Response: Pregnancy outcomes following different surgical approaches for heterotopic interstitial and angular pregnancy

We thank Dr. Shen and colleagues for their thoughtful Letter to the Editor regarding our article “Pregnancy outcomes following different surgical approaches for heterotopic interstitial and angular pregnancy.”1 We appreciate their interest in this rare and clinically challenging condition and welcome the opportunity to clarify several aspects of our study design and interpretation. As noted by Shen et al., embryo quality, luteal phase support, and patient compliance are important determinants of intrauterine pregnancy outcomes. In our cohort, however, several practical constraints limited our ability to rigorously control these variables. First, our series spans almost 10 years (from 2014 onward) and involves an extremely rare condition. Except for preimplantation genetic testing cycles, embryo quality cannot be directly and objectively measured; for most in vitro fertilization (IVF) conceptions, there is no reference standard post-transfer assessment of embryo competence. Second, luteal support is routinely provided to all IVF patients, regardless of singleton or twin gestation, but specific regimens vary widely across centers and over time. Some patients receive additional oral dydrogesterone, while others do not; intramuscular progesterone dose and frequency also differ, and there is currently no consensus on the “optimal” combination.2, 3 Typically, progesterone support is discontinued around 10–12 weeks of pregnancy, when placental function becomes sufficient. Clinically, luteal support aims to prevent miscarriage caused by luteal insufficiency; it neither prevents missed abortion due to chromosomal or embryonic anomalies nor improves intrinsic embryo quality.4 Beyond maternal age and genetic background, embryo quality for each conception also has a substantial stochastic component. Given these constraints and the rarity of heterotopic interstitial/angular pregnancy, our primary objective was not to isolate the effect of subtle differences in embryo quality or luteal protocols. Instead, we focused on the impact of different surgical approaches on uterine myometrial integrity at the interstitial/angular region and their ability to support a continuing pregnancy. We agree that future larger, prospective, or registry-based studies incorporating standardized embryo grading, detailed luteal support documentation, and advanced methods such as propensity score matching would further refine causal inference, but such granularity was beyond the scope and feasibility of our retrospective case series. Shen et al. suggest that more comprehensive perinatal indicators, such as fetal growth restriction, maternal complications (e.g., pre-eclampsia, gestational diabetes), and longer-term outcomes (e.g., intrauterine adhesions, time to subsequent pregnancy), should be evaluated. We fully agree that a dual perspective, including fetal safety and maternal short- and long-term health, is ideal. In our study, we deliberately concentrated on core pregnancy outcomes most directly related to the structural integrity of the uterine wall at the operated interstitial/angular site: continuation of pregnancy, live birth, gestational age at delivery, and catastrophic events such as uterine rupture. Heterotopic interstitial and angular pregnancies differ from isolated interstitial pregnancies in that the intrauterine pregnancy continues immediately after surgery, without a prolonged interpregnancy interval for uterine healing. Accordingly, our central clinical question was whether different surgical approaches and techniques lead to myometrial defects or scars that fail to support the pregnancy into the third trimester, thereby increasing the risk of uterine rupture or other severe obstetric events. The pregnancy process itself is highly complex. Maternal age, previous pregnancy and delivery history, previous surgeries, pre-existing conditions, weight gain and metabolic status in the current pregnancy, and lifestyle and dietary factors all contribute to complications such as pre-eclampsia, gestational diabetes, and fetal growth abnormalities.5, 6 In many cases, these risks are only loosely related, or unrelated, to the specific surgical technique used to treat the ectopic component. In our multicenter, long-term retrospective series, detailed and homogeneous data on all these variables and long-term reproductive outcomes were not consistently available. We therefore chose to focus on robust primary obstetric outcomes directly linked to the surgery while clearly acknowledging this as a limitation. We concur that future multicenter prospective studies and dedicated registries should incorporate serial fetal growth assessments, standardized neonatal follow up, maternal complication rates, and subsequent fertility outcomes to provide a more holistic risk–benefit profile. Shen et al. also raise important questions regarding postoperative progesterone support. In our cohort, oral dydrogesterone or intramuscular progesterone was provided for luteal support in viable intrauterine pregnancies up to approximately 10–12 weeks of pregnancy, in line with common IVF practice. However, the specific route, dosage, and schedule were individualized according to attending physicians' preferences and evolving institutional protocols, and adherence was difficult to quantify retrospectively. From a pathophysiologic perspective, progesterone supplementation is primarily intended to correct luteal phase deficiency and reduce early miscarriage attributable to insufficient corpus luteum function. It does not rectify intrinsic embryonic or chromosomal abnormalities and cannot prevent missed abortion or late fetal demise due to embryo-driven factors.4 In our analysis and clinical interpretation, we therefore considered embryo-related losses (missed abortion or intrauterine fetal death) as largely independent of the mode of surgical management of the ectopic component. Our main finding was that, apart from such embryo-related events, overall pregnancy outcomes were generally favorable and did not suggest that any particular surgical approach substantially compromised uterine wall integrity or markedly increased adverse obstetric outcomes. We acknowledge that detailed stratification by preoperative progesterone levels, exact dosing regimens, and adherence, and inclusion of these variables in multivariable models, would provide additional insight into the interaction between progesterone support and surgical techniques. We appreciate this constructive suggestion and agree that future research, especially prospective studies with standardized luteal support protocols, should address this question and may help to develop more cost-effective and individualized strategies. In summary, we are grateful to Shen et al. for their careful appraisal of our work. Our study aimed to address a focused yet clinically critical question: in women with heterotopic interstitial and angular pregnancies, where an intrauterine pregnancy continues immediately after surgical management of the ectopic component, do different surgical approaches compromise uterine myometrial integrity and increase the risk of poor pregnancy outcomes, particularly uterine rupture? Within the limitations of a small, retrospective cohort of a very rare condition, our findings suggest that, beyond embryo-quality-related losses, overall prognosis can be good and that appropriately selected surgical approaches can allow many patients to achieve satisfactory pregnancy outcomes. We hope that our data, together with the thoughtful points raised by Shen et al., will stimulate larger, collaborative, prospective studies to optimize management protocols and counseling for this challenging but increasingly encountered clinical scenario. Dan Feng, Tianjiao Liu, Li He, and Li Lei drafted the manuscript. Li Lei takes responsibility for the content. All authors approved the submission. The authors have no conflicts. The authors declare no use of any Generative AI tools for this correspondence. Not applicable.