of interpregnancy interval evolutionary theories, but would benefit from a more unbiased initial presentation of the studies and evidence. First, there have been some challenges to the assumption that shorter birth intervals are causally associated with adverse birth outcomes . The WHO recommendations are outdated and based on 1 study that did not do an adequate job of controlling for confounding factors. Second, one can alternatively imagine that increased maternal education levels and workforce participation has contributed to delayed maternal childbearing and an elongation of interpregnancy intervals. Third, work has also shown that long interpregnancy intervals are similarly problematic – also associated with adverse birth outcomes (like a ‘U’ shaped curve). I think this issues can simply be addressed by including some of these alternate perspectives and citations.As I continued to read the introduction, the above mentioned topics were discussed. Therefore, perhaps a reordering of the presentation may help to paint a less one-sided take to the evidence.2. This claim is uncited: “Raising two or more children of similar age is even more demanding, and the elevated need to provide intensive care is likely to affect parental stress” and is an assumption. The citation that occurs a few sentences later is in regards to twins and does not support this claim. This claim needs citation as, it could alternatively be the case that having two children of similar age is beneficial for the parents as the parents are therefore more familiar with the developmental needs and abilities of a certain age group, they can participate in similar activities with their children rather than having to meet the needs of two different levels all the time, even daily hassles such as similar bedtimes, napping needs, and feeding abilities would be lessened. This is all to say that arguments can be made in either direction, but if they are made, they need to be cited or framed as hypotheses. This again, may be addressed by rearranging the presentation of the introduction.Methods:1. Can you explain the separation of Women and Men in Table 1? Is it the case that these might be the same children? Am I correct in understanding that the parental sex was included in models, but not the child’s sex?2. It would be helpful to have percentages for all variables (e.g. divorces) in Table 1.3. Was it possible to use interpregnancy interval as opposed to interbirth interval ?4. Please make more clear what your reference intervals are. As it is stated in the abstract, one might imagine that interbirth intervals over 4 years are the reference.5. What is the reasoning behind the choice to look at the first birth interval and the second birth interval separately within the 3 child families? Why would one believe that those two intervals contribute to divorce differently? It seems that this possibility is not introduced until the discussion and renders investigating if there is a difference between those intervals as slightly unfounded.6. Using different interval spacing models makes your findings a bit difficult to synthesize. I believe your findings would translate more cleanly to previous research if a consistent model was used throughout the paper and those categories were similar to what previous work has used (perhaps being interbirth rather than interpregnancy).Discussion:1. This reviewer appreciates the limitations of causal interpretations the authors provide. These explanations might deserve more attention as they appear stronger than the explanation of stress caused by having two kids close together causing divorce. The authors state that quasi-experimental studies are needed to “strengthen” the argument of a causal relation between short interbirth interval and divorce, but I don’t believe that this study has the ability to make that initial claim at all. Perhaps a quasi-experimental study is needed to challenge the explanation that people who have closely spaced children also have a higher likelihood of divorce .Minor:1. Gender is used interchangeably with sex and should not be.2. The abbreviation of SES is not defined when first used and then inconsistently used.3. Line 330: Obstain not obtain.Reviewer #2: This is in many ways a competent and interesting manuscript. However, I have concerns about how the research addresses the underlying hypothesis, which is that short birth intervals negatively affect family functioning and in turn increase subsequent divorce, in part due to maternal depletion: the analysis does not test this pathway. Second, I question the use of socioeconomic status as a proxy variable representing fast life-history strategies. The life-history strategy argument is not made clearly enough as a theoretical approach: the authors need to convince the reader that short birth intervals are part of a fast life-history strategy. Usually it is only applied to the timing of maturity and reproduction, not to short birth intervals. Under this hypothesis, low socioeconomic status couples are presumably focussed on offspring quantity over quality, and short birth intervals with subsequent divorce and remarriage could be part of this reproductive strategy.It would be worth developing and tightening the theoretical framework and determining whether the FINNUNION data can more directly address any hypothesised mechanisms linking short birth intervals and the likelihood of divorce. This is not easy, as FINNUNION is specifically focussed on marriage and does not appear to contain relevant intermediary variables. One possibility is related to the idea that boys increase maternal depletion relative to girls. For example, women consume more calories during pregnancy with a male offspring . If depletion is a root cause of marital stress and subsequent divorce, then a boy-boy pair with short birth spacing should be the most depleting for mothers, and a girl-girl pair should be the least depleting. Perhaps instead of dropping infant sex from the analyses you could use the infant sex data to more directly address the maternal depletion-related hypothesis.An alternative hypothesis that could be tested with the FINNUNION sample is that rather than being related to fast versus slow life-histories, short birth intervals followed by divorce could result from alternative male mating strategies. If, like in other nations, divorce results in an increased maternal childcare burden and reduced paternal involvement , short birth intervals followed by divorce could be a male mating strategy: have a few children closely spaced then move on to a new partner. This can be addressed using the Finnish data: controlling for age, do men who divorce after short birth intervals marry again sooner than men who divorce after longer birth intervals? This would entail an analysis of divorced individuals, with birth intervals predicting time from divorce to remarriageMinor comments:Summarize sensitivity analyses in the main part of the paper: readers will want to see what difference it makes to use particular subsamples and different model specifications. In STATA, there is an add-on for creating coefficient plots to graphically summarise hazard ratios from several separate statistical analyses (Jann 2014).I don’t understand why birth interval was categorised – why not keep it as a continuous independent variable?The gap of divorce by years since 2nd birth continues to widen between birth interval groups long beyond the period of high infant dependency. Is it still stressful to have a short birth interval when they are both in school?References:Tamimi et al, (2003). Average energy intake among pregnant women carrying a boy compared with a girl. BMJ 326:1245-6.Kalmijn, M. (2015). Father-Child Relations after Divorce in Four European Countries: Patterns and Determinants. Comparative Population Studies, 40, n. 3.Jann B. (2014). Plotting regression coefficients and other estimates. The Stata Journal 2011;14(4):708-37.**********what does this mean?). If published, this will include your full peer review and any attached files.6. PLOS authors have the option to publish the peer review history of their article  digital diagnostic tool,  26 Dec 2019Response to reviewers.We thank the anonymous reviewer and Dr. David Waynforth for the time and effort they have invested in our study, and for the insightful comments and critique they have provided. Below are our point by point answers to their comments.Reviewer #1: PLOS One reviewSummary: The current manuscript uses Finnish population data to examine the relation between interbirth intervals and divorce rates over a 37 year span of time with an average follow-up of 10 years. They find that shorter intervals are associated with increased divorce rates. The paper would be improved by a reorganization of the introduction and a greater consideration of alternative explanations.Abstract:1. Adjust language that it is established that short interbirth intervals are associated with adverse perinatal outcomes, as this is still somewhat debated.Author response #1: We have adjusted the language in the abstract.Introduction:1. The first paragraph of the introduction briefly provides some history of interpregnancy interval evolutionary theories, but would benefit from a more unbiased initial presentation of the studies and evidence. First, there have been some challenges to the assumption that shorter birth intervals are causally associated with adverse birth outcomes . The WHO recommendations are outdated and based on 1 study that did not do an adequate job of controlling for confounding factors. Second, one can alternatively imagine that increased maternal education levels and workforce participation has contributed to delayed maternal childbearing and an elongation of interpregnancy intervals. Third, work has also shown that long interpregnancy intervals are similarly problematic – also associated with adverse birth outcomes (like a ‘U’ shaped curve). I think this issues can simply be addressed by including some of these alternate perspectives and citations.As I continued to read the introduction, the above mentioned topics were discussed. Therefore, perhaps a reordering of the presentation may help to paint a less one-sided take to the evidence.Author response #2: We have revised the beginning of the introduction in many ways: i) We deleted the reference to the WHO guideline; ii) we deleted the part referring to short intervals being risky from the first paragraph; iii) we made more clear that the idea that postponement of parenthood and higher education among women are associated with shorter birth intervals is based on research findings, not an assumption; iv) we mention the U-shaped association between birth intervals and health outcomes right at the beginning or the paragraph discussing these findings; and v) we have more explicitly stated that the causality between birth intervals and health outcomes is currently under debate.2. This claim is uncited: “Raising two or more children of similar age is even more demanding, and the elevated need to provide intensive care is likely to affect parental stress” and is an assumption. The citation that occurs a few sentences later is in regards to twins and does not support this claim. This claim needs citation as, it could alternatively be the case that having two children of similar age is beneficial for the parents as the parents are therefore more familiar with the developmental needs and abilities of a certain age group, they can participate in similar activities with their children rather than having to meet the needs of two different levels all the time, even daily hassles such as similar bedtimes, napping needs, and feeding abilities would be lessened. This is all to say that arguments can be made in either direction, but if they are made, they need to be cited or framed as hypotheses. This again, may be addressed by rearranging the presentation of the introduction.Author response #3: We have revised this part of the introduction to include the potential positive outcomes of tighter sibling spacing, and more clearly state the speculative / hypothetical nature of our assumption on short birth intervals and increased parental stress.Methods:1. Can you explain the separation of Women and Men in Table 1? Is it the case that these might be the same children? Am I correct in understanding that the parental sex was included in models, but not the child’s sex?Author response #4: The data include individuals, not married couples, but since this is a random 11% sample of Finns, it is possible that a small fraction of the sample are individuals married to each other . Yes, parental sex was included in the model, because it is known that men are more likely to divorce . To control for this in a sample including both men and women, we included parental sex in the models. Children’s sex was not associated with parental divorce risk, so it was left out from the final models.2. It would be helpful to have percentages for all variables (e.g. divorces) in Table 1.Author response #5: We added the percentages in Table1, wherever they were lacking.3. Was it possible to use interpregnancy interval as opposed to interbirth interval ?Author response #6: Unfortunately, our data do not contain information on gestational length, so we could only examine birth intervals, not interpregnancy intervals. 4. Please make more clear what your reference intervals are. As it is stated in the abstract, one might imagine that interbirth intervals over 4 years are the reference.Author response #7: We have added a mention on the reference interval in the “Statistical analysis”-part of the Methods-section, and also state it now explicitly in all the tables. In the abstract, in our opinion, it would still be best to keep the comparison as it is, as XX% higher risk is more intuitive and easy to understand than XX% lower risk .5. What is the reasoning behind the choice to look at the first birth interval and the second birth interval separately within the 3 child families? Why would one believe that those two intervals contribute to divorce differently? It seems that this possibility is not introduced until the discussion and renders investigating if there is a difference between those intervals as slightly unfounded.Author response #8: To us, this was an intuitive choice because 3-child families have two birth intervals. We did not have a specific hypothesis about this, but feel looking at them separately is the most open way of examining the effects of the two intervals. We have now justified our choice explicitly: “In models concerning individuals with three children, the first and second birth intervals were examined separately, mutually adjusted, and in interaction, to see if the two intervals had independent, additive, or interactive associations with the risk of divorce.”6. Using different interval spacing models makes your findings a bit difficult to synthesize. I believe your findings would translate more cleanly to previous research if a consistent model was used throughout the paper and those categories were similar to what previous work has used (perhaps being interbirth rather than interpregnancy).Author response #9: The paper uses interbirth intervals as the predictor , and we do not have information on interpregnancy. In studies with interpregnancy interval as the main predictor, the shortest category is usually max. 5 months  – however, our shortest reference category is a bit longer (18 months) because we didn’t have enough cases in the shorter categories to maintain statistical power. Different limits for the highest birth interval category in different analyses were used because we wanted to keep as many separate categories for the longer intervals as possible to investigate the possibility of a U-shaped effect between birth intervals and divorce risk. Very long intervals were so rare in the first IBI for people with 3 children that the categorization here was different. However, we have now changed the categorization in all analyses to be similar, that is, highest category is now always longer than 72 months.Discussion:1. This reviewer appreciates the limitations of causal interpretations the authors provide. These explanations might deserve more attention as they appear stronger than the explanation of stress caused by having two kids close together causing divorce. The authors state that quasi-experimental studies are needed to “strengthen” the argument of a causal relation between short interbirth interval and divorce, but I don’t believe that this study has the ability to make that initial claim at all. Perhaps a quasi-experimental study is needed to challenge the explanation that people who have closely spaced children also have a higher likelihood of divorce .Author response #10: We have revised this bit of text, and it now reads: ”Quasi-experimental studies based on exogenous variation in birth intervals would be needed to investigate the causality in the association between birth intervals and parental risk of divorce.”Minor:1. Gender is used interchangeably with sex and should not be.2. The abbreviation of SES is not defined when first used and then inconsistently used.3. Line 330: Obstain not obtain.Author response #11: Thank you, these mistakes are now corrected.Reviewer #2: This is in many ways a competent and interesting manuscript. However, I have concerns about how the research addresses the underlying hypothesis, which is that short birth intervals negatively affect family functioning and in turn increase subsequent divorce, in part due to maternal depletion: the analysis does not test this pathway. Author response #12: Please see Author response #14. Second, I question the use of socioeconomic status as a proxy variable representing fast life-history strategies. The life-history strategy argument is not made clearly enough as a theoretical approach: the authors need to convince the reader that short birth intervals are part of a fast life-history strategy. Usually it is only applied to the timing of maturity and reproduction, not to short birth intervals. Under this hypothesis, low socioeconomic status couples are presumably focussed on offspring quantity over quality, and short birth intervals with subsequent divorce and remarriage could be part of this reproductive strategy.Author response #13: We have made the point of short birth intervals being a part of fast life history more clear in the introduction: “In resource scarce and dangerous environments with a lower life expectancy, it is more optimal to invest in current reproduction rather than future reproduction because the future is uncertain, and in quantity rather than quality of offspring because of lack of resources (40–44). These features of faster reproductive strategy lead to shorter birth intervals between children (42).”To accommodate the reviewers concern about SES being a good indicator of fast life history strategy, we conducted a new analysis examining the interaction between age at first reproduction and length of birth intervals with a similar assumption than the SES-interaction analyses . The results for this additional analysis are in accordance with and confirm the SES-interaction analyses: no significant interactions were found (except for one just significant in the opposite direction than hypothesized). These new results are given in supplementary table S5, and summarized in the text.It would be worth developing and tightening the theoretical framework and determining whether the FINNUNION data can more directly address any hypothesised mechanisms linking short birth intervals and the likelihood of divorce. This is not easy, as FINNUNION is specifically focussed on marriage and does not appear to contain relevant intermediary variables. One possibility is related to the idea that boys increase maternal depletion relative to girls. For example, women consume more calories during pregnancy with a male offspring . If depletion is a root cause of marital stress and subsequent divorce, then a boy-boy pair with short birth spacing should be the most depleting for mothers, and a girl-girl pair should be the least depleting. Perhaps instead of dropping infant sex from the analyses you could use the infant sex data to more directly address the maternal depletion-related hypothesis.Author response #14: With this comment, we realize that we have been somewhat unsuccessful in explaining the assumed pathway from short birth intervals to parental stress and divorce. We do not assume that this pathway would result from maternal depletion during pregnancy, but rather the strains of everyday life related to bringing up children of similar age – affecting mothers as well as fathers. We have altered the introduction to make our point clearer and to state more openly the hypothetical nature of this stress-related pathway (see Author response # 3). For this reason, we think that testing the maternal depletion hypothesis the way suggested by the reviewer would not be compatible with the research questions in this study, and have not conducted them . An alternative hypothesis that could be tested with the FINNUNION sample is that rather than being related to fast versus slow life-histories, short birth intervals followed by divorce could result from alternative male mating strategies. If, like in other nations, divorce results in an increased maternal childcare burden and reduced paternal involvement , short birth intervals followed by divorce could be a male mating strategy: have a few children closely spaced then move on to a new partner. This can be addressed using the Finnish data: controlling for age, do men who divorce after short birth intervals marry again sooner than men who divorce after longer birth intervals? This would entail an analysis of divorced individuals, with birth intervals predicting time from divorce to remarriageAuthor response #15: This is an excellent idea, and definitely worth investigating – however, we feel that it would be a topic of a different study (we would be happy collaborate with the reviewer in conducting such a study). In this paper, we are mainly interested in establishing an association between birth intervals and risk of divorce, which is a new finding in itself, and be cautious about this association not necessarily being causal. In our opinion, adding analyses with follow-up starting at divorce would draw the reader’s attention away from the main point of the current study. Minor comments:Summarize sensitivity analyses in the main part of the paper: readers will want to see what difference it makes to use particular subsamples and different model specifications. In STATA, there is an add-on for creating coefficient plots to graphically summarise hazard ratios from several separate statistical analyses (Jann 2014).Author response #16: We plotted the HRs from main analyses and sensitivity analyses in what is now Fig. 3, and added a section called “Sensitivity analyses” at the end of Results, summarizing the analyses.I don’t understand why birth interval was categorised – why not keep it as a continuous independent variable?Author response #17: Birth intervals are regularly categorized in literature examining this topic, and in order to keep our results comparable with the literature, we have categorized the birth intervals .The gap of divorce by years since 2nd birth continues to widen between birth interval groups long beyond the period of high infant dependency. Is it still stressful to have a short birth interval when they are both in school?Author response #18: Divorce processes in marital relationships are usually long and take years to develop. Stress related to bringing up closely spaced siblings in infancy may have long-term ramifications on the marital relationship that only manifest later .Author note: In addition to the changes requested by the reviewers, we have made a small number of changes to improve the clarity of the manuscript.AttachmentBergV_IBI_divorce_plosone_ResponseToReviewers.docxSubmitted filename: Click here for additional data file. 13 Jan 2020Shorter birth intervals between siblings are associated with increased risk of parental divorcePONE-D-19-28900R1Dear Dr. Berg,We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at onepress@plos.org.If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact With kind regards,David MeyreAcademic EditorPLOS ONEAdditional Editor Comments :Reviewers' comments: 17 Jan 2020PONE-D-19-28900R1 Shorter birth intervals between siblings are associated with increased risk of parental divorce Dear Dr. Berg:I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. onepress@plos.org.If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact plosone@plos.org. For any other questions or concerns, please email Thank you for submitting your work to PLOS ONE.With kind regards,PLOS ONE Editorial Office Staffon behalf ofDr David Meyre Academic EditorPLOS ONE


Rectal duplication cysts are rare gastrointestinal congenital duplicate cysts with various clinical presentations that require different management.We present a case of a lady with a double rectal duplicate cyst which was found incidentally on a follow-up CT abdomen and pelvis scan. The patient initially had a mucocele excision, and following that, she had a non-contrast CT abdomen and pelvis to investigate post-operative pain. The CT scan revealed a single rectal duplicate cyst. She had a posterior approach excision to have it removed, and only intra-operatively, she was found to have a double rectal duplicate cyst. She had them both removed via a midline incision running from the perineal pigmentation and extending until the coccyx. She had another follow-up CT which showed complete excision of the cysts.After a thorough review of the literature regarding rectal cysts, there was no mention of a double rectal duplicate cyst. The purpose of this paper is to point out the various potential presentations of a rectal cyst as well as the idea that a double cyst is managed effectively in a similar way as the single one. Duplicate rectal cysts are the least common between the gastrointestinal congenital cysts, forming only 4% of them , and theWe present the following lady with a double rectal duplication cyst which was an incidental finding. She was initially admitted because of her appendix mucocele that was resected surgically. No further intra-operative findings suggested a rectal cyst presence. However, she was still having symptoms such as lower abdominal pain and discomfort while sitting. She had a non-contrast CT scan of the abdomen and pelvis to investigate these post-operatively and to make sure there were no post-operative complications. She was, therefore, found to have a “5.7 × 2.7 cm thin-walled well-defined low attenuation structure in the right ischiorenal/ischianal fossa in close relation with the posterolateral wall of the distal rectum, extending superiorly”. This structure was crossing the levator ani and appeared to have interconnecting components but no soft tissue nodularity. These findings were consistent with a rectal duplication cyst.This lady was still complaining about pain while sitting down that was eventually attributed to the existence of her duplication cyst. As a result, she was investigated further and had an MRI scan Figs. , 2 and 3Retrorectal developmental cysts are lesions that can be categorised according to their histopathological features and origins. The commonest kinds are the epidermoid cyst, dermoid cyst, rectal duplication cyst, rectal cystic hamartoma and teratoma . RegardiA double rectal duplication cyst has never before been reported in the literature. However, clinical presentation, diagnostic tools and management are similar to the other GI duplicate cysts, and patients should be managed according to their symptomatology.


It is well-established that couples’ fecundities vary widely. Each couple has a relatively constant monthly probability of conceiving, which can vary from zero to quite high. This underlying probability is usually expressed as the time  the couple requires to conceive. Couples with high fecundity will, on average, need fewer cycles than couples with low fecundity. It is also well-documented that almost all human populations exhibit seasonal variation in births. Most European countries show seasonal variation that usually peak in the spring and are the lowest during the last quarter of the year. The increasingly strong pattern of depressed birth rates in November and December is likely explained by the December–January cut-off threshold for Swedish pupils’ school entry and their parents increasing awareness of the negative effects on school outcomes for children who are juniors in the school-entry cohort they belong to. To actively plan births for a specific time of the year, couples need to have some knowledge of the time required for them to conceive.second births. We hypothesize that in a society with highly controlled fertility and a strong norm of having at least two children, sub-fertile couples will on average show less seasonal variation in second births. Sub-fertile couples, requiring more time to conceive the first time, will be less likely to try to target a desired birth month for their second child because doing so could jeopardize fulfilling their desired family size. We apply multinomial logistic regressions on 81,998 Swedish couples who married while being childless and subsequently gave birth to at least two children between 1990 and 2012, to investigate fecundity’s role in seasonal variation in second births.We use the duration between marriage of childless couples and first birth as a proxy measure of couples’ fecundity. Based on this time-to-pregnancy measure we study to what extent couples’ capacity to conceive affects the seasonality of their We found that seasonal variation in second births was strongly associated with couples’ observed fecundity, measured as the duration between marriage formation and first birth. Our results support the hypothesis that sub-fertile couples, requiring more time to conceive the first time, show less seasonal variation in second births. The seasonal variations in second order births among couples with normal fecundity shows some similarities to traditional patterns as seen in agricultural and industrial societies of the past, with high numbers of births during the spring, and low numbers during the last quarter of the year. However, two important differences are notable. The characteristic Christmas peak in September has vanished, and the low birth rates in November and December come out much stronger than in the past.The birth seasonality among couples with normal fecundity are what we would expect if couples actively plan their births according to the cut-off date for Swedish pupils’ school entry. We argue that our findings support the notion that scheduled childbirth is a reality in contemporary sociality. It is well-documented that almost all human populations exhibit seasonal variation in births. Increasingly strong pattern of depressed birth rates in November and December, in recent decades, is likely explained by the December–January cut-off threshold for Swedish pupils’ school entry and their parents increasing awareness of the negative effects on school outcomes for children who are juniors in the school-entry cohort they belong to. To actively plan births for a specific time of the year, couples need to have some knowledge of the time required for them to conceive. Couples’ fecundities vary widely. Each couple has a relatively constant monthly probability of conceiving, which can vary from zero to high. We use the duration between marriage of childless couples and first birth as a measure of couples’ fecundity. We hypothesize that in a society with highly controlled fertility and a strong norm of having at least two children, sub-fertile couples will on average show less seasonal variation in second births. Sub-fertile couples, requiring more time to conceive the first time, will be less likely to try to target a desired birth month for their second child because doing so could jeopardize fulfilling their desired family size. Studying 81,998 Swedish couples who married while being childless and subsequently gave birth to at least two children between 1990 and 2012, we found that seasonal variation in second births was strongly associated with couples’ observed fecundity. Seasonal variation in the physiological ability to reproduce and cultural behaviours linked to the likelihood of sexual intercourse may still matter for when under the year births occur. However, our study supports the notion that the impact of these factors is relatively weak in contemporary societies. We argue that our findings support the notion that scheduled childbirth is a reality in contemporary sociality.Researchers have repeatedly reported strong seasonal variation in human births and that the patterns vary across geographic regions . Human bTo actively plan births for a specific time of the year, couples need to have some knowledge of the time required for them to conceive. Previous research has shown that mothers who re-partnered between births displayed less seasonal variation than mothers who resumed childbearing with the same partner . A possiIt is well-established that couples’ fecundities vary widely. Time-to-pregnancy (TTP) is considered one of the most direct methods to measure natural fecundity in humans . Each cosecond births as reflected in the birth month of their second children. No previous study has addressed birth seasonality in relation to couples’ fecundity using a TTP measure. We hypothesize that in a society with highly controlled fertility and a strong norm of having at least two children, sub-fertile couples will on average show less seasonal variation in second births. Sub-fertile couples, requiring more time to conceive the first time, might be less likely to try to target a desired birth month for their second child because doing so could jeopardize fulfilling their desired family size. Evidently, they are also less able to achieve any specific target they may try to reach.In the current study, we use the duration between marriage of childless couples and their first birth as a proxy measure of couples’ fecundity. Based on this TTP measure we study to what extent couples’ capacity to conceive affects the seasonality of their We apply multinomial logistic regressions on 81,998 Swedish couples who married while being childless and subsequently gave birth to at least two children between 1990 and 2012, to investigate fecundity’s role in seasonal variation in second births.Contemporary Sweden is a particularly good setting to study this issue. With our study design, the studied population needs to meet at least three criteria. First, it is vital that most couples who marry while still being childless also start trying to conceive in conjunction with their marriage. In Sweden, few couples enter marriage without previously living together , marriagData were retrieved from the Swedish multigenerational register, with information on all Swedes born from 1932 onwards who have been registered as residents in Sweden at any time since 1961. The data contain highly accurate information on vital events such as childbirths and changes in marital status. The information used in the present study includes all Swedish couples who married and gave birth to at least two children anytime between 1990 and 2012. Women and men who had previously been married, had children from a prior relationship, or re-partnered between births one and two were excluded. Women older than age 40 at marriage were also excluded due to the risk that their relatively high age would affect the duration between marriage and first birth. Couples who had ever adopted, had multiple births at first pregnancy, or separated before a second birth were also excluded from the analysis. The study only analysed Swedish-born men and women as the meaning of marriage and its relation to childbearing decisions might differ among individuals from different cultural backgrounds. A small number of parents who experienced their firstborn child’s death were also excluded from the analysis. We included couples who had their first child up to five years after their marriage. Finally, couples who gave birth less than nine months following the marriage were excluded as we only want to study couples who commence their childbearing careers subsequent to marriage formation. A total of 81,998 Swedish couples met all these criteria. As we only include couples with no prior marriage or children and assume that these men and women have not previously actively been trying to conceive, we analyse couples that, to a large extent, had no prior knowledge about their levels of fecundity.The dependent variable in this study is the second child’s month of birth. We report the differences between the expected and observed probability of second childbirth for each month in the calendar year for couples with different levels of observed fecundity.TTP, the duration from the time a couple starts attempting to become pregnant until they succeed, is the most widely used measure of natural fecundity in humans. Sub-fertility is usually defined as a failure to conceive after one year (or sometimes two years) of trying . In the In addition to the main independent variable that measures fecundity, we also included control variables for maternal education and mother’s age at first birth. Fertility is to a considerable extent negatively correlated with female age , making P-values < 0.05 were considered markers of statistical significance. All statistical analyses were performed utilizing STATA 15 .Multinomial logistic regressions were used to calculate predicted probabilities of giving second birth in each calendar month. The results are reported as the observed versus expected probability of childbirth for each month. The baseline (expected probability) is expressed as 100 births per month. Each month’s number of days was taken into consideration (February is assumed to have 28.25 days on average). Using multinomial logistic regression rather than simply comparing expected and observed numbers of births allows for multivariate analyses with the controls for potentially confounding factors. Two-tailed Current patterns in Swedish birth seasonality are a relative new phenomenon. Figure The distribution of Swedish couples’ achieved duration time between marriage and first birth is shown in Fig. The differences between the expected and observed probabilities of second births for each month by couples’ fecundity are shown in Fig. A clear difference emerges in seasonality of live births between more and less fertile couples. Normally fertile couples show a typical seasonal variation of Sweden with high numbers of births during the spring and low numbers during the last quarter of the year. Among couples with normal fecundity, we observe around 120 births in March, April and May per 100 expected births. Sub-fertile couples, on the other hand, show significantly less seasonality in second births. Between January and September, sub-fertile couples show only minor seasonal variation in births. Normally fertile and sub-fertile couples show depressed birth rates in November and December, but the depressed second birth rates are significantly amplified among the more fertile couples. Couples with normal fecundity show around 70 births in November and December per 100 expected births. The same figure for sub-fertile couples is around 80.All meaningful differences reported are statistically significant. We also carried out two sensitivity analyses. First, we tested if the results changed significantly if we increased the studied population by included couples who gave birth to their first child up to seven years after marriage. However, this did not change the results in any way. Second, we carried out separate analyses for different years of marriage formation to see if the difference in seasonal variations in second births between normal and sub-fertile couples had changed during the period studied. However, we did not detect any meaningful changes in patterns.We found that seasonal variation in second births was strongly associated with couples’ observed fecundity, measured as the duration between marriage formation and first birth. The results support the hypothesis that sub-fertile couples, requiring more time to conceive the first time, show less seasonal variation in second births. Normally fertile and sub-fertile couples all show decreased birth rates at the end of the year, but the pattern was significantly stronger among the more fertile couples. Normally fertile couples also displayed a substantial peak in births in the spring, but sub-fertile couples displayed almost no variations in second births over the first nine months of the year. The results are in line with previous research that has shown that mothers who re-partnered between subsequent births displayed less seasonal variation than mothers who resumed childbearing with the same partner . MothersTTP is not a measure of fecundability for each individual couple, but the best measure of couple fecundity that we have at the population level. All types of TTP data have their advantages and disadvantages. Sampling, memory, and truncation biases are the main disadvantage with traditional TTP measures . A prospIn our data, two-thirds of couples had a first birth between nine and 23 months since marriage formation. The median TTP was 19 months. In general, survey-based TTP estimates - both retrospective and prospective - tend to report higher proportions of couples with normal fecundity and lower proportions with sub-fecundity. However, the median TTP in our study corresponds quite well with other TTP measures –36.For a correct interpretation of our results, we note that the proxy we defined for couples’ fecundity builds on two assumptions. First, that couples start trying to conceive in conjunction with their marriage, and second, that couples have no prior knowledge about their fecundity when getting married. As already mentioned, marriage in Sweden is mainly considered an act of commitment in an existing relationship, and childless couples who get married mainly enter the next stage in their family formation, namely parenthood. Some of the men and women in the studied population may already have tried to become a parent but did not succeed and thereby had some knowledge about their level of fecundity. However, by excluding men and women who had previously been married or had children from a prior relationship, we minimize this risk. Restricting the study population as we did, our results should be robust enough to support the hypothesis that sub-fertile couples are less likely to target a specific time of the year for their second child.These findings support the assumption that couples to quite some extent plan their childbearing according to specific desired birth months. Our results do not only show stronger seasonality in second births among couples with normal fecundity than for sub-fertile couples. They also show that the birth seasonality among couples with normal fecundity are what we would expect if couples actively plan their births according to the cut-off date for Swedish pupils’ school entry.To some extent, the seasonal variations in second order births among couples with normal fecundity shows similarities to traditional patterns as seen in agricultural and industrial societies of the past, with high numbers of births during the spring, and low numbers during the last quarter of the year. However, two important differences stand out: The characteristic Christmas peak in September has vanished, and the low birth rates in November and December come out much stronger than in the past.Sweden is often considered one of the most gender equal countries in the world where mothers’ labor force participation, shared parental leave, and dual-earner dual-carer couples are the norm , 38. In We cannot yet rule out, that seasonal variation in nutrition, daylight and cultural behaviours linked to the likelihood of sexual intercourse still matter for when under the year births occur. However, our study supports the notion that the impact of these factors is relatively weak in contemporary societies, and that increased individual autonomy has contributed to more conscious planning of the timing of childbirths. In contemporary societies with below-replacement and highly controlled fertility, active choices matter more for childbearing than the physiological ability to reproduce. Our study thus supports the notion of scheduled childbirths . Active


The development of topical inserts for the prevention of sexually transmitted infections (STIs), particularly human immunodeficiency virus (HIV), represents a promising alternative to oral and parenteral pre-exposure prophylaxis (PrEP) dosage forms. They may be used for vaginal and/or rectal administration of a variety of agents with antiviral activity. Topical inserts deliver drugs to the portal of viral entry, i.e., the genital or rectal mucosa, with low systemic exposure, and therefore are safer and have fewer side effects than systemic PrEP agents. They may dissolve fast, releasing the active drugs within minutes of insertion, or slowly for long-acting drug delivery. Furthermore, they are user-friendly being easy to administer, discreet and highly portable. They are also economical and easy to manufacture at scale and to distribute, with excellent stability and shelf-life. Altogether, topical inserts represent a particularly promising form of drug delivery for HIV and STI prevention. Highlighted within this review are end-user acceptability research dedicated to understanding preferred attributes for this form of drug delivery, advantages and disadvantages of the formulation platform options, considerations for their development, clinical assessment of select placebo prototypes, future directions, and the potential impact of this dosage form on the HIV prevention landscape. Globally, human immunodeficiency virus (HIV) remains a major public health crisis, with approximately 1.8 million new infections annually, and almost 38 million people living with HIV in 2018 [®), is highly effective when taken consistently [Oral pre-exposure prophylaxis (PrEP), specifically daily tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)  that are intended for placement and retention in a body cavity, such as the vagina or buccal cavity. Per the USP Nomenclature Guidelines , supposiTopical inserts, depending on the formulation technology used, may release drug either rapidly or slowly via one of several drug delivery mechanisms  into the surrounding cervicovaginal fluid and tissue. Further, depending on the physicochemical properties and mechanism of action of the actives used, vaginal inserts may function by distributing drug lumenally, to local target cells and tissue, and/or via systemic circulation. Like oral tablets, topical inserts are in general economical, readily manufacturable, stable and user-friendly. Unlike vaginal gels, inserts are compact and do not require an applicator for administration, and therefore may be packaged, stored and used discreetly. Together, topical inserts are a versatile and convenient dosage form. A few examples of the many FDA approved vaginal insert products are listed in Although, topical inserts are used for a range of sexual and reproductive health indications, only a few research and development (R&D) groups are actively advancing topical inserts to clinical stages of development for HIV or multipurpose STI prevention . HoweverDepending on the type of formulation technology used and mechanism of action of the specific drug(s) to be delivered, topical inserts may be designed to quickly disintegrate or dissolve within the vagina or rectum to release therapeutic drugs quickly for on-demand (event-driven) use, or provide an extended/controlled drug release through bioadhesive properties that may prolong retention and pharmacokinetics (PK). The mechanism and rate of insert disintegration is a complex phenomenon, dependent upon the excipient and drug properties and vaginal fluid, which varies further in pH, composition and volume depending on a woman’s age, menstrual cycle and microbiota. Disintegration may follow a process of bulk or surface erosion, or a combination of both. Also depending on the excipients used, an insert may dissolve or disintegrate into the vaginal fluids or transform into a gel. In general, fast-disintegration requires rapid absorption of water into the core of the insert creating pores for faster dissolution of the inserts. In the case of surface erosion, an insert erodes from the surface creating a loss in mass that is faster than the absorption of water into the bulk of the product A. With bIn the following sections, we describe the different types of insert technologies, products and platforms in development and/or consideration for HIV prevention.Fast in vivo degradation and drug release are critical for the development of a rapidly-disintegrating topical microbicide insert platform. Common classes of excipients used to make fast-dissolving inserts include: Disintegrants (superdisintegrants), diluents, binding agents, dispersing agents, glidants, osmoattractants, buffering agents, lubricating and pore formers or channel creators. The major technologies for manufacturing fast-dissolving/disintegrating inserts are direct compression and freeze-drying which have been primarily used for vaginal/rectal insert manufacturing and discussed here.Direct compression is a process involving drug-excipient blending, typically by either direct blend or dry/wet granulation methodologies, followed by compaction using a tablet press. Compared to other methods of insert manufacturing, direct compression has several advantages. It is a simple, robust and cost-effective method with a limited number of processing steps involved. It allows for the production of a less-friable insert with high mechanical strength, thus better handling and packaging feasibility. The disadvantages of this process include the manufacturing of less porous inserts, which means a longer dissolution time is likely needed for dissolution or disintegration, especially when compared to freeze-dried inserts. Dissolution rate is affected by the level of compression, which affects the porosity and mechanical strength or hardness of the insert. Therefore, an appropriate balance is needed for achieving sufficient porosity (for fast disintegration/dissolution) and mechanical strength .CONRAD’s topical insert development program for HIV/STI prevention has focused primarily on the use of the compressed insert platform, due to ease of manufacture, low cost, and compatibility with different ARVs. Our first generation product B was intThe International Partnership for Microbicides (IPM) is developing a compressed, fast-dispersing tablet for the vaginal delivery of DS003 C, a highCompared to compressed inserts, freeze-dried inserts are highly porous structures that allow for rapid dissolution or disintegration of the dosage form even in very low fluid volume environments, such as the vagina. The process to make freeze-dried inserts involves dissolving or dispersing the actives and excipients in aqueous solutions, pouring this solution into an open mold , then lyophilizing to form the final solid dosage form. In addition to being very fast dissolving, the freeze-dried manufacturing process uses low temperatures, minimizing adverse thermal effects that may affect drug stability, and results in amorphous structures of excipients and drug, leading to enhanced dissolution. For biologics especially, this method of manufacturing may improve product stability ,30. Howe® fast-dissolving technology platform original developed for oral drug delivery [During CONRAD’s early development of inserts for vaginal delivery of ARVs, we developed a freeze-dried, rapidly dissolving insert using Catalent’s Zydisdelivery . Prototydelivery ,32. WhilThe most advanced freeze-dried vaginal insert in development for prevention of HIV and sexually transmitted infections (STI) is the Griffithsin (GRFT)/Carrageenan (CG) fast-dissolve insert from Population Council in collaboration with PATH ,33. GRFTLactobacillus jensenii that secrete a modified form of the potent HIV-1 entry inhibitor protein, Cyanovirin-N  for a longer, “intermediate” duration  compared to, say, intravaginal rings that last one or more months. A large question mark for the clinical feasibility of extended-release inserts, however, is whether vaginal retention of these products will be sufficiently long, especially during ambulation, physical activity and coitus. Evidence from studies with intravaginal rings and vaginal films suggest presence of the vaginal product during sex is acceptable ,38,39,40The simplest of the extended-release formulation approaches is through the incorporation of mucoadhesive polymers in either compressed or hot-melt extruded inserts. In a collaboration with Dr. Karl Malcolm  and CONRAD, a sustained-release hydroxypropyl methylcellulose (HPMC)-based mucoadhesive TFV vaginal insert formulation was developed using a direct compression technique . By varyOsmotic pump-like inserts are polymer-coated inserts containing a semi-permeable, non-swellable outer membrane with a small, typically laser-drilled, orifice. These systems are formulated with osmoattractants in the tablet core to drive water to diffuse through the outer membrane. In turn, the osmotic pressure increases in the core, which is constrained by the rigid membrane, and drives the sustained release of drug out through the drug delivery orifice. One of the advantages of these systems is that the release mechanism is largely drug-independent, with a high degree of in vitro and in vivo correlation. However, the more complex manufacturing and thus higher cost than conventional tablet technologies, as well as potentially a higher risk of dose dumping if the coating were to rupture or otherwise fail, represent known limitations of osmotically controlled technologies. Dr. Patrick Kiser (Northwestern University) first reported on the application of osmotic pump technology in a sustained-release microbicide vaginal insert containing the pyrimidinedione analog IQP-0528 . FollowiMultiparticulate-based drug delivery systems have the potential to achieve several properties that may be desirable for topical PrEP insert formulations, including potential for drug targeting to specific cells or mucosal tissue, increased mucous and tissue penetration, bioadhesion, and retention, and ability for sustained, controlled and/or stimuli-triggered drug release after vaginal administration ,50,51,52As mentioned earlier, product developers are increasingly including user feedback in early stages of development to help ensure that products are aligned with user preferences. Most clinical trials measure acceptability in some form, primarily via willingness to use in the future. In general, such studies have shown positive acceptability of vaginal microbicides. More recently, studies have examined preferences across products and focusing on specific attributes. These studies have used a mixed methods approach, including discrete choice experiments (DCE) and conjoint analysis, to understand preferences by comparing and weighing different attributes. Pre- and post- product use questionnaires can also provide qualitative and quantitative feedback on user preferences and rankings when comparing different dosage forms. Together, these studies have shown the variability of preferences for HIV prevention products across groups and geographies indicating the need for multiple delivery systems to address women’s needs and preferences ,63. n = 526) [In 2009, a consumer product preference study was conducted by IPM comparing a placebo vaginal film, soft-gel capsule and vaginal insert among women in Burkina Faso, Tanzania and Zambia (n = 526) . While tThe recent Quatro study, a collaboration between CONRAD and RTI International, assessed preferences across four vaginal placebo products  among women in Zimbabwe and South Africa using a randomized crossover design . ProductA study with 68 former VOICE trial participants from South Africa, Zimbabwe and Uganda explored preferences for eight different potential microbicide dosage forms  . While tCurrently there is an online survey from Population Council on women’s preferences for multipurpose prevention technologies (MPTs) and HIV/STI prevention methods to understand preferred attributes but also to see if women can be grouped by needs and preferences. While the survey is not complete, it has reached more than 700 women across 50 countries. As of May 2019, a fast dissolving insert (64%) was the most selected method, with gel before sex (63%) and pill before sex (62%) close behind [Building on this growing evidence from end-user research that vaginal inserts are a promising and acceptable dosage form for HIV prevention, studies have also been conducted to further optimize the desirability of inserts. Throughout the development of the CONRAD vaginal insert, for example, acceptability data from clinical use and human-centered design studies were used to inform iterative development of the lead formulation and form. Overall, the insert has been found easy to use and highly acceptable, especially after reformulation between first and second generation products to minimize discharge or leakage see  below. TAs alluded to early in this review, there are a number of factors to take into account when designing and developing an insert for HIV prevention. Key points under each of these factors are presented below in Potency, duration and mechanism of action of the drug(s) to be delivered are important. For example, Population Council’s Griffithsin is a lumenally-active entry inhibitor that must be delivered rapidly to the vagina and retained through the period of potential HIV exposure (coitus); a fast-dissolve, freeze-dried insert that dissolves into a gel form is therefore highly appropriate for this target product profile. For CONRAD’s TAF/EVG insert, however, these two drugs require tissue uptake and, in the case of TAF, intracellular metabolism to the active TFV-diphosphate. For these drugs, a simple compressed insert formulation may be sufficient to enable rapid drug permeation into the surrounding tissues. Understanding the target population and sexual practices of that population is equally important. If a product can be used vaginally as well as rectally, such as the design of CONRAD’s TAF/EVG insert, this may widen the prophylactic coverage across multiple at-risk populations, providing further value added. Physiological factors, including changes or differences in vaginal pH, menstrual cycle, hormone levels, vaginal fluid volume, and stage in the reproductive cycle , must be considered for their effects on insert dissolution/disintegration and drug distribution and absorption . MoreoveArguably the best animal model for evaluating the safety, PK, PD and efficacy of a candidate vaginal insert formulation for HIV prevention is the non-human primate (NHP) model. Of the macaque species used in HIV prevention R&D , rhesus Small animals are also commonly used to evaluate inserts ,35. DispCONRAD has used both macaque and rabbit models in their effort to advance and guide the development of ARV containing inserts and define their safety and PK profiles. Rabbit and pigtail macaque models were used to assess the local and systemic PK of the first-generation TFV/FTC vaginal inserts compared to 1% TFV gel, with similar PK patterns observed across species ,23. The Population Council has used a similar approach to demonstrate the safety and efficacy of their non-antiretroviral product, GRFT/CG insert. The rabbit model was used to evaluate local vaginal irritation. The rat model was used to evaluate vaginal irritation and test for systemic absorption and anti-drug antibodies . The GRFAnimal models can pose limitations, however, for accurately predicting the disintegration and dissolution time of inserts clinically, as discovered during CONRAD’s development of the first-generation TFV/FTC insert product. When tested in both the rabbit and macaque, the TFV/FTC vaginal insert was no longer present at 30 min; however, when tested clinically in women, CONRAD 117, the insert was still intact at 30 min in over 50% of the 48 participants . For at In CONRAD’s experience with compressed inserts, nothing has proven more effective in the confirmatory development of a new formulation than early clinical assessment of placebo formulations. As previously discussed, CONRAD’s first-generation vaginal inserts failed to replicate what had been observed in vitro and in animal models when tested clinically. Therefore, when evaluating the disintegration, residue leakage and acceptability profiles of reformulated inserts, we turned to a small clinical study to inform our lead selection decision making. In CONRAD 134 (NCT02534779) a clinical study conducted at the CONRAD/Eastern Virginia Medical School (EVMS) Clinical Research Center, four placebo vaginal inserts of different composition, technology (compressed v. freeze-dried), shape and/or size  were invIn this study, all four of the improved insert prototypes studied in CONRAD 134 disintegrated faster and had enhanced acceptability over our first-generation inserts in CONRAD 117. Inserts showed rapid initial disintegration, occurring in most cases within 15 min after insertion, with the freeze-dried insert (Type D) being the fastest to completely disappear, doing so within 30 minutes after insertion in all women. Across all groups, minimal to no leakage or product residue was reported. Product acceptability, as assessed by a standardized acceptability questionnaire, focused on two key attributes of the insert: (1) Ease of handling and placement of the vaginal insert, and (2) leakage. Overall, the vaginal insert types were found to be highly acceptable, with a majority of participants reporting they “definitely would” or “probably would” use the insert if it were shown to be effective in preventing HIV and they felt they were at risk. Insertion was rated “very easy” or “fairly/somewhat easy” by 100% of participants in this study. Most of the women (83.3–91.7%) reported that the more directional shape  versus the biconcave disk (Type D) was helpful for insertion. About three-quarters of the users of each insert type felt the size was appropriate, with a greater proportion favoring the Type A and C size over the larger Type B and indicated they did not feel that a smaller insert would be easier to insert. Together, the results from CONRAD 134 provided clinical evidence supporting the continued development of a formulation and form similar to Type C , for theTopical inserts are a promising, user-friendly dosage form for vaginal and/or rectal, on-demand prophylaxis against HIV and/or other STIs. Several product candidates, each employing unique antiviral modalities and drug combinations, are currently in late preclinical or early clinical development, with increasing evidence supporting the acceptability of this highly versatile dosage form. Through incorporation of extensive user feedback, the insert formulations advancing today align with stated user preferences, including how they may better fit into users’ lifestyles and therefore provide potential to more effectively expand the HIV prevention method mix with a discreet, portable, low cost and potentially forgiving on-demand or extended, intermediate dosing regimen. Some of these products are also uniquely suited for developing country manufacturing, storage and distribution. With preclinical proof-of-concept demonstrated for the leading insert candidates in development, and Phase I testing recently completed for some, the greatest challenge for this dosage form is securing the continued support and R&D prioritization amongst potential funding stakeholders to enable further development and clinical advancement of the most promising HIV prevention insert products.Although the current trend in HIV prevention R&D is to develop long-acting systemic formulations, topically applied inserts represent an on-demand option for HIV-negative men and women who do not like to be constantly exposed to HIV drugs, experience side effects, or prefer user-controlled methods. Topical inserts would also be a preferred option for individuals having infrequent sex or short patterns (“seasons”) of potential exposure to HIV and risk. Due to their malleability and the ability to deliver multiple drugs with different physicochemical properties, topical inserts are especially suited for combination methods and multi-indication products or MPTs. With STIs on the rise again, the ability to deliver multiple drugs at high concentrations in the compartments where the infections develop, i.e. cervicovaginal and rectal tracts, will make this dosage form a critical addition to the existing and in-development HIV/STI prevention tools.


To investigate the association between maternal anemia and low/insufficient birth weight.A prospective cohort study of pregnant women who underwent prenatal care at the healthcare units in a municipality of northeast Brazil together with their newborn infants was carried out. The pregnant women were classified as having anemia when the hemoglobin level was below 11 g/dl. Infants who were born full term weighing less than 2500 grams were classified as low birth weight, and those weighing between 2500 and 2999 grams were classified as insufficient weight. The occurrence of maternal anemia and its association with birth weight was verified using crude and adjusted Relative Risk (RR) estimates with their corresponding 95% confidence intervals (95%CIs).adjusted = 1.38 [95% CI: 1.07 to 1.77].The final sample was comprised of 622 women. Maternal anemia was considered a risk factor for low/insufficient birth weight, after adjusting the effect measurement for maternal age, family income, urinary infection, parity, alcoholic beverage consumption during pregnancy and gestational body mass index: RRMaternal anemia was associated with low/insufficient birth weight, representing a risk factor for the gestational outcomes studied. Low birth weight has been widely studied and is an important risk factor for infant morbidity and mortality –4. HowevThe classic risk factors for low birth weight are associated with unfavorable biological, social and environmental conditions that may occur before or during the pregnancy period , 11–13. Although the determinants of both low and insufficient weight at birth are similar, the mechanism that links maternal anemia to insufficient birth weight is not fully known. Few prospective cohort studies have analyzed the association between maternal anemia and low birth weight –25. IndeGiven the relevance of the theme, the high frequency of insufficient birth weight in the studied group, and the knowledge that the association between maternal anemia and birth weight is affected by demographic and socioeconomic factors, an investigation of this relationship in diverse populations is necessary to identify the groups at greatest risk. The objective of this study was to verify the frequency of maternal anemia and its association with low/insufficient birth weight in users of the public health service from a population in northeastern Brazil.A prospective analytical cohort study was carried out with pregnant women, who underwent prenatal follow-up at healthcare units in the urban area of Santo Antônio de Jesus, Bahia, Brazil, and their newborns. The data collection period was from January 2013 to March 2017.versus not exposed to anemia of 1:3. A study power of 80%, alpha error of 5% and the 95% confidence interval were also considered. Thus, the minimum estimated sample size was 141 pregnant women in the group diagnosed with anemia and 421 in the non-anemic group. In addition, 10% was added to the sample size to correct for possible losses, with a minimum sample calculation of 618 pregnant women. The sample size was calculated using Epi Info , version 7 [To calculate the sample size, the following parameters were used: an Odds Ratio of 2.36 , the freersion 7 .The present study was approved by the Research Ethics Committee of Feira de Santana State University. All pregnant women voluntarily participated in the study and signed the Free Consent Form.The pregnant women in this study had the following: pregnancy with fetal gestational ages between 8 and 32 weeks, assistance from the public health system, prenatal care from the selected healthcare units, live births, and children available for the study.Women were excluded from the study if they had a twin pregnancy, preterm birth or a history of bleeding that required hospital treatment for at least 24 hours.Information concerning the pregnant women was first obtained through interviews. Then, trained researchers performed blood collections, and oral examinations of all teeth were performed by a dentist according criteria defined previously , 29.The data that could not be obtained during the interview were acquired from the patient's chart and/or pregnancy card. During the postpartum period, information on birth weight was collected from the birth registration document (Declaration of Live Births).The questionnaire form was divided into six sections: 1) identification, socioeconomic-demographic data and environmental data; 2) nutritional information; 3) gynecological-obstetric history; 4) drug information; 5) variables related to the anthropometry of the pregnant woman; and 6) information concerning childbirth.The blood collection followed the standard criteria of collection and storage  to obtaiBirth weight was measured immediately after delivery on a precise scale and subsequently recorded in the Declaration of Live Birth by a health professional who participated in the birth .Study participants were diagnosed as having maternal anemia when the hemoglobin level was below 11 g/dl or when the hematocrit was less than 33% 32). Additionally, the participants were diagnosed with iron deficiency anemia when the reference value for serum ferritin was less than 15 femtoliters and the mean corpuscular volume (MCV) was less than 80 femtoliters [. AdditioThe classification of birth weight was defined according to the criteria of the World Health Organization . ChildreDescriptive analysis for all selected variables was performed, according to the relative and absolute frequency. The Kolmogorov-Smirnov test  was applThe investigation of the association between maternal anemia and low/insufficient birth weight was performed using logistic regression analysis by estimating the crude and adjusted odds ratio (OR) with their 95% confidence intervals and a significance level of 5%. Poisson model was used to convert the association measurement in relative risk (RR) with it 95% confidence interval.Initially, a conceptual framework was adopted to select the following covariables involved in the multicausality of the association between maternal anemia and low/insufficient birth weight: maternal age, family income, urinary infection, parity, alcoholic beverage consumption during pregnancy and gestational BMI.Subsequently, potential confounding factors and effect modification were selected by stratified analysis. The interaction identification was performed using the maximum likelihood ratio test, according to the definition of the saturated and reduced models for each of the possible effect modifier variables. A covariable was considered confounding when, after being eliminated from the saturated model, the covariable promoted a variation in the effect measurement that was greater than 10%compared to the main association measurement. In addition, the criterion of epidemiological importance for the selection of confounding covariables was adopted during modeling. The diagnosis of the model was performed using the Hosmer-Lemeshow test .To evaluate the relationship between hemoglobin levels and the outcome, the multicollinearity test was performed, followed by univariate and multiple linear regression analysis using the common minimum squares technique , after cThe sample consisted of 622 pregnant  women whThe pregnant women were classified into two groups per the maternal anemia diagnostic criteria: 24.9% (n = 155) with anemia and 75.1% (n = 467) without anemia. Regarding the severity of maternal anemia, 20.1% of the pregnant women were diagnosed with mild anemia, and 4.8% were diagnosed with moderate anemia; there was no record of severe maternal anemia. The frequency of iron deficiency anemia was 6.0% among the participants, whereas the frequency of anemia of chronic disease was 18.9%. Iron deficiency was present in 16.4% of the pregnant women.The socioeconomic-demographic data are described in Regarding birth weight, 29.4% (183) of the participants had children with birth weights less than 3000 g, with 3.4% of the live births being classified as low birth weight and 26% being classified as insufficient birth weight. The frequency of mothers who had children of satisfactory weight was 70.6% (439). The centile for birthweight were 2940 grams, 3272 grams and 3565 grams for 25%, 50% and 75%, respectivelyThe central tendency measures of the descriptors used for the diagnosis of maternal anemia, according to birth weight, are summarized in crude = 1.36; 95% CI: 1.06 to 1.76). According to the multiple-adjusted model, pregnant women with anemia had a 38% higher risk of having children with low/insufficient weight at birth than the women without anemia  in the weight of the newborn per 1 g/dl of reduced maternal hemoglobin during the gestational period. In the saturated model, which was adjusted for the above-mentioned confounders, there was a 0.20-g decrease (p = 0.05) in birth weight per 1 g/dl of maternal hemoglobin lost during pregnancy.Despite a rigorous search of a large number of electronic databases, only two cohort studies were found that discussed the relationship between maternal anemia and insufficient birth weight , 6. StudThe biological plausibility of the association between maternal anemia and low/insufficient birth weight is not fully understood , 46. HowThus, low hemoglobin levels may stimulate changes in placental angiogenesis and favor fetal hypoxia. According to this theory, a reduction in nutrients and oxygen to the fetus due to deficits in placental transport may result from hemoglobin depletion. The potential framework of uterine growth restriction begins with a reduction in blood perfusion in the uterus, an elevation in vascular resistance and growth restriction of the trophoblastic surface, which is responsible for ejecting maternal arterial blood into the placenta. These events may result in the restriction of gas exchange within the maternal-fetal complex and, consequently, in low/insufficient birth weight .Within the scope of the present investigation, the findings of only one study clearly point to the association between maternal anemia and a birth weight of less than 3000 g  since thMultiple investigations have shown that maternal anemia is associated with low birth weight –55. ConvA similarity does exist between low birth weight and insufficient weight, but the former is considered more serious than the latter for the newborn. However, the unfavorable effect produced by insufficient birth weight cannot be ignored since this condition may contribute to inadequate cognitive development and infant growth and increase the morbidity and mortality of this age group .The findings of the present investigation are relevant in that they contribute to a better understanding of the importance of insufficient birth weight to pediatric health, and several method-related parameters, such as the sample size, diagnostic criteria for maternal anemia and treatment of confounders, should be carefully evaluated when comparing these results to those of previous studies on the topic.The sample size of the present study exceeded the minimum calculated sample size to estimate the effect measurement. The total number of pregnant women involved in the study by Mesa et al. (2012)  was apprRegarding the diagnosis of anemia in the present investigation, to improve internal validity, a laboratory test was used to define maternal anemia, establishing a hemoglobin reference value <11 g/dl and confirming the result with a hematocrit <33%. These criteria are recommended by the World Health Organization . Mesa etThe subclassification of maternal anemia is highly valuable to ensure the adequate monitoring of pregnant women. For example, the diagnosis of iron deficiency anemia may facilitate therapy for the disease with iron supplementation. Increasingly, iron deficiency anemia has been classified as maternal anemia since multiple reports in the literature support the hypothesis that the primary cause of anemia in pregnant women is ferritin deficiency , 59–62. Regarding severity levels, the participants in this study had a higher frequency of mild anemia. This severity was expected because much of the research converges in this direction , 66–69.In the present investigation, the effect measurement was adjusted by confounders, due to knowledge of the possible effects of these covariables on both the exposure factor and the outcome. This criterion was also used in the study by Raisanen et al. (2014) , which cAccording to the conceptual framework adopted here and the multicausality involved in the association between maternal anemia and low/insufficient birth weight, the following covariables were considered in the adjustment of the final model: maternal age, family income, urinary infection, parity, alcoholic beverage consumption during pregnancy and gestational BMI.Unfavorable socioeconomic-demographic factors can influence both the exposure and the gestational outcome of interest. Maternal age, in its extreme age ranges, is a classical confounding variable because younger women do not have complete biological maturity for gestation and because older women are more likely to have comorbidities, such as maternal anemia , 64). ReInfectious processes, such as urinary infection, influence the metabolism of new hemoglobin, leading to the development of maternal anemia , and intAlcoholic beverage consumption during pregnancy can cause inflammatory disorders that restrict intrauterine growth, a contributing factor to low/insufficient birth weight , 70. AlcRegarding the limitations of this investigation, the self-reported information may have produced calibration bias. Although the sample is representative of the urban population of the municipality investigated, caution should be exercised when interpreting the results by extrapolating them to other locations that do not have a population group that is similar to the one in this study. Other limitation is the exclusion of preterm births, since the source of information in Brazil about gestational age may be distorted, due to the absence of standardization of criteria used to define preterm birth. On the other hand, the low birth weight as outcome gave higher quality to the measurement due to its standardized form of collection , 71. RegFinally, this research can contribute information that has not previously been elucidated toward confirming the hypothesis. The temporality of the events, namely, the order of the exposure relative to the outcome, is established since the laboratory tests for the diagnosis of maternal anemia preceded delivery and birth. Possible sample losses were measured prior to the study, which assures the representativeness and power of the sample size and the reliability of the presented findings. The adoption of these criteria also minimizes the possibility of a spurious association. Furthermore, the use of validated instruments by the researchers, who were previously trained, strengthens the internal validity of this study.Based on the method employed and the limitations described, the exposure investigated was confirmed as a risk factor for low/insufficient birth weight. Given the findings, a far-reaching measure in public health would be the implementation of healthcare actions for the prevention and control of maternal anemia, aiming to reduce unfavorable gestational outcomes.