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Date: Nov 14, 2019 To: "Andrew Chon"
From: "The Green Journal" [email protected] Subject: Your Submission ONG-19-1847
RE: Manuscript Number ONG-19-1847
A case of refractory immune thrombocytopenia in pregnancy: multi-drug therapy Dear Dr. Chon:
Your manuscript has been reviewed by the Editorial Board and by special expert referees. Although it is judged not acceptable for publication in Obstetrics & Gynecology in its present form, we would be willing to give further consideration to a revised version.
If you wish to consider revising your manuscript, you will first need to study carefully the enclosed reports submitted by the referees and editors. Each point raised requires a response, by either revising your manuscript or making a clear and convincing argument as to why no revision is needed. To facilitate our review, we prefer that the cover letter include the comments made by the reviewers and the editor followed by your response. The revised manuscript should indicate the position of all changes made. We suggest that you use the "track changes" feature in your word processing software to do so (rather than strikethrough or underline formatting).
Your paper will be maintained in active status for 21 days from the date of this letter. If we have not heard from you by Dec 05, 2019, we will assume you wish to withdraw the manuscript from further consideration.
REVIEWER COMMENTS:
Reviewer #1:
I have read with interest the case report on refractory ITP in pregnancy by Cohen A et al.
The issue of resistant ITP in pregnancy is very important and deserves research and publications to guide the medical staff taking care of these women.
I recommend the authors to have a look at four important publications, the first two are on pregnancy thrombocytopenia and the other two are on the recent changes in treatment approach to ITP:
1. ASH guidelines on ITP in pregnancy (2013 Clinical Practice Guide on Thrombocytopenia in Pregnancy. Anita Rajasekhar, Terry Gernsheimer, Roberto Stasi, Andra H. James)
2.How I treat thrombocytopenia in pregnancy.
Terry Gernsheimer, Andra H. James, and Roberto Stasi. (Blood. 2013 121(1):38-47
3.Revised ASH guidelines on treatment of ITP (Neunert CE, Cooper N. Evidence based management of immune thrombocytopenia: ASH guideline update. Hematology Am Soc Hematol Educ Program 2018,568-75), with changing treatment options compared to the past.
4. Matzdorff A, Meyer O, Ostermann H et al. Immune thrombocytopenia — current diagnostics and therapy:
recommendations of a joint working group of DGHO, ÖGHO, SGH, GPOH, and DGTI.
Oncol Res Treat 2018;41:Suppl 5:1-30.
My comments on the manuscript are as following:
1.line 44- corticosteroids and/or intravenous immunoglobulins .
2.line 85, 89,93,100-what was the IVIG protocol used? 0.4 gr/kg/d for 5 days or 1gr/kg/d for 2 days? how was the IVIG dose calculated?
3.line 91-92-Did the patient have bleeding phenomena in fundi/mucosa examination at 17 weeks?
4. line 88-What was the indication for platelets infusion on 17 weeks ?was there any evidence for major bleeding? life threatening bleeding? planned procedure? platelet transfusion is generally ineffective in ITP.
5.line 95,105-it should be clarified that splenectomy is recommended during second trimester because of increased preterm labor during early pregnancy and technical problems during third trimester.
View Letter .
1 of 5 12/2/2019, 10:47 AM
6.line 96-97- how was the rituximab dose calculated?375mg/m2?
7.line 97-why was romiplastin started one week after rituximab? rituximab effect may take a few days to weeks….
8.line 111-112- what was the platelet count in delivery room?
9. Did the patient get platelet transfusion during c-section?
10.line 144-145- the statement is incorrect for non- pregnant adults!!!! (see German guidelines and ASH 2018 guidelines).
It may be true for 2nd trimester pregnant women, unless there are contraindications.
11.line 158- platelet count falls below 30 x 109 /L (ASH 2013)
Reviewer #2: Thank you for this case report Abstract:
I am glad to see 6 month follow up, can you put in one line about planned follow up for the infant beyond this (if any) Can you make clear if the three medications were added together or sequentially.
I would add a teaching point on the necessary follow up and what to look for in the neonate.
Intro: I would include a line in this section about the transplacental passage of antibodies as this is an important point of management and you address it later.
Case:
line 118: first sentence reads strangely, and should be readdressed.
Otherwise well described.
Discussion:
Overall a thorough discussion. The question I came away with after your case description was how does ritumixab differ from belimumab in action, as the patient seemed stable on the second medicine before and after pregnancy, and was there consideration of using that? If not, why not. As a general OBGYN I am not intimately familiar with these different immune modulators and why one would be used over another in pregnancy.
Reviewer #3:
General:
This is a case report describing the medical management of a woman with refractory ITP managed with during her pregnancy.
Specific:
1. Line 77-78: Is her history of preeclampsia relevant to her current pregnancy? Does this information need to be included in the case report.
2. Line 78-79: As this patient has SLE complicated by ITP, is the treatment of her refractory ITP generalizable to a patient without SLE? This should be discussed in the discussion section.
3. Lines 84-93: Who was involved in the treatment decisions of her ITP? Was this a multidisciplinary team involving MFM, Hematology, etc? This information should be included.
4. Line 95-96: How was this patient counseled regarding risks and benefits of medical management vs splenectomy?
And who was involved in the counseling? Do you think this introduced bias in her decision? What were the patient's reasons for declining splenectomy?
5. Line 109-110: How would you describe worsening thrombocytopenia? Is there a specific platelet count at which you would recommend a preterm delivery? Or would this be based on a combination of things? Is a preterm delivery for ITP indicated?
6. Line 145: Please reword.
View Letter ..
2 of 5 12/2/2019, 10:47 AM
7. Line 147-149: How common are splenectomy complications?
8. Line 151-153: How high is the risk for sepsis and thromboembolic complications in a patient with SLE? Could her thromboembolic risks not be reduced with DVT prophylaxis? Do you think these risks were too high to offer her a splenectomy?
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- please use full sentences in your manuscript.
- how is it known that this drug is the caue of the infant's B-cell suppression? What special care if anywas recommended for the child until the B-cell suppression corrected?
- Is this severe ITP data or severe thrombocytopenia from any cause?
- efficacy and safety data for what?
- any concerns about prescribing steroids in the face of pneumonia?
- normal or appropriate post vaccine titres were present?
- please comment on bleeding anticipated at time of delivery
- Would you consider moving the information from lines the drugs used in her care a bit earlier in the discussion? Many of our readers will be unfamiliar with these medications, their side effects, and the idea of using them synergistically. Please consider adding some estimate of costs for the medications she received based on your hospital's charge master. Then give discuss the specifics about her care you wish to highlight.
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3 of 5 12/2/2019, 10:47 AM
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View Letter
5 12/2/2019, 10:47 AM
Nancy C. Chescheir, MD Editor-in-Chief
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View Letter
5 12/2/2019, 10:47 AM
November 28, 2019
Re: A case of refractory immune thrombocytopenia in pregnancy: multi-drug therapy Dear Editors:
Enclosed please find the revised version of above-referenced manuscript that we are re-
submitting for your consideration in Obstetrics & Gynecology. Portions of this manuscript have not been presented elsewhere.
This case report describes the antenatal course and postnatal outcome of a patient with severe refractory immune thrombocytopenia (ITP). We report on the usage of second-line medications, highlighting romiplostim and rituximab. The patient was able to avoid a splenectomy and delivered at full-term. Furthermore, we provide postnatal outcomes for the infant.
Each reviewer comment was addressed and the changes were incorporated with track changes.
Although the case report now exceeds the recommended word and reference limits, we request that the Editors still consider our submission as there are limited data available on romiplostim and rituximab use in pregnancy. We believe that readers of Obstetrics & Gynecology, many of whom care for pregnant patients with ITP will be interested in learning about additional medications that can effectively raise maternal platelet counts beyond intravenous immunoglobulin and corticosteroids.
Dr. Chon shall be the correspondent of record. The telephone number, fax number and address are on the title page of the manuscript. All authors certify that they have participated sufficiently in the writing of the manuscript. This case report has not been published nor is being considered for publication elsewhere. The manuscript will not be submitted elsewhere unless a final negative decision is made by the Editors of Obstetrics & Gynecology.
Dr. Chon affirms that this manuscript is an honest, accurate, and transparent account of the case being reported; that no important aspects of the case have been omitted. A signed consent form has been obtained from the patient described in the case report and retained by the authors. We certify that we have no affiliation with or financial involvement in any organization or entity with a direct financial interest in the subject matter, or materials discussed in the manuscript. Again, thank you very much for your consideration of this manuscript. If we can answer any questions, please do not hesitate to contact us.
Sincerely yours,
Andrew H. Chon, MD
REVIEWER COMMENTS:
Reviewer #1:
I have read with interest the case report on refractory ITP in pregnancy by Cohen A et al.
The issue of resistant ITP in pregnancy is very important and deserves research and publications to guide the medical staff taking care of these women.
Thank you for the comment. Please see our responses below.
I recommend the authors to have a look at four important publications, the first two are on pregnancy thrombocytopenia and the other two are on the recent changes in treatment approach to ITP:
1. ASH guidelines on ITP in pregnancy (2013 Clinical Practice Guide on
Thrombocytopenia in Pregnancy. Anita Rajasekhar, Terry Gernsheimer, Roberto Stasi, Andra H. James)
2.How I treat thrombocytopenia in pregnancy.
Terry Gernsheimer, Andra H. James, and Roberto Stasi. (Blood. 2013 121(1):38-47
3.Revised ASH guidelines on treatment of ITP (Neunert CE, Cooper N. Evidence based management of immune thrombocytopenia: ASH guideline update. Hematology Am Soc Hematol Educ Program 2018,568-75), with changing treatment options compared to the past.
4. Matzdorff A, Meyer O, Ostermann H et al. Immune thrombocytopenia — current diagnostics and therapy: recommendations of a joint working group of DGHO, ÖGHO, SGH, GPOH, and DGTI.
Oncol Res Treat 2018;41:Suppl 5:1-30.
Thank you for the recommendations. The 2013 publication by Rajasekhar et al. and Gernsheimer et al. were added to support the threshold of platelet counts < 30 x 109/L for ITP treatment in pregnancy in the 2nd paragraph on page 8.
We referenced the Matzdorff et al. article in the Introduction in the section discussing transplacental passage of antiplatelet antibodies.
Both the Neunert et al. (2018) and Matzdorrf et al. references were incorporated into the Discussion as recommended by the reviewer when discussing recent expert opinion on
splenectomy versus second-line medications on page 8. The Matzdorrf et al. reference was also utilized in the Discussion on platelet thresholds for major surgery on page 9.
My comments on the manuscript are as following:
1.line 44- corticosteroids and/or intravenous immunoglobulins .
Thank you for the comment. We edited the abstract Background as, “Severe immune thrombocytopenia (ITP) complicating pregnancy may require treatment beyond first-line medications (intravenous immunoglobulins and/or corticosteroids).”
2.line 85, 89,93,100-what was the IVIG protocol used? 0.4 gr/kg/d for 5 days or 1gr/kg/d for 2 days? how was the IVIG dose calculated?
Thank you for the comment. The IVIG dose was calculated with the intent of using the minimum dose to achieve the desired therapeutic effect. We did not adhere to a strict protocol. Rather, used the combined experience of Hematology and MFM, as well as the patient’s response to prior antenatal doses. The 2nd paragraph on page 4 was edited as, “The dose of IVIG administered throughout the antenatal course did not adhere to a strict protocol. The estimated lowest dose that was able to maintain the desired therapeutic effect on the platelet counts was administered.”
3.line 91-92-Did the patient have bleeding phenomena in fundi/mucosa examination at 17 weeks?
Thank you for the comment. The patient did not undergo ophthalmologic examination at that time but was not complaining of vision changes. This has been clarified on page 4 of the case description as, “The patient did not undergo ophthalmologic evaluation as there were no acute changes in her vision.”
4. line 88-What was the indication for platelets infusion on 17 weeks? Was there any evidence for major bleeding? life threatening bleeding? planned procedure? platelet transfusion is generally ineffective in ITP.
Thank you for the comment. There was no life-threatening bleeding or a planned procedure.
However, the indication for platelet transfusion was active bleeding based on gingival bleeding and new purpura in the setting of critically low platelet counts. From the ASH 2011 guidelines:
"...because of the critical nature of the situation, physicians may wish to try treatments with evidence limited to case reports but which may be in theory more rapidly acting than IVIg and/or corticosteroids. The following have been reported to be effective in the treatment of bleeding:
Platelet transfusion ranging from transfusions every 30 minutes to 8 hours, and platelet transfusions in conjunction with a continuous infusion of IVIg. These report either a rapid reduction in bleeding and/or an improvement in the platelet count. The effect on the platelet count does appear to be short-lived.”
The statement on page 4 has been clarified as, “She was given one apheresis unit of platelets for active bleeding…”
5.line 95,105-it should be clarified that splenectomy is recommended during second trimester because of increased preterm labor during early pregnancy and technical problems during third trimester.
Thank you for the comment. The patient was informed that the occurrence of pregnancy loss is often cited as a reason to avoid surgery in the 1st trimester. However, the caveat being that in most scenarios, the surgery itself is not considered the cause of pregnancy loss. Rather, that pregnancy loss naturally occurs more often in the 1st trimester compared to the 2nd and 3rd trimesters. We agree that the gravid uterus poses technical challenges to performing a
splenectomy, whether it be by laparoscopy or laparotomy. The details of this discussion were added to page 6 as, “Included in this discussion was the potential need for requiring a
splenectomy at a later gestational age and the technical challenges in the 3rd trimester due to the gravid uterus (i.e., need for laparotomy, preterm labor from uterine manipulation).”
6.line 96-97- how was the rituximab dose calculated? 375mg/m2?
Thank you for the comment. We agree that the typical dose of rituximab for ITP treatment is 375mg/m2 x 4 weekly doses. Based on Hematology recommendations, the rituximab dose utilized in this case was 500mg/m2 x 2 doses. This has been clarified in the two locations within the case description on page 5 as, “Rituximab 500 mg/m2 IV was subsequently administered.”
and “She continued to have mild intermittent thrombocytopenia and a 2nd dose of rituximab 500 mg/m2 was given at 21 weeks
7.line 97-why was romiplastin started one week after rituximab? rituximab effect may take a few days to weeks….
Thank you for the comment. We agree that the time for the platelet count to respond to rituximab is on the order of several weeks. The decision was made by Hematology to add romiplostim without waiting this interval due to the severity of maternal thrombocytopenia. Page 9 of the Discussion has added this as a limitation, “Due to overlapping intervals from medication administration and time to platelet count response (weeks), the individual therapeutic contribution of each drug could not be determined.”
8.line 111-112- what was the platelet count in delivery room?
The maternal platelet count prior to delivery was 194 x 109/L. The sentence has been edited as,
“The patient was induced at 37 weeks for gestational hypertension with a platelet count of 194 x 109/L.”
9. Did the patient get platelet transfusion during c-section?
The patient did not require any pRBC or platelet transfusions. The second paragraph on page 6 was edited as, “An emergent cesarean delivery was performed without complications for umbilical cord prolapse. The patient did not require transfusion of blood products.”
10.line 144-145- the statement is incorrect for non- pregnant adults!!!! (see German guidelines and ASH 2018 guidelines). It may be true for 2nd trimester pregnant women, unless there are contraindications.
Thank you for the comment. We have edited the lines on page 8 to reflect more recent guidelines as, “Surgical management via splenectomy historically was recommended in non-pregnant adults as second-line therapy if corticosteroids were ineffective. However, recent guidelines suggest that the decision to proceed with splenectomy versus adding second-line treatment options such as thrombopoietin receptor agonists and rituximab should be individualized since such drugs have the potential to be splenectomy sparing.”
11.line 158- platelet count falls below 30 x 109/L (ASH 2013)
Thank you for the comment. We have edited the statement on page 9 as, “In pregnancy,
treatment is generally reserved for when the patient is symptomatic, platelet count falls below 30 x 109/L”
Reviewer #2:
Thank you for this case report
Abstract:
I am glad to see 6 month follow up, can you put in one line about planned follow up for the infant beyond this (if any)
Thank you for the comment. Routine follow-up is planned beyond the 6-month period. An additional clarifying statement has been added at the end of the case presentation on page 7, “At the time of this writing, the infant was meeting all developmental milestones at 7 months of age and is being followed in our primary care clinic.”
Can you make clear if the three medications were added together or sequentially.
Thank you for the comment. The patient was sequentially glucocorticoids, IVIG, rituximab, romiplostim and azathioprine. The timeline of administration of each agent is described in the case report as well as visually depicted in Figure 1 which is referenced in the 2nd paragraph on page 4.
I would add a teaching point on the necessary follow up and what to look for in the neonate.
Thank you for the suggestion. We have added an additional teaching point on page 2 as, “After maternal rituximab administration, the neonate should be monitored for transient B-cell
suppression and other hematologic abnormalities.”
Intro: I would include a line in this section about the transplacental passage of antibodies as this is an important point of management and you address it later.
Thank you for the comment. We have added a brief explanation of the neonatal implications of transplacental passage of antibodies in the Introduction as, “The fetus can also be affected by maternal ITP due to transplacental passage of platelet antibodies leading to thrombocytopenia in the newborn. The risk of severe neonatal thrombocytopenia (< 50 x 109/L) is approximately 10%, with intracranial hemorrhage occurring in less than 1.5% of infants with
thrombocytopenia.”
Case:
line 118: first sentence reads strangely, and should be readdressed.
Otherwise well described.
Thank you for the comment. We have edited the statement as, “After delivery, the neonate was initially closely followed by the neonatologist and hematologist.”
Discussion:
Overall a thorough discussion. The question I came away with after your case description was how does ritumixab differ from belimumab in action, as the patient seemed stable on the second medicine before and after pregnancy, and was there consideration of using that? If not, why not. As a general OBGYN I am not intimately familiar with these different immune modulators and why one would be used over another in pregnancy.
Thank you for the comment. Due to the space limitations, the similarities and differences between rituximab and belimumab were not originally discussed in the manuscript.
Although both are monoclonal antibodies, they have different mechanisms of action. Rituximab is a B-cell monoclonal antibody that induces apoptosis of B-cells. It binds specifically to antigen CD20 on pre-B and mature B lymphocytes and mediates B-cell lysis via complement-mediated mechanisms. Belimumab is a monoclonal antibody that inhibits the binding of soluble human B lymphocyte stimulator protein (BLyS) to its receptors on B-cells. BLyS is a B-cell survival factor, and belimumab therefore inhibits the survival of B-cells and reduces the differentiation of B-cells into immunoglobulin producing cells.
The use of rituximab in SLE management is controversial and not routinely used. Rather, it is more commonly used for conditions such as ITP, B-cell lymphoma, and rheumatoid arthritis. On the contrary, belimumab is used in SLE patients because levels of BLyS are elevated in some lupus patients. For instance, it has been reported to be effective in lupus patients with
musculoskeletal manifestations who are unresponsive to glucocorticoids or other
immunosuppressive agents. The use of belimumab is not well-studied in ITP and considered investigational.
The following paragraph has been added to page 9 of the Discussion to elaborate on rituximab compared to belimumab. “Belimumab, a monoclonal antibody that binds the soluble B-cell growth factor B lymphocyte stimulator (BLyS, alternatively B-cell activating factor {BAFF}), reduces B-cell activity and has been studied in the management of SLE. As it inhibits B-cell activation and expansion via removal of growth factor, it does not remove memory B-cells.
Unlike rituximab, thus far it has not been extensively studied for ITP and is not in current guidelines for ITP. Its effect on the fetus has not been formally studied, but one trial noted similar rates of pregnancy loss with placebo and another noted primarily normal live births.”
Reviewer #3:
General:
This is a case report describing the medical management of a woman with refractory ITP managed with during her pregnancy.
Specific:
1. Line 77-78: Is her history of preeclampsia relevant to her current pregnancy? Does this information need to be included in the case report.
We agree that the history of preeclampsia is not relevant to her current pregnancy. The statement has been removed from the case description. The patient description now reads, “The patient is a 29-year-old G2P0101 with a history of systemic lupus erythematosus (SLE) with ITP diagnosed 7 months after her first pregnancy which responded to methylprednisolone followed by
rituximab.”
2. Line 78-79: As this patient has SLE complicated by ITP, is the treatment of her refractory ITP generalizable to a patient without SLE? This should be discussed in the discussion section.
Thank you for the comment. The management of ITP with or without SLE is similar. This concept has been highlighted in the Discussion on page 7 as, “ITP can occur prior to the
development of SLE, acutely during a lupus flare, or as a chronic complication. The management of ITP with or without concurrent SLE is similar and glucocorticoids are usually considered first- line therapy. In cases of refractory ITP associated with a SLE flare, control of the flare may lead to improvement in thrombocytopenia and reduce the need for second-line medications.
Our patient had ITP in the absence of a lupus flare and required five medications in the antepartum period to maintain the platelets at an acceptable level.”
3. Lines 84-93: Who was involved in the treatment decisions of her ITP? Was this a multidisciplinary team involving MFM, Hematology, etc? This information should be included.
We agree it is important to highlight the coordinated multidisciplinary care of this patient. The case presentation details on page 4 has been edited as, “The platelet count continued to fall, and under the guidance of Maternal-Fetal Medicine, Hematology and Rheumatology at 16 weeks her prednisone was increased to 20 mg daily and she was given IVIG 500 mg/kg (preceded by dexamethasone 10 mg).”
4. Line 95-96: How was this patient counseled regarding risks and benefits of medical management vs splenectomy? And who was involved in the counseling? Do you think this introduced bias in her decision? What were the patient's reasons for declining
splenectomy?
Thank you for the comment. Maternal-Fetal Medicine coordinated the multidisciplinary care between MFM, Hematology, and General Surgery. The pros and cons of splenectomy versus escalation of medical care were discussed in detail with the patient. We believe bias was
minimized in this patient’s counseling because both the surgical and non-surgical medical teams were had significant experience in managing refractory ITP as well as operating in pregnant patients. The surgeons involved with the care of this patient had the ability to perform a splenectomy either via laparoscopy or laparotomy. Similarly, the Hematologists and Maternal- Fetal Medicine physicians were experienced with the management of ITP in pregnancy.
The patient ultimately declined splenectomy twice because she was unwilling to incur the potential surgical risks (conversion to laparotomy, catastrophic bleeding, venous
thromboembolism, infection, etc). Understanding that there was limited data available on the second-line agents in pregnancy, and that there may be potential maternal and/or fetal risks that have yet to be reported, she elected to proceed with medical management.
The main points of this discussion between providers and the patient was highlighted on page 4 as, “Given the persistence of severe thrombocytopenia despite first-line agents, a
multidisciplinary meeting was held with the patient and Maternal-Fetal Medicine, General Surgery, and Hematology to discuss the options of laparoscopic splenectomy versus escalating medical management. She was informed that splenectomy results in an initial increase in platelet counts in approximately 80% of patients, thereby reducing the likelihood of requiring additional medications. Risks included conversion to laparotomy, bleeding, venous thromboembolism, infection and non-response of platelet counts. Escalation of medical care would avoid the upfront surgical risks; however, she was informed that the available data on second-line agents was limited and potential long-term adverse effects on the offspring remain largely unknown. After a thorough discussion of the pros and cons of management options, the patient was unwilling to accept the surgical risks and elected to continue medical management. She did however receive prophylactic vaccinations indicated for asplenia in the event splenectomy would be performed in the future.”
5. Line 109-110: How would you describe worsening thrombocytopenia? Is there a specific platelet count at which you would recommend a preterm delivery? Or would this be based on a combination of things? Is a preterm delivery for ITP indicated?
Thank you for the comment. In general, there is not specific platelet count with ITP in which delivery is recommended. However, in light of what was already known about how severe and refractory this patient’s thrombocytopenia could become, we remained cautiously optimistic as the gestational age reached full-term. Particularly, we anticipated needing to balance the risk of maternal bleeding complications at delivery as well as her candidacy for regional anesthesia. The case description on page 5 was edited as, “Although ITP is not an indication for iatrogenic preterm delivery, in light of what was already known about this patient’s refractory nature of thrombocytopenia, consideration was given to possible delivery beyond 34 weeks if platelet counts trended downwards. The patient’s candidacy for regional anesthesia as well as potential for bleeding complications at delivery were considered factors in this decision making.”
6. Line 145: Please reword.
Thank you for the comment. As part of our response to reviewer #2 in discussing more recent guidelines, we have edited the line as, “Surgical management via splenectomy historically was recommended in non-pregnant adults as second-line therapy if corticosteroids were ineffective.”
7. Line 147-149: How common are splenectomy complications?
Reported splenectomy complications vary widely. Based on limited data, certain complications such as blood transfusion and longer hospital stay may be more common in pregnant than non- pregnant patients. The Discussion on page 8 has been edited as, “Reported complication rates vary widely, but are estimated to occur at a rate of 13% with laparotomy and 10% with laparoscopy. Certain complications such as blood transfusions and longer hospital stay may occur more frequently in pregnant compared to non-pregnant patients.”
8. Line 151-153: How high is the risk for sepsis and thromboembolic complications in a patient with SLE? Could her thromboembolic risks not be reduced with DVT prophylaxis?
Do you think these risks were too high to offer her a splenectomy?
Thank you for the comment. Patients with SLE are at a relatively increased risk of infections and thromboembolic events. More than 1/3 of SLE patients are diagnosed with an infection at some point. The risk of a thromboembolic event is estimated to be approximately 10%. Such details were omitted from the Discussion given the limited space. We have since added supporting references for the interested reader to further investigate. If the reviewer feels strongly that they specific statistics should be included, we can certainly insert them. Although the risk of
thrombosis is reduced with DVT prophylaxis, both Hematology and MFM had reservations about anticoagulation in the setting of the patient’s vacillating platelet counts.
In spite of such risks, the multidisciplinary team did not feel the absolute risks of infection and thrombosis were too high to offer a splenectomy. Although it was presented as an option to the patient, she ultimately declined surgical management. This has been clarified in the first paragraph in the Discussion on page 8 as, “Such relative risks were discussed with the patient, but were not considered contraindications to proceeding with a splenectomy.”
Not all infections lead to sepsis, therefore we have edited the statement in the Discussion to more accurately reflect this as, “In addition, our patient was at higher risk for infection and
thromboembolic complications associated with splenectomy because of her underlying SLE…”
EDITOR COMMENTS:
Thank you for your submission to Obstetrics & Gynecology. In addition to the comments from the reviewers above, you are being sent a notated PDF that contains the Editor’s specific comments. Please review and consider the comments in this file prior to submitting your revised manuscript. These comments should be included in your point-by-point response cover letter.
1. We no longer require that authors adhere to the Green Journal format with the first submission of their papers. However, any revisions must do so. I strongly encourage you to read the instructions for authors (the general bits as well as those specific to the feature- type you are submitting). The instructions provide guidance regarding formatting, word and reference limits, authorship issues, and other things. Adherence to these requirements with your revision will avoid delays during the revision process, as well as avoid re-
revisions on your part in order to comply with the formatting.
Thank you for the comment. The manuscript is revised to the specifications of the Green Journal.
Prior to the requested revisions, the abstract and manuscript word counts met the recommended limits. As a result of incorporating the revisions, the word limits have been exceeded. However, we strongly believe that the manuscript in its entirety provide relevant information on a
challenging clinical dilemma. Please inform us if the exceeded word limit is unacceptable and we will put forth every effort to trim the content further.
2. please use full sentences in your manuscript.
Thank you for the comment. The statement in the case presentation of the abstract on page 2 edited as, “The patient is a 29-year-old with early-onset severe ITP at 13 weeks’ gestation.”
3. how is it known that this drug is the cause of the infant's B-cell suppression? What special care if any was recommended for the child until the B-cell suppression corrected?
Thank you for the comment. Given prior reports of rituximab being associated with transient B- cell suppression in the neonate, this was assumed to be cause of mildly decreased IgM levels in our case. “This point is elaborated on page 10 as, “Our neonate initially had a mildly suppressed level of IgM level—suggestive of transient B-cell suppression from transplacental passage of rituximab—followed by rapid normalization of IgM levels, demonstrating return of adequate B- cell function. Furthermore, normal anti-toxoid antibody formation implied adequate T- and B- cell function.”
After a discussion with Pediatric Immunology, the decision was made to proceed with Centers for Disease Control and Prevention immunization schedule, understanding that the immune response to the vaccines may be inadequate and may have to be repeated. The exception was the rotavirus vaccine as it was delayed until normal immunoglobulin levels were present to reduce the risk of infection from a live vaccine. The 2nd paragraph on page 7 has a statement describing this as, “The live attenuated vaccine for rotavirus was held at 2 months of age while evaluating response to tetanus and diphtheria toxins.”
4. Is this severe ITP data or severe thrombocytopenia from any cause?
Thank you for the comment. A cut-off of platelets < 50 x 109/L is often used specifically in the ITP literature to describe ‘severe’ disease.
5. efficacy and safety data for what?
The statement has been clarified as, “Efficacy and safety data regarding the use of second-line drugs in pregnancy is limited.”
6. any concerns about prescribing steroids in the face of pneumonia?
Thank you for the comment. The potential for adverse effects was considered when giving prednisone in the setting of pneumonia. However, the benefits were thought to outweigh the potential risk of immunosuppression in this particular case since the platelets were rapidly
decreasing. Although our patient did not meet such criteria, some experts consider in select cases, adjunctive glucocorticoids to reduce the inflammatory response to pneumonia and decrease morbidity/mortality.
7. normal or appropriate post vaccine titres were present?
Correct, diphtheria and tetanus anti-toxoid antibody levels were at appropriate levels when measured by the Pediatric Immunologist.
8. please comment on bleeding anticipated at time of delivery
Thank you for the suggestion. The platelet threshold depends on the route of delivery with experts recommending 30 x 109/L for a vaginal delivery and 50 x 109/L for a cesarean delivery.
Page 9 has been edited as, “The recommended minimum platelet count thresholds for a vaginal and cesarean delivery are 30 x 109/L and 50 x 109/L, respectively. Furthermore, regional anesthesia is generally considered to be safe if the platelet count is above 70 x 109/L.”
9. Would you consider moving the information from lines the drugs used in her care a bit earlier in the discussion? Many of our readers will be unfamiliar with these medications, their side effects, and the idea of using them synergistically. Please consider adding some estimate of costs for the medications she received based on your hospital's charge master.
Then give discuss the specifics about her care you wish to highlight.
Thank you for the suggestion. The points highlighting the various medications and mechanisms of action was moved to the beginning of the Discussion. Further into the Discussion, details of romiplostim and rituximab are presented to provide the reader with a more in-depth perspective.
Regarding the cost of specific mediations, our hospital was unable to provide an itemized invoice because Medical reimburses the hospital a general dollar amount for each patient’s
hospitalization. Instead, we have inserted a statement at the end of the first paragraph on page 10 in the Discussion as, “Furthermore, the cost of these medications deserve mention. The estimated price of Rituximab is $112.74 for 100 mg/10 mL (per mL) and romiplostim is $2,230.30 for 250 µg (per each).”
