Middle cerebral artery peak systolic velocity monitoring of fetal anemia during chemotherapy in pregnancy

Abstract

Introduction

Chemotherapy during pregnancy can increase the risk of fetal anemia. Severe fetal anemia can lead to the development of hydrops fetalis and potentially fetal demise. Hence, it is imperative to implement consistent monitoring methods in the context of chemotherapy treatment. This study aimed to diagnose and monitor fetal anemia using middle cerebral artery peak systolic velocity (MCA‐PSV) as a diagnostic tool during chemotherapy in pregnant women.

Material and methods

The study employed a prospective analysis involving a case series of 15 patients diagnosed with cancer during pregnancy and subsequently underwent chemotherapy. MCA‐PSV was used to identify fetal anemia. The patients were scheduled for ultrasound examinations of the MCA‐PSV. The first examination was performed on the same day as the administration of chemotherapy, while the second occurred on the 10th day after chemotherapy. The measurement technique used in the study was based on the methodology proposed by Mari and Barr. The multiples of the median were calculated using the calculators provided by Medicina Fetal Barcelona. Based on these values anemia severity was determined. When moderate or severe anemia was identified, chemotherapy was individually modified. Additionally, a blood count analysis was conducted immediately after the delivery of the newborn.

Results

Five patients were diagnosed with fetal or newborn anemia. With MCA‐PSV, we identified moderate fetal anemia in two patients and severe fetal anemia in one. The complete blood count testing of newborns revealed mild anemia in three patients. One case was unrelated to chemotherapy‐induced anemia. During treatment, fetal anemia did not corelate with maternal anemia.

Conclusions

In four cases of anemia the combination of cisplatin and iphosphamide was used as a chemotherapy agent. No anemia was observed in other drug combinations. Our findings suggest that MCA‐PSV is a reliable method for identifying anemia and should be included in the treatment protocol for chemotherapy‐induced fetal anemia.

Chemotherapy during pregnancy can increase the risk of fetal anemia. Severe fetal anemia can lead to the development of hydrops fetalis and potentially fetal demise. Middle cerebral artery – peak systolic velocity (MCA‐PSV) was used to identify fetal anemia. The patients were scheduled for ultrasound examinations of the MCA‐PSV. When anemia was identified, chemotherapy was individually modified. Using MCA‐PSV we are able to monitor fetal anemia and tailor the patient's treatment to ensure optimal oncological treatment without endangering maternal safety and to optimize fetal outcomes.

Abbreviations

CBC

complete blood count

Hgb

hemoglobin

MCA‐PSV

middle cerebral artery peak systolic velocity

MoM

multiples of median

Key message.

Fetal anemia can develop as a complication during chemotherapy in pregnancy. Using middle cerebral artery peak systolic velocity we are able to monitor fetal anemia and tailor the patient's treatment to ensure optimal oncological treatment without endangering maternal safety and to optimize fetal outcomes.

1. INTRODUCTION

The concomitant incidence of cancer and pregnancy is estimated to account for 17–25 cases per 100 000 pregnancies. Cancer incidence during pregnancy has demonstrated a notable rise in recent years, primarily attributed to the prevailing tendency to delay plans for childbearing. ¹ , ² , ³ , ⁴ A cancer diagnosis in pregnant individuals presents significant therapeutic challenges for healthcare professionals as they must carefully consider the well‐being of the developing embryo or fetus and the maternal prognosis. Hence, most therapeutic concerns stem from the various treatment modalities, focusing mainly on chemotherapy during pregnancy.

Commonly used chemotherapy agents are taxanes, platinum, anthracyclines, etoposide, and bleomycin. ² , ⁵ , ⁶ Although chemotherapy administration during the second or third trimester has been generally associated with a low risk of severe fetal complications, ⁷ there is still a potential risk of fetal anemia, particularly when platinum derivatives are used. ⁸ Severe anemia may result in hydrops fetalis or lead to fetal demise. ⁹ , ¹⁰

One technique for monitoring fetal anemia involves measuring blood flow velocity in the middle cerebral artery (MCA‐PSV). In contrast to the previously widespread practice of umbilical cord sampling, ¹¹ using MCA‐PSV represents a dependable and noninvasive approach for assessing cases of moderate to severe anemia. ⁹ , ¹² The Society for Maternal‐Fetal Medicine also recommends using MCA‐PSV to detect fetal anemia in at‐risk individuals. ¹³

This study, which represents the largest case series to date, aimed to expand the existing body of knowledge regarding the monitoring and management of chemotherapy‐induced anemia in pregnant patients. A second aim was to assess the difference in toxicities of various types of chemotherapeutic treatment for the fetus and its risk of developing chemotherapy‐induced anemia.

2. MATERIAL AND METHODS

2.1. Study design and participants

This study was a prospective, single‐center observational study of pregnant patients diagnosed with a cancer—inclusion period from September 2016 through February 2023. Patients were included in the study if they received a cancer diagnosis during pregnancy and chemotherapy was indicated as a treatment modality. Patients were enrolled regardless of malignancy type, stage, or pregnancy status.

2.2. Study procedures

Letters A through O were assigned to each participant in the trial (Table 1).

TABLE 1.

Description of cohort characteristics.

Patient	A	B	C	D	E	F	G	H	I	J	K	L	M	N	O
characteristics
Age	30	29	25	40	43	32	31	34	29	32	31	39	31	42	29
BMI at delivery	29	32,5	38,5	26,8	20	24,1	25,7	29,7	28,7	29,1	NA	27,3	25,4	24,3	41,4
Gravidity/parity	I/I	V/IV	I/I	I/I	I/I	IV/II	I/I	II/II	II/II	II/II	II/I	I/I	II/II	II/II	II/II
Diagnosis	Breast	Cervical	Cervical	Breast	Bbreast	Lymphoma	Breast	Breast	Lymphoma	Breast	Cervical	Cervical	Breast	Breast	Cervical
Histological type	NST ductal	SCC	SCC	NST ductal	NST ductal	B cell lymphoma	NST ductal	NST ductal	Hodgkin lymphoma	NST ductal	SCC	SCC	NST ductal	NST ductal	ADC
GA at diagnosis	5	27	22	28	6	16	22	27	28	18	14	19	12	18	24
CHT agent	AC	I + DDP	I + DDP	AC	AC‐T	R‐CHOP	AC	AC	ABVD	AC	I + DDP	I + DDP	AC	AC‐T	D + DDP
No. of cycles	4	3	5	2	9	5	3	3	4	5	3	5	6	8	4
GA at first CHT	14 + 3	28 + 3	21 + 5	31 + 2	14 + 0	20 + 2	26 + 6	27 + 6	27 + 3	21 + 2	15 + 0	20 + 3	17 + 3	18 + 1	24 + 6
GA at last CHT	23 + 3	34 + 0	34 + 0	33 + 1	35 + 3	32 + 2	32 + 6	33 + 5	33 + 1	33 + 2	19 + 0	32 + 0	31 + 6	36 + 1	32 + 3
Delivery (GA)	38 + 1	36 + 2	37 + 2	36 + 5	37 + 1	37 + 2	37 + 1	37 + 4	37 + 0	37 + 2	NA	37 + 1	38 + 1	38 + 1	36 + 3
Type of delivery	Spontaneous	SC	SC	SC	SC	Spontaneous	Spontaneous	Spontaneous	SC	SC	NA	SC	SC	Spontaneous	SC
Hgb level < 100 g/L during CHT	Yes, 97	No	No	No	No	No	No	Yes, 97	No	No	No	Yes, 95	No	No	Yes, 93
Fetal characteristics
Fetal anemia	No	No	Moderate	No	No	No	No	No	No	No	Severe	Moderate	No	No	No
Newborn characteristics
Sex	Female	Male	Male	Female	Male	Male	Male	Female	Female	Male	NA	Female	Male	Male	Male
Birthweight (g)	2540	2860	2600	1930	2440	2610	2700	2680	2280	2680	NA	2250	2910	3090	2620
Percentile (weight)	7	65	14	0	6	15	25	23	4	20	NA	3	28	49	30
Apgar score	10, 10, 10	9, 9, 9	9, 10, 10	9, 10, 10	10, 10, 10	8, 10, 10	8, 8, 10	9, 10, 10	8, 8, 10	8, 9, 10	NA	9, 10, 10	9, 10, 10	10, 10, 10	8, 9, 9
Hgb after delivery (g/L)	152	126, NA*	135, 140*	150	173	192	159	196	185	163	NA	140	168	192	123, 119*, 102**
NICU admission	No	No	No	Yes	No	No	No	No	No	No	NA	No	No	No	Yes

Abbreviations: ABVD, doxorubicin (25 mg/m²), bleomycin (10 000 IU/m²), vinblastine (6 mg/m²), dacarbazine (375 mg/m²); AC, cyclophosphamide (500–600 mg/m²), doxorubicin (50–60 mg/m²); AC‐T, cyclophosphamide (500–600 mg/m²), doxorubicin (50–60 mg/m²), from fifth cycle paclitaxel weekly (175 mg/m); ADC, cervical adenocarcinoma; BMI, body mass index; CHT, chemotherapy; D, doxorubicin (50–60 mg/m²); DDP, cisplatin (75 mg/m²); GA, gestational age; Hgb, hemoglobin; I, iphosphamide (1500 mg/m²); NICU, newborn intensive care unit; R‐CHOP, cyclophosphamide (750 mg/m²), rituximab (375 mg/m²), vincristine (1.4 mg/m²); SC, cesarean section; SCC, cervical squamous cell carcinoma.

^*First control Hgb level.

^**Second control Hgb level.

2.3. Oncological treatment

All participants received appropriate chemotherapy treatment for their malignancy following published guidelines. ² , ¹⁴ Chemotherapy was administered during the gestational period ranging from 14 to 35 weeks, depending on the specific gestational week at which the malignancy was diagnosed. The maternal blood count was monitored throughout the treatment regimen, starting on the day of chemotherapy administration and 10 days after the administration during each cycle.

2.4. Fetal anemia measurement and management

The MCA‐PSV examination was performed using the Toshiba Aplio i700 ultrasound machine equipped with the i8CX1 transducer, which operates within a frequency range of 1.8–6.2 MHz. The MCA‐PSA measurement technique was implemented per the methodology proposed by Barr and Mari. ⁹ , ¹⁵ Appendix A provides an in‐depth description.

The values of the MCA‐PSV were converted to multiples of the median (MoM) using calculators provided by Medicina Fetal Barcelona (https://portal.medicinafetalbarcelona.org/calc/) since MCA‐PSV value varies itself during the course of the pregancy. The calculator used in this study is founded on nomogram curves outlined by Mari et al., ⁹ which establishes a correlation between the hemoglobin (Hgb) level and the MCA‐PSV value.

Fetal anemia can be classified into three stages (Halaska, 2014): mild (up to 1.29 MoM), moderate (1.29–1.50 MoM), and severe (≥1.50 MoM), as based on the value of MoM obtained from MCA‐PSV. ⁹ , ¹⁰ , ¹⁵ , ¹⁶ Cordocentesis should be performed to verify cases in which value of MoM of MCA‐PSV exceeds a threshold of 1.50, ¹⁶ intrauterine transfusion should be administered ‐ the specific indications for cordocentesis can be found in Appendix B. Following the intrauterine transfusion procedure, revised threshold values have been introduced for fetal anemia, with moderate anemia up to 1.32 MoM ¹⁶ and severe anemia up to 1.69 MoM. ⁹ The fetal MCA‐PSV was assessed (i) immediately before each cycle of chemotherapy on the same day of administration and (ii) 10 days after the administration of each chemotherapy cycle.

If fetal anemia was detected 10 days after chemotherapy, the patient was scheduled for a follow‐up examination in approximately 5 days. If anemia persisted on the scheduled day of the subsequent cycle of chemotherapy, it was recommended to postpone further chemotherapeutic treatment until the fetal MCA‐PSV decreased below 1.29 MoM.

In the context of the paclitaxel weekly treatment protocol the evaluation of MCA‐PSV was limited to the day preceding the administration of the subsequent cycle of chemotherapy.

Immediately after the delivery, a complete blood count (CBC) and comprehensive physical examination of the newborn were performed. ²

2.5. Statistical analysis

The results were evaluated using standard descriptive analysis. Due to the limited sample size, the data were not subjected to further statistical analyses.

3. RESULTS

3.1. Patient characteristics

Table 1 summarizes participant characteristics enrolled in the research and their newborns' corresponding characteristics. Each mother and newborn were assigned a letter corresponding to their pair.

This research project included a cohort of 15 patients diagnosed with cancer during pregnancy and who subsequently underwent chemotherapy. Eight patients were diagnosed with breast cancer, five with cervical cancer, and one each with Hodgkin lymphoma and B cell lymphoma. Following established oncological treatment protocols, all patients received chemotherapy treatment, with the number of treatment cycles varying from two to nine.

All pregnancies documented in the research were classified as singleton pregnancies. During the pregnancy there were no other risk factors for fetal anemia discovered (eg cytomegalovirus and Parvovirus B19 infection or signs of blood group antagonisms). A total of 14 newborns (93%) were delivered successfully, while one fetal demise (7%) occurred throughout the treatment. Three newborns (21%) were born prematurely. Five newborns (36%) were delivered through vaginal birth, while nine (64%) were delivered via cesarean section and one case resulting in fetal demise. All 14 live‐born neonates had physiological Apgar score postpartum with no signs for perinatal hypoxia. A newborn called “D” was admitted to the neonatal intensive care unit due to fetal growth restriction and preterm delivery despite exhibiting normal postpartum adaptation. The neonate “O” was admitted to the neonatal intensive care unit due to respiratory distress syndrome. The condition was managed using nasal continuous positive airway pressure for 48 h.

Throughout the treatment, four cases of moderate maternal anemia were documented. In contrast, no cases of severe maternal anemia were recorded (refer to Table 1 for further details and consult Appendix C for the definition of anemia in pregnancy).

3.2. Anemia incidence and treatment optimization

Five cases of anemia were reported within our case series. Three cases of fetal anemia were identified using MCA‐PSV (20%), two cases of moderate and one case of severe. In these three patients there were no other signs for anemia (eg fetal tachycardia). None of them had a cordocentesis to confirm it. Three cases of mild neonatal anemia were detected using CBC testing performed right after delivery. One case of neonatal anemia was previously identified as moderate fetal anemia using MCA‐PSV.

In four of five cases of detected anemia, a treatment protocol involving the combination of iphosphamide and cisplatin for cervical squamous cell carcinoma management was used. An additional one case of neonatal anemia corresponded with the therapeutic regimen of doxorubicin and cisplatin for managing cervical adenocarcinoma. Table 2 provides a detailed summary of the results.

TABLE 2.

Patients with diagnosed anemia.

Patient	B	C	K	L	N
Age	29	25	31	39	29
Diagnosis	SCC	SCC	SCC	SCC	ADC
Stage	IB1	IB2	IB1	IB2	IB3
GA at diagnosis	27	22	14	19	24
Number of cycles	3	5	3	5	4
Cisplatin dose (mg), dosing 75 mg/m2	150	160	120	120	145
Iphosphamide dose (g), dosing 1500 mg/m2	3	3	3	3
Doxorubicin (mg), dosing 50 mg/m2					95
First cycle	28 + 3	21 + 5	15 + 0	20 + 3	24 + 6
MCA‐PSV (MoM)	0,88	1,29	NA	1,15	1,08
Anemia	No	No		No	No
Reaction	No	No		No	No
MCA‐PSV (MoM) 10th day	1,14	1,26	NA	1	0,99
Anemia	No	No		No	No
Reaction	No	No		No	No
Second cycle	31 + 3	24 + 0	17 + 0	23 + 3	27 + 2
MCA‐PSV (MoM)	0,99	1,48	NA	1,16	0,84
Anemia	No	Yes		No	No
Reaction	No	No		No	No
MCA‐PSV (MoM) 10th day	1,05	NA	1,77	1,44	NA
Anemia	No		Yes	Yes	No
Reaction	No	No	No	Check up in 5 days ‐ 1,1 MoM	No
				Next CHT as scheduled
Third cycle	34 + 0	27 + 0 scheduled day	19 + 0	26 + 0	29 + 3
		28 + 6 CHT administration
MCA‐PSV (MoM)	1,1	1,33/1,4/1,21*	NA	1,1	0,81
Anemia	No	yes		No	No
Reaction	No	CHT administration postponed, change to cisplatin only		Reduction of Iphosphamide ‐ 2 g	No
MCA‐PSV (MoM) 10th day	1,04	1,15	NA	1,24	0,95
Anemia	No	No		No	No
Reaction	No	No	SLNM, trachelectomy (22+)	No	No
			First post‐OP day ‐ fetal demise
Fourth cycle		31 + 6		29 + 0	32 + 3
MCA‐PSV (MoM)		1,28		1,4	0,93
Anemia		No		Yes	No
Reaction		No		Change to cisplatin‐only protocol	No
MCA‐PSV (MoM) 10th day		1,25		1,22	1,11
Anemia		No		No	No
Reaction		No		No	No
Fifth cycle		34 + 0		32 + 0
MCA‐PSV (MoM)		1,27		1,43
Anemia		No		Yes
Reaction		No		Cisplatin dose reduction ‐ 100 mg
MCA‐PSV (MoM) 10th day		1,31		1,33
Anemia		Yes		Yes
Reaction		No, SC planned		No
Newborn Hgb level (g/l)	126	135		140	123
Anemia	Yes	Yes		No	Yes
Control Hgb level (g/l)	NA	140 (third day)		No	119 (second day), 102 (14th day)
Three‐week interval	No	Yes	NA	Yes	Yes

Abbreviations: ADC, cervical adenocarcinoma; CHT, chemotherapy; GA, gestational age; Hgb, hemoglobin; MCA‐PSV, middle cerebral artery peak systolic velocity; MoM, multiples of median; NA, not available; OP, operation; SC, cesarean section; SCC, cervical squamous cell carcinoma; SLNM, sentinel lymph node mapping.

^*‐ check‐up every 5 days.

3.2.1. Cases of anemia–live births

Patient “B” was diagnosed with mild newborn anemia, as evidenced by an Hgb level of 126 g/L based on CBC testing. Throughout the pregnancy, the levels of MoM of MCA‐PSV never exceeded 1.27 MoM, indicating that no intervention or adjustment in treatment was required.

Moderate fetal anemia (1.48 MoM) was detected in patient “C” on the day of the scheduled second cycle of chemotherapy. There were no adjustments made to the treatment plan. On the day of the scheduled third cycle of chemotherapy, moderate anemia was detected again (1.33 MoM). In light of the outcome, regular evaluations of the MCA‐PSV at intervals of 5 days were conducted, and the administration of chemotherapy was postponed. Normalization of MCA‐PSV was observed within 10 days ‐ after the second check‐up. The decision was made to adjust the chemotherapy regimen, particularly to follow a cisplatin‐only protocol to prevent the reoccurrence of fetal anemia. No indications of fetal anemia were observed until the 10th day following the administration of the fifth cycle of chemotherapy, at which point moderate fetal anemia was once again identified (1.31 MoM). It was the last cycle of the treatment. After the delivery, CBC testing detected mild neonatal anemia (Hgb level of 135 g/L) despite adhering to the recommended 3‐week interval between the last chemotherapy cycle and delivery. A control CBC testing was performed 3 days later, yielding an Hgb level of 140 g/L.

Patient “L” demonstrated signs of moderate fetal anemia (1.44 MoM) after the second cycle of chemotherapy. The normalization of MCA‐PSV was observed before the third cycle's expected date. The dosage of iphosphamide was decreased during the third cycle to minimize the potential recurrence of fetal anemia. Nevertheless, on the day of the scheduled fourth cycle of chemotherapy, moderate fetal anemia (1.40 MoM) was redetected. As a result, a subsequent modification was made to the therapeutic strategy, transitioning to a cisplatin‐only protocol. On the day of the scheduled fifth cycle, the MCA‐PSV corresponded to moderate fetal anemia (1.43 MoM). The dose of cisplatin was decreased in response to that moderate level. Throughout the remainder of the fifth cycle of chemotherapy, MCA‐PSV levels remained within the range of moderate fetal anemia (1.33 MoM), and close monitoring of the fetus was performed. After the delivery, the Hgb levels of the newborn were found to be within the normal range, measuring 140 g/L.

Following CBC testing, patient “N” was diagnosed with mild neonatal anemia (Hgb level of 123 g/L). The MCA‐PSV displayed normal values throughout the pregnancy. Consequently, a control CBC testing was performed 3 (Hgb level of 119 g/L) and 14 days later (Hgb level of 102 g/L).

3.2.2. Case of anemia ‐ fetal demise

For patient “K” severe fetal anemia (1.77 MoM) was detected using MCA‐PSV 10 days after the second cycle of chemotherapy. Because the mother prioritized her oncological treatment, no additional diagnostics were performed, and the course of treatment was not altered. After the completion of the third cycle of chemotherapy, trachelectomy and sentinel lymph node mapping were performed. Fetal demise was confirmed on the first postoperative day. Based on the pathologist's findings, asphyxia was the identified cause of death. The examination revealed the presence of a recent thrombus within the umbilical cord, in addition to multiple false umbilical cord knots. No signs of severe fetal anemia were discovered (eg hydrops fetalis or cardiomegaly).

4. DISCUSSION

This prospective study involved performing perinatal MCA‐PSV examinations of the fetus to detect and monitor fetal anemia. Fetal anemia may develop due to chemotherapy treatment for cancer during pregnancy. ⁸ The study comprised 15 participants enrolled between 2016 and 2023. The administration of chemotherapy is contraindicated before the 14th week of gestation due to its teratogenic effects. Additionally, it is not advised to administer chemotherapy beyond the 35th week of gestation to ensure a 3‐week interval between the final chemotherapy cycle and the delivery. The presence of this window is crucial as it facilitates the recovery of fetal bone marrow, thereby preventing transient myelosuppression of the fetus. ² , ¹⁷ Fetal anemia is a representative of overall hematotoxicity (including thrombocytopenia, leukopenia), therefore we aimed to prevent the overall hematotoxicity, rather than treating anemia with an intrauterine transfusion. In the first case of neonatal anemia (patient “B”), the patient received treatment consisting of cisplatin and iphosphamide. In this case there was a mere 2‐week period between the final chemotherapy cycle and delivery, leading to insufficient time for the fetus to adequately recover from myelosuppression. The decision to end the pregnancy before the recommended 3‐week interval was made based on the presence of regular contractions; therefore, a cesarean section was performed. In the second instance of neonatal anemia (patient “N”) the patient received treatment with doxorubicin and cisplatin. No indications of fetal anemia were observed throughout the pregnancy, and the recommended 3‐week interval between the final chemotherapy cycle and delivery was adhered to, allowing sufficient time for the fetus to recover from myelosuppression. According to neonatologists, based on the blood cell morphology in CBC, the cause for the persistent decline in Hgb levels has not been attributed to chemotherapy treatment, and further investigation is required to ascertain the underlying cause. The neonate has been scheduled for additional examinations. No correlation was found between the four cases of moderate maternal anemia and the occurrence of fetal anemia. Blood transfusions were unnecessary, and administration of per os ferrotherapy improved the maternal blood count.

Three patients (“A”, “E”, “K”) were treated from the early second trimester. Patient “K” was the only one who had signs of fetal anemia. This patient received treatment with iphosphamide and cisplatin. Iphosphamide has significantly higher hematotoxicity than other therapeutic agents and can cause chemotherapy‐induced anemia. Patients “A” and “E” received the treatment combination of cyclophosphamide and doxorubicin with or without paclitaxel and showed no signs of fetal anemia.

There are only two published studies and one conference presentation describing MCA‐PSV monitoring of fetal anemia after the administration of chemotherapy in pregnancy. During the 18th World Congress on Ultrasound in Obstetrics and Gynecology, the study conducted by Ramirez et al. introduced the use of MCA‐PSV monitoring as a noninvasive method to determine the potential risk of fetal anemia in pregnant individuals undergoing breast cancer treatment. ¹⁷ The study by Fruscio et al. documented the cases of nine patients diagnosed with cervical cancer during pregnancy who subsequently received chemotherapy starting from the 16th week of gestation. This study presented a singular instance of neonatal anemia necessitating a blood transfusion. No additional details were provided. ¹⁸ The pilot study conducted by Halaska et al. involved MCA‐PSV monitoring of six patients diagnosed with cancer during pregnancy and treated with chemotherapy. It is noteworthy that a slightly modified protocol was used in this study. Chemotherapy treatment was administered to all patients after the beginning of the second trimester. A solitary occurrence of borderline fetal anemia was observed, whereas no instances of anemia in newborns were identified. ¹⁶

The MCA‐PSV method demonstrates high reliability in identifying and monitoring fetal anemia, as supported by previously published research. ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ Despite the limited size of our cohort, our empirical findings indicate the existence of several possibilities for adjusting the treatment strategy when moderate anemia is identified.

When close monitoring of MCA‐PSV is available, it becomes feasible to postpone chemotherapy. Nevertheless, a significant delay in initiating treatment may result in a diminished efficacy of cancer therapy. ¹⁶ The meta‐analysis conducted in 2020 recommends minimizing treatment delays because a 4‐week delay increased mortality rates. ¹⁶ , ¹⁹ In our study, patient “C” was an illustrative case as chemotherapy was delayed by 1 week due to moderate fetal anemia (Table 2).

Alternative treatment regimens can also be used. Several studies exploring alternative treatment protocols have been published. Bernardini et al. described the platinum‐based neoadjuvant chemotherapy treatment for cervical cancer during pregnancy. This treatment covered three protocols: cisplatin only, cisplatin/paclitaxel, and carboplatin/paclitaxel. All children were alive and well when the study was published. ²⁰ Huang et al. comprehensively described platinum‐based treatment protocols for managing cervical cancer during pregnancy, highlighting the favorable outcomes observed for both the mother and the fetus. ²¹ Our study modified the treatment protocol for patient C″ through a cisplatin‐only regimen (Table 2).

Several chemotherapy agents can be used for cancer treatment during pregnancy, with the most significant variety of therapeutic agents available for cervical cancer treatment. However, it is worth noting that a universally accepted standardized regimen has yet to be established. ²² The potential use of cisplatin and paclitaxel as therapeutic options for cervical squamous cell carcinoma during pregnancy is worth considering. The limited transplacental paclitaxel transfer contributes to potentially reducing its adverse effects. ⁶ Accordingly, there is a possibility of reducing the likelihood of fetal anemia during treatment. However, it is crucial to consider the potential ototoxicity associated with platinum derivatives. Adjusting therapeutic dosage is a viable strategy for tailoring treatment protocols, especially in cases of high drug toxicity. For patient “L” a decision was made to initially decrease the dosage of iphosphamide, followed by a subsequent modification of the treatment protocol to cisplatin monotherapy (Table 2).

The major strength of the study was its prospective single‐center design with a methodology of MCA‐PSV measurement. The limitation of the study was the heterogeneity of administered chemotherapy.

5. CONCLUSION

Despite the limited size of our cohort, the findings indicate that fetal anemia could develop as a potential complication of chemotherapy during pregnancy. Notably, the coexistence of maternal and fetal anemia during treatment does not manifest in parallel. The data presented in our study highlight the importance of identifying and monitoring fetal anemia when administering chemotherapy during pregnancy. Close monitoring is crucial, especially in treatment protocols employing platinum derivatives, either as monotherapy or with other pharmaceutical agents, particularly in combination with iphosphamide. Given the proven reliability and noninvasiveness of MCA‐PSV as a modality for monitoring chemotherapy‐induced fetal anemia, we advocate for its incorporation into the standard treatment protocol outlined in the guidelines for all patients. This fetal monitoring method allows us to adjust treatment strategy individually on a case‐by‐case basis. Results of this study indicate potential advancements in the management and treatment of malignancies in pregnant patients, achieving optimal oncological treatment while ensuring maternal safety and maximizing fetal well‐being. The results of our study, however, also indicate the need for further research in this area.

AUTHOR CONTRIBUTIONS

Anna Babkova: Project administration, investigation and writing. Lukas Rob: Funding acquisition. Martina Kubecova: Validation. Martin Hruda: Formal analysis. Michael J Halaska: Supervision and methodology.

FUNDING INFORMATION

This study was supported by the Cooperation program, Maternal and Childhood Care 207 035, Third Faculty of Medicine, Charles University.

CONFLICT OF INTEREST STATEMENT

No conflict of interest in connection with this article was declared by any of the authors.

ETHICS STATEMENT

The protocol obtained approval from the Institutional Review Board of Charles University in Prague and the University Hospital Kralovske Vinohrady (EK 259/08 on March 12, 2008 and EK VP/05/0/2019 on February 6, 2019). Before enrolling in the study, all participating patients provided informed consent by signing the necessary documentation. Before taking part in the study, all participants were provided with information about the course of the study and the anonymous processing of results as part of their informed consent.

APPENDIX 1. The MCA‐PSA measurement technique followed Barr and Mari protocol. ⁹ , ¹⁵

1.1.

1. The fetus needs to be in a period of rest (no breathing or movements).

2. The circle of Willis is imaged with the color Doppler.

3. The sonographer zooms the area of the middle cerebri atery (MCA) so that it occupies more than 50% of the screen. The MCA should be visualized for its entire length.

4. The sample volume (1 mm) is placed soon after the origin of the MCA from the internal carotid artery (1–2 mm).

5. The angle between the direction of blood flow and the ultrasound beam is as close as possible to zero degrees. The angle corrector should not be used.

6. The waveforms (between 15 and 30) should be similar. The highest peak systolic velocity is measured.

7. Repeat the above steps at least three times.

APPENDIX 2. Indications of intrauterine transfusion following the cordocentesis. ²³ , ²⁴

2.1.

1. Hemoglobin concentration 4–5 SDs below mean for gestational age

2. Hemoglobin deficit >5 g/dL

3. Absolute hemoglobin concentration < 10 g/L

4. Hematocrit <30

APPENDIX 3. Definition of maternal anemia in pregnancy ²⁵

3.1.

1. Mild anemia: hemoglobin level 100 to 109 g/L

2. Moderate anemia: hemoglobin level 70 to 99 g/L

3. Severe anemia: hemoglobin level less than 70 g/L

Babkova A, Rob L, Kubecova M, Hruda M, Halaska MJ. Middle cerebral artery peak systolic velocity monitoring of fetal anemia during chemotherapy in pregnancy. Acta Obstet Gynecol Scand. 2024;103:660‐668. doi: 10.1111/aogs.14759